C13.Skin diseases

The skin is the largest single organ of the body, with an area of about 1.75 m2 for an average adult. Because the skin is visible and accessible and gives the first impression from which we judge people, patients are self-conscious about any perceived abnormality. They may expect faster, more complete resolution of a superficial lesion than an invisible, internal one. The unique skin symptom, itch, can lead to sleep loss and irritability if severe, and can cause emotional problems if associated with a visible, possibly disfiguring lesion.

Dermatological problems comprise about 10% of a GP’s case load, and probably more for pharmacists. Diagnosis and treatment leave much to be desired and pharmacists need to learn to diagnose and advise patients confidently. This requires knowledge and experience. Further, the incidence of atopic dermatitis and skin malignancies has doubled over the past 20 to 30 years and these conditions need to be recognized early.

This chapter deals primarily with eczema and dermatitis, psoriasis, acne, rosacea and

urticaria, which comprise most of the dermatological case load and discusses the special drug

classes used (corticosteroids and retinoids). It concludes with brief discussions of drug side-effects

on the skin and of transdermal absorption, an important, developing drug delivery system.

There are 16 full colour plates (between pp. 822 and 823) to aid recognition and some of

the specialist books listed in the References and further reading section give further assistance

with this.

Skin anatomy and physiology

Functions

The skin has five principal functions:

•  To   protect  the   underlying   organs   from

            physical, chemical and mechanical injury.

•  To control fluid loss from the body (the skin

contains nearly 20% of the total body water).

•  To assist in controlling the body tempera-

ture  by  sweating  and  radiation  from  the surface.

•  To act as an important sensory organ  for

            touch, pain and external temperature etc.

•  To act an organ of emotional expression, as it

exhibits feelings by its colour, e.g. flushing and

blanching, and sweat and odour production.

Anatomy

There  skin  consists  of  three  principal  layers (Figure 13.1): the epidermis, the dermis and the subcutaneous tissues.

Epidermis

This is the main protective layer of the skin, and therefore of the entire body.

Structure

The epidermis is composed of four subsidiary

layers (Figure 13.1), most of which (95%) are

derived from the keratinocytes. These comprise:

•           The basal (germinal) layer, the deepest part,

normally consists of a single sheet of cycling

stem cells, most of which divide progressively

and mature to form the other three layers of the

epidermis. There is a small proportion of resting

stem cells that can be recruited into growth to

repair damage (see Chapter 2). The basal cells

are joined by intercellular bridges, desmosomes

and hemidesmosomes, that enhance strength

and distribute mechanical stresses more evenly

through the skin. Desmosomes join adjacent

skin cells, hemidesmosomes join the basal layer

to dermal tissue.

•           The prickle cell layer, composed of cells also

joined by intercellular bridges, is just above

the basal layer and contains cells in interme-

diate stages of development into the granular

layer.  The  prickle  cell  layer  also  contains

Langerhans cells, which are immunologically

important  dendritic  cells  that  are  APCs,

express  class  II  MHC  antigens  and  have

receptors for complement (see Chapter 2).

•           The granular layer comprises a few rows of

cells containing granules derived from their

degenerating  nuclei.  These  cells  gradually migrate towards the surface and finally form the outermost horny layer.

•  This horny layer (stratum corneum) consists

            of keratinized, enucleate cells that are shed

continuously as small scales from the surface.

There is thus a continual replacement of the

hard, keratinized, horny layer from the basal

cells.  The  horny  layer  varies  considerably  in

thickness, being very thick on those areas that

are subject to wear and pressure. i.e. the palms

and soles of the feet, and thinnest in the flex-

ures, e.g. axillae and eyelids. Keratin, an insol-

uble fibrous protein, is the principal constituent

of the horny layer and the skin appendages, the

nails and hair, and the organic matrix of tooth

enamel.

All of these structures, together with the oily secretions of the glands (see below), serve to

protect the underlying tissues, the dermis and deeper tissues, from mechanical damage and to control undue water and heat loss.

The nails are extensions of the horny layer

and  consist  of  solid  plates  of  translucent

keratin. Finger nails grow at the rate of approx-

imately  0.1 mm  daily,  taking  4-5  months  for

complete replacement. Toe nails grow at about

half this rate, so treatment of toe nail condi-

tions  needs  to  be  more  prolonged  than  for

finger nails.

Melanocytes form about 5% of the basal layer.

They are dendritic cells, forming an irregular

network that is very variable in extent. The

melanin  that  they  synthesize  is  transferred

through their dendrites to other epidermal cells.

Exposure to sunlight or ultraviolet (UV) radia-

tion promotes melanin synthesis, the concentra-

tion of which in the epidermis influences the

basic skin pigmentation of individuals. However,

skin colour also depends on the extent of dilata-

tion of the skin capillaries, the relative propor-

tions of oxidized and reduced Hb in them, and

on  the  presence  of  yellow  carotene  pigments

in  the  blood  vessel  walls  and  surrounding

tissues. Carotenes are present primarily in fatty

tissue  and  are  precursors  of  vitamin  A.  Dark-

skinned  people  have  the  same  proportion  of

melanocytes in the basal layer as do the fair-

skinned, but they synthesize melanin at a faster

rate.

Skin anatomy and physiology    817

Associated features

These include the hair and the apocrine, eccrine

and sebaceous glands. The hair arises in tubular

downgrowths   from   the   epidermis   into   the

dermis, the hair follicles. At the base of the hair

follicle is a bulb containing the root and the

papilla. The latter is a projection of the dermis

into the bulb and contains blood vessels, nerves

and melanocytes. There are three types of hair:

•  The long hairs of the scalp, beard, moustache,

            axillae and pubic areas.

•  Vellus (downy) hair occurring on the rest of

            the surface.

•  A small amount of short, stiff hairs on the

            eyebrows and eyelids, in the nostrils and ear

canals and the face in males.

Growth  of  the  long  and  stiff  hair  is  under

androgenic control, so hair growth varies with

sex, age, during pregnancy, etc. The hair follicles

are  formed  naturally  only  during  embryonic

growth and the number is therefore fixed at birth,

so hair loss due to follicular degeneration cannot

normally  be  restored.  However,  it  has  been

reported that the expression of two compounds

in mouse epithelial cells, beta-catenin and LEF-1,

causes adult epithelial cells to revert to an embry-

onic state and produce new hair follicles. Two

problems  remain  to  be  solved  before  this

discovery can be translated into treatment for

hair loss: whether the results are applicable to

humans and elucidating the control mechanisms

for this process, to prevent excessive hair growth

and the possible formation of (benign) follicular

tumours.

Loss   of   hair  (alopecia)   or   its   abnormal

increased production (hirsutism) may thus be

an indicator of endocrine abnormality, systemic

disease (Table 13.1) or autoimmunity. All visible

hair is dead, and no medical treatment can affect

it once it has been formed, though its appear-

ance may be improved (or harmed) cosmetically.

Scalp hairs grow continuously for some 2-6 years

at the rate of about 10 mm per month before

falling out. They are replaced by regrowth or by

activation of dormant follicles. All treatments for

hair   loss   are   unsatisfactory,   though   topical

minoxidil will promote the growth of vellus hair

for as long as it is used. High-potency topical or

intralesional  corticosteroids (see  Table 13.11) and ciclosporin may induce regrowth, but regres-

sion  occurs  on  withdrawal  of  all  treatments.

Oral photochemotherapy (PUVA, p. 847) has

been reported to be successful in up to 30% of

patients.

There are two types of sweat glands. The apo-

crine glands are large glands that open mostly

into the hair follicles in the axillae, scalp, anogen-

ital area and around the nipples. They produce

a  milky  secretion  containing  carbohydrates,

proteins, fatty acids etc., the production of which

is stimulated by emotions such as pain, fright

and sexual excitement. These glands develop at

puberty and are therefore part of the secondary

sexual characteristics.

Eccrine  glands  occur  all  over  the  skin,

though their concentration varies enormously

with the site, and they play an important role

in temperature regulation. Eccrine glands occur

as  coils  of  cells  in  the  dermis  and  open  via

invisible  pores  onto  the  surface  where  they

discharge the sweat, a watery fluid containing

0.5-1% of chlorides, lactic and other acids and nitrogenous compounds, mostly urea.

The sebaceous glands are present all over the

body, except the palms and soles. They are espe-

cially  common  on  the  scalp,  face,  forehead,

chin,  chest  and  back,  opening  into  the  hair

follicles. They do not have ducts, but the cells

break  down  to  release  the  waxy  sebum.  The

function of sebum is uncertain, though super-

ficial  spread  of  its  waxy  component  influ-

ences water movement out of the skin and its

retention  there.  The  skin  also  produces  large amounts  of  a  mixture  of  substances,  known

collectively  as  natural  moisturising  factor.

Because  sebum  production  is  partly  under

hormonal control, its odour presumably has a

sexual role. Modified sebaceous glands produce

wax (cerumen) in the ears and form the meibo-

mian glands of the eyelids. The latter occasion-

ally  become  blocked,  forming  small,  benign,

irritant cysts (chalazion): if these are trouble-

some  they  are  removed  surgically.  Chalazion

should not be confused with styes, which are

infections of the hair follicles.

Dermis

The outermost papillary part of the dermis lies

immediately under the epidermis and rises irreg-

ularly into it, producing the dermal papillae,

which contain blood vessels and nerve elements.

The deeper part of the dermis contains a variety

of elements:

•  Connective  tissue,  e.g.  collagen  and  elastic

            fibres, which supports the epidermis, confers

elasticity and helps to maintain skin hydration

•  Cellular elements: migratory, i.e. a few leuco-

cytes (histiocytes) that are phagocytic and also

form  reticulin  fibres,  and  fixed,  i.e.  fibro-

blasts and mast cells. These cellular elements

are important, since they control the differ-

entiation  and  function  of  the  overlying

epidermal epithelium, resistance to infection

and reactions to environmental allergens.

•  Blood vessels, which nourish the skin and

help to regulate local temperature.

•  Smooth muscle fibres, which erect the hairs

            and cause ‘gooseflesh’.

•  Nerves,   which   are   sensory  (touch,   pain,

temperature) and autonomic (controlling the

blood vessels and hair follicles).

•  Lymphatic vessels, for drainage of intercel-

            lular fluid.

Subcutaneous tissue

Below  the  dermis  is  a  layer  of  loose,  areolar connective tissue, containing adhesion proteins, nerves and fat, plasma cells (see Chapter 2) and mast cells, embedded in a semi-solid matrix. This layer has important functions:

Clinical features of skin diseases            819

•  Storage of water and fat, helping to maintain

            dermal and epidermal hydration.

•  Insulation against excessive heat loss or gain.

•  Provision of an access route for nerves and

blood vessels to muscles and the dermis. •  Protection of underlying tissue.

Clinical features of skin diseases

Histopathology

The  pathological  changes  that  occur  in  skin

due to disease are often not diagnostic, unless

invading  microorganisms  can  be  recognized.

However,  there  may  be  characteristic  changes

in the epidermis in diseases such as psoriasis

(p. 838) or pemphigus, or in the dermis, e.g. in

scleroderma (see Chapter 12). The structures of

some types of lesions are illustrated in Figure

13.2,  and  common  pathological  changes  are listed in Table 13.2.

Many   skin   conditions   are   inflammatory or  have  inflammation (see  Chapter 2)  as  a significant component.

Diagnosis

History

The  important  aspects  of  the  dermatological history (see also Chapter 1) are:

•  Where did it start? (Figure 13.3). •  Duration.

•  What changes have occurred in the severity?

•  The extent when seen, and in the past, i.e.

changes over time, distribution (Figure 13.3).

•  Features (Tables 13.3 and 13.4): wet or dry,

colour, size, itch (pruritis).

•  Interference  with  sleep,  work,  leisure  and

            social contacts.

•  Aggravating or relieving factors, e.g. treat-

            ments,   diet,   clothing,   light,   tempera-

ture,  seasonal  variation,  emotional  stress, medicines.

•  Family history, e.g. allergies and atopic condi-

            tions, eczema (p. 849) and psoriasis (p. 838).

•  Medication history.

•  Occupation and hobbies.

•  Cosmetic    usage,    including    hair    dyes,

            perfumes, aftershave lotions, and creams, etc.

The  last  two  of  these  categories,  and  the

patient’s own observation, may provide valuable

clues as to the cause of contact dermatitis (p.

852). The emotional response of the patient may

also be very important because visible lesions may  cause  considerable  distress  even  though they are benign, and the associated emotions

may aggravate the condition.

Inspection and identification of the types of

skin changes and of lesions (Figures 13.2 and

13.3, the Plates and Tables 13.2-13.6) require a good light and sometimes magnification.

Psychological features

Patients  with  skin  diseases  tend  to  be  more

disturbed  by  their  condition,  relative  to  its

severity,  than  are  those  with  other  types  of

illness. This is particularly true of visible lesions.

Many common skin diseases, although poten-

tially  disfiguring,  are  completely  benign  and

non-transmissible, e.g. naevi, dermatitis, psori-

asis and acne. Patients often experience what has

been called the ‘leper complex’, being at least

somewhat rejected by their families, friends and

acquaintances, or expecting to be so, and thus

becoming miserable and reclusive.

Itching, a common accompaniment to many

dermatoses, may make patients restless during

the  day  and  sleepless  at  night,  leading  to

tiredness, irritability, demoralization and social difficulties.

A clear diagnosis and simple explanation will

often help patients enormously. A readiness to

touch non-infectious lesions, demonstrating the

conviction of the healthcare worker or carer that

the disease is benign and non-transmissible, can

be a very effective way of reducing anxiety.

Examination

General aspects

In community pharmacy it may be difficult to

gain a sufficiently broad experience, over a long

enough time, to be able to recognize even some

common  skin  lesions  readily.  It  is  certainly

impracticable to learn to do so adequately as a

student, though there are several well-illustrated

books that can be of great help (see References

and further reading). Prior self-treatment, espe-

cially with corticosteroids, may alter the appear-

ance   of   lesions   dramatically.   There   is   a

temptation to proceed directly to examination

of the patient and to form a diagnosis on that

basis,   because   patients   often   present   by

showing a readily visible lesion and asking for

advice.  Although  skin  symptoms  and  signs

may be pathognomonic, e.g. in acne or stable

plaque psoriasis, the history is usually of prime

importance,  because  the  skin  has  only  a

limited repertoire of symptoms with numerous

possible  causes.  Also,  the  characteristics  and

severity of lesions may vary widely, even in the

same patient with the same disease at different

times.

Some   general   symptom   groups   and   the

features which may make it possible to identify

the nature of the problem and come to a diag-

nosis are described below, but the details of the

most common diseases are described later in this

chapter.

Allergic conditions

These are usually very itchy (itch arises solely in

the epidermis). Localized lesions may be due to

contact dermatitis (Plate 1), atopic dermatitis

(Plates 13 and 14 and p. 852) or urticaria (p. 864).

Rashes

These  are  temporary  skin  eruptions,  varying from small spots to larger areas.

Facial rashes.   These are often due to environ-

mental factors, e.g. weather or sunlight, or may

be readily recognizable, e.g. acne. If they are due

to atopic dermatitis there is often a fairly charac-

teristic appearance: dry, finely scaling skin, facial

pallor, swelling or creasing around the eyes and,

possibly, a ‘creased’ pigmentation on the neck.

Lesions localized to the eyebrows and perinasal

area are usually due to seborrhoeic dermatitis

(p. 853), while those around the eyes or mouth

may  be  a  contact  dermatitis (p. 852)  from

cosmetics, cleansers or medicated creams. Fluori-

nated corticosteroid creams (see Table 13.11),

which should never be used on the face, are one

Clinical features of skin diseases            823

regrettable,  avoidable  cause  or  aggravator  of perioral dermatitis (Plate 3).

Areas of inflammation that flush with heat,

foods or stress and that tend to become papular

are usually due to rosacea (Plate 4 and p. 863).

Aggravating factors, e.g. corticosteroids, vasodila-

tors,  alcohol,  hot  drinks  and  hot  sunshine,

should be avoided. There is possible confusion

between acne (p. 856) and rosacea, but there are

no comedones (blackheads) with rosacea. If acne

is mild it may be left untreated, but topical

antibiotics (metronidazole  or   tetracycline)   are

usually effective.  Oral  tetracyclines,  or  even  a

retinoid (p. 835) may be necessary in resistant

disease:   eye   involvement   requires   specialist

management.

Other  common  causes  of  facial  rashes  are seborrhoeic dermatitis and infections, especially in children and teenagers, e.g. herpes simplex and impetigo (see Chapter 8).

SLE (see Chapter 12) is a potentially serious disease that may present with a butterfly-shaped rash over the cheeks and bridge of the nose,

though accompanying symptoms, e.g. arthralgia and fever, are usual. A benign form, discoid

lupus,   causes   more   limited,   well-defined, erythematous plaques on the cheeks.

Scaly rashes.   An approach to the identifica-

tion of scaly rashes is outlined in Table 13.4.

Serious problems may arise for the patient if

large areas of skin are affected moderately or

severely, because temperature and water regula-

tion  mechanisms  may  then  be  impaired.  In

severe cases this may lead to hypothermia and

dehydration.

Acute generalized rashes.   It is to be hoped that patients with lesions of this type (Table 13.5)

will  consult  their  doctors  promptly.  However, patients are frequently reluctant to do this or fail to realize the severity of their condition.

Generalized rashes, especially in childhood,

are  often  caused  by  infections,  when  there

will be associated systemic symptoms, e.g. sore

throat, fever, aches and joint pains, possibly with

a history of recent case contact. Guttate psori-

asis (p. 840), with widespread small lesions, may

also be triggered by mild infections, especially

sore throats.

Erythroderma  (widespread inflammation of

the skin) may occur as a complication of eczema

and psoriasis. Nearly the whole skin becomes

dry, dusky red and there is profuse scaling, hence

the term ‘exfoliative dermatitis’, accompanied

by pitting oedema (see Chapters 4 and 14) and

grossly enlarged lymph nodes. The increased

blood flow through the skin stresses the heart

and this extra load may precipitate heart failure

(see   Chapter 4).   Temperature   regulation   is

compromised and patients may become seri-

ously  hypothermic.  Further,  gut  function  is

impaired, due to diversion of blood from the

intestines, and may cause malabsorption (see

Chapter 3).  The  condition  occurs  mostly  in

males and in the elderly, and is potentially life-

threatening. If it occurs without a prior skin

disease,  a  search  must  be  made  for  possible

underlying   disease,   e.g.   HIV   infection   or

neoplastic disease (lymphoma or leukaemia).

Localized lesions

The  diagnosis  of  these  should  always  be

approached  carefully  because,  although  the

majority are benign, they are occasionally malig-

nant, especially in older patients and if they are

isolated. The most common cutaneous malig-

nancyis the basal cell carcinoma (BCC, Plate 5),

which is much more common in fair-skinned

races, especially if there has been prolonged skin

exposure in sunny climates. Patients often regard

the lesion as a minor, benign ‘sore’, but must be

strongly encouraged to see their doctor as soon as

possible, without alarming them unduly, because they metastasize late and early treatment carries an excellent prognosis, whereas delay can lead to severe damage to underlying tissues.

Moles and warts are common and are usually

recognized  readily,  but  any  change  in  them

should be regarded very seriously. If there is any

doubt about the nature of an isolated lesion,

prompt medical referral without causing undue

alarm is mandatory, though patients are often

reluctant to see their doctors. The characteristics

of some localized lesions are given in Table 13.3.

Special signs

Koebner’s sign is the occurrence of lesions along the track of a skin injury, e.g. a scratch, sunburn or chickenpox lesions, and may be a feature of psoriasis, lichen planus or warts.

Nikolsky’s  sign  is  the  easy  separation  of apparently normal epidermis from the dermis by pinching or rubbing. It occurs in pemphigus

vulgaris, a blistering disease in which there is a  loss  of  cohesion  of  the  more  superficial epidermal cells, though the basal layer remains attached to the dermis.

Investigation

Patch tests for contact dermatitis are done by

sticking  a  strip  of  a  non-allergenic  carrier,

impregnated at intervals with solutions or gels of

different suspected compounds, to a patient’s

back or arm and observing the occurrence of a reaction after 48 h (Figure 13.4). Such reactions may persist for 4-7 days. Prick (scratch) tests

may occasionally be used to identify systemic allergens in atopic subjects, though such pro-

cedures carry the risk of severe generalized reac-

tions and should only be carried out where full resuscitation facilities are available.

Other tests include microscopical examination

of skin, hair and nails, or scrapings from the

bases of vesicles; blood counts and pathogen

culture,  serology,  etc.,  the  biopsy  of  chronic

lesions, especially if there is a possible malig-

nancy  and  inspection  under  Wood’s  light

(365 nm UV), to observe hair fluorescence in

some types of tinea.

The  radioallergosorbent   test   (RAST,  see

Chapter 5, Figure 5.16) is used to determine the presence and titre of reaginic antibodies (IgE; see Chapter 2) when investigating atopic conditions, e.g. dermatitis and urticaria.

Various techniques of ultrasonography, which provide a two-dimensional picture through the skin, are now being used in specialized units.

Clinical features of skin diseases            825

The skin and systemic disease

The  association  of  skin  lesions  with  systemic

symptoms may indicate the presence of severe

underlying disease and must always be taken seri-

ously. Conditions in this group include thyroid

and  kidney  diseases,  renal  failure,  diabetes

mellitus,  hyperlipidaemias  and  malignancies

(Table 13.6).

Common associated systemic features include general malaise, muscle weakness, joint pains, fever   and   weight   loss.   The   dermatological features that may be warning signs of serious

disease include the following:

•  Acute onset, especially over 50 years of age,

            e.g. cancer, etc.

•  Progressive  symptoms,  e.g.  cancer,  chronic

            diseases.

•  Blistering and widespread urticaria.

•  Erosion  of  tissue,  e.g.  venous (‘varicose’)

ulcers, cancer.

•  Generalized   itching,   unrelated   to   local

            lesions, in liver and renal disease.

•  Recurrent boils (diabetes mellitus).

•  Xanthomas (yellowish plaques of cholesterol

deposition,  often  around  the  elbows  and knees,  indicative  of  hyperlipidaemias;  see Chapter 4), especially in young adults. When these occur around the eyelids, usually in

middle-aged patients, the condition is known as xanthelasma (Plate 6).

A widespread rash following treatment of a

sore throat with ampicillin is virtually pathogno-

monic for glandular fever. Purpuras are rashes

due to bleeding into the skin and always require

urgent medical referral. They may be distin-

guished from rashes that are inflammatory in

origin because they do not blanch under pres-

sure: a clear plastic spatula or a drinking glass

pressed  onto  the  skin  compresses  dilated

blood   vessels   and   so   causes   temporary

blanching  of  inflammatory  rashes  but  not  of

purpuric  ones.  Purpuras  may  be  caused  by

allergic   reactions   to   drugs,   resulting   in

platelet  destruction  and  clotting  failure (Plate

7; Chapter 11), to other clotting  or  vascular

defects             (Chapter           11),   or  to  infection,  e.g.

meningococcal meningitis. Because drugs are a

common cause, a medication history may give

important clues.

General management of skin diseases    dition  deteriorates  while  using  a  product  of

known effectiveness against it, an adverse reac-

Basic approach

There are two essential considerations:

•  Reassurance of the patient and the reduction

            of anxiety (see above).

•  Avoidance of actual or potential irritants and

            precipitants.

The range of the latter is very wide and includes soaps, detergents, cosmetics, perfumes, clothing, foods, plastics, rubber, metals (jewellery), lubri-

cating oils, cement, drugs, components of vehicle bases of medicaments, etc. This important aspect requires considerable detailed attention.

An  example  of  the  problems  involved  is

provided by the use of rubber gloves: they often

do not give adequate protection and are prone to

leakage  and  internal  contamination,  causing

contact dermatitis. If rubber gloves are used,

they should be disposable or they should be

turned inside out, washed and dried to remove

contaminants,  preferably  after  each  occasion

of use. Further, plasticizers and other additives

in  glove  materials  may  cause  similar  trouble,

and extensive trials of different manufacturers’

gloves may be needed to find an acceptable

brand for an individual. It may also be necessary

to wear cotton gloves inside the rubber gloves.

These problems affect professionals, e.g. doctors,

dentists,  pharmacists  working  in  production

units  handling  cytotoxic  drugs  and  making

additions to IV infusions, as well as housewives

and kitchen workers. When handling cytotoxic

drugs there is the additional problem of drug

penetration through the gloves.

Intensity of treatment

There is a considerable danger of over-treatment

and the application of medicaments that are

known to have serious potential side-effects, e.g.

potent  corticosteroid  creams  and  ointments

(Table 13.11). Products may contain unsuspected

allergens, e.g. the drug itself, lanolin, antiseptics

or antioxidants, and may aggravate the original

condition or add further problems. If the con-

tion should always be suspected, rather than

drug resistance. Further, excessively frequent or

vigorous application of medicaments, or their

removal from damaged skin, may further harm

sensitive  areas.  Minimal  treatment  with  the

simplest and mildest effective product should be

the rule.

There are five basic target groups of condi-

tions, for each of which a different degree of

intervention is appropriate:

•  Lesions  from  which  the  skin  will  usually

            recover  spontaneously  with  minimal  inter-

vention,   e.g.   contact   dermatitis,   many

occupational skin diseases, mild acne.

•  Conditions which require protection of the

skin by the application of emollients, barrier

creams or ‘inert’ preparations, e.g. mild nappy

rash.

•  Conditions  which  will  respond  to  active

            treatment, e.g. psoriasis, acne and eczema.

•  Infections  and  infestations  which  require

specific antimicrobial or antiparasitic treat-

ment, e.g. impetigo and scabies.

•  Those  conditions  in  which  little  can  be

            done currently to influence their course, e.g.

cutaneous scleroderma.

Medical   management   is   essential   in   the following situations:

•  Lesions affecting more than 10% of the body

            surface area (BSA; see Table 13.7).

•  Conditions with associated systemic features.

•  Progressive lesions, increasing in severity or

size.

•  Ulcerating lesions or those that are breaking

            down centrally.

•  Pigmented  lesions,  other  than  static  ones

            which are clearly warts or moles.

•  Any lesion which has recently changed in

            character.

•  Conditions in which there is a significant

            inflammatory component.

•  Blistering lesions, unless they are known to be

            due to a minimal insult, e.g. an insect bite,

and the patient is otherwise well.

•  Conditions which markedly interfere with the

            patient’s lifestyle or occupation.

•  Any unidentified lesion which arises acutely

            in the middle-aged or elderly.

Selection of treatment

Clinical features

Clearly the choice of treatment will depend on:

•  The nature, extent and severity of the lesions.

•  Whether they are visible and consequently

cause the patient considerable anxiety.

•  The   duration   and   progression   of   the

condition.

•  What is known about the natural history of

            the condition, i.e. whether it is likely to remit

or to have serious sequelae.

•  Patient preference, e.g. for a particular formu-

            lation or type of emollient.

The patient’s perception of their condition is

important because steps must be taken to relieve

their distress, even though it may be known that

the disease is benign and self-limiting: a holistic approach is required.

The general treatment of target symptoms is outlined in Table 13.8.

Type and amount of product

There is sometimes confusion as to whether to

use ointments or creams, but the simple rule is

‘wet on wet, dry on dry’. Thus oil-in-water (o/w)

creams are usually used on moist lesions (oint-

ments will not stick anyway), and ointments or

w/o creams on dry or scaly lesions, which also

aid skin rehydration. This may need to be modi-

fied according to patient acceptability and the

site, e.g. lotions and gels are usually preferred on

the scalp.

Table 13.7 gives an indication of the propor-

tion of the BSA represented by various parts of

the  body,  and  the  approximate  amounts  of

product required for treatment. However, the

amounts used, even by specially trained derma-

tology nurses, may vary considerably. A simpler

approach is to use the fingertip unit of Long

and Finlay. Patients using grossly more than the amounts indicated are likely to be using the

product excessively.

It is important to remember that virtually any product used in treatment may itself be irritant or allergenic for some patients due to components of the base, additives or medicaments. Even hydro-

cortisone cream has been known to cause rashes. If the condition fails to respond or deteriorates, this may be the result of inappropriate treatment or some component of the medicament.

Targeting symptoms

Dryness

Emollients are invaluable in the management of

dry skin conditions, whether they are primary,

or secondary to other diseases such as eczema,

and are the fundamental basis of dry skin treat-

ment. They leave an oily film that prevents

evaporation of water and thus maintains skin

hydration: adding external water provides only transient hydration that is lost rapidly.

Emollients may give substantial relief when

used alone and will at least reduce the need for

potent medication. A useful routine is given

below, but this needs to be tailored flexibly to

patient preference to achieve the desired result:

•  Avoid soaps and household detergents, which

            may be irritant or allergenic and promote

drying  by  removing  the  film  of  natural

moisturizing factor (see below).

•  Use emulsifying ointment, or aqueous cream

            or  a  commercial  alternative,  to  wash  and

bathe, or a bath oil or gel, as the patient

prefers.

•  Use a ‘light’ emollient cream, i.e. relatively

            non-greasy and readily absorbed (Table 13.9),

after  bathing  or  washing,  over  the  entire

affected area. However, in dry skin conditions

a greasier product (‘heavy cream’) may be

preferable, because it gives better skin hydra-

tion, though it is very uncomfortable if large

areas of skin are covered with an oily film. If

this cannot be tolerated by the patient, a

compromise has to be found. Emollients may

also relieve skin tenderness.

•  A barrier cream (see BNF Section 13.2.2) may

            be used on the hands before work, but may

cause its own problems (p. 827).

The   skin   produces   large   quantities   of   a

complex mixture of substances, known collec-

tively as natural moisturizing factor (NMF),

which is believed to be intimately involved in

the maintenance, repair and hydration of the

epidermis. Some inherited dry skin conditions,

e.g. ichthyosis, are presumably the result of an

inadequate production of NMF. One component

of NMF is sodium pidolate, a potent humectant

used in some commercial emollients.

Pruritus (itching)

Itch is a symptom that is unique to the skin,

and may be caused by a variety of diseases and

conditions (Table 13.10). The natural response

is to scratch the affected site, but this provides

only  temporary  relief  and  the  itch  returns,

to  be  followed  by  more  scratching.  If  this

‘itch-scratch-itch cycle’ persists, the skin may

become  lichenified,  i.e.  thickened  and  rough-

ened,  or  even  excoriated,  i.e.  scratched  suffi-

ciently  to  cause  bleeding,  and  the  skin  may

become infected or be permanently damaged.

Topical treatment.   Aqueous cream with 1-2%

menthol, and physiological saline are widely used

to relieve minor itching, and some commercial

bath oils, e.g. Balneum Plus and Dermalo, have

antipruritic properties. Lotions may be cooling,

protective, astringent and antipruritic and are

often  used  on  inflamed  and  weeping  skin.

Although  previously  used  widely,  aluminium

acetate lotion and calamine lotion, sometimes with

ichthammol,  are  now  uncommon.  Crotamiton

lotion  may   be   preferred   by   some   patients,

although there is little objective evidence of

effectiveness. Coal tar products may also help to

reduce  itching.  Calamine  lotion  may  be  too

drying  and  should  not  be  used  for  scaling

dermatoses, for which the oily preparation is

preferable. Calamine preparations are rarely used

nowadays, because they are ineffective.

Provided that there is no infection, occlusive

medicated bandages, e.g. zinc paste with coal tar

or ichthammol, covered with stockinette or crepe

bandage, can be left in place for a week or more.

This helps to break the itch-scratch-itch cycle

and so allows the skin to heal. Some of these are

particularly easy to remove without damaging

the skin.

A cream formulation of the tricyclic antide-

pressant doxepin is licensed for treating pruritus

in  dermatitis.  However,  it  may  cause  local discomfort and systemic antimuscarinic effects if

it is significantly absorbed, e.g. urinary reten- tion, drowsiness, dry mouth etc. (see Chapter 6).

Systemic   treatment.   Antihistamines  should

be given orally as antipruritics and not used

topically, because they may cause sensitization.

Although many patients use topical antihista-

mines without any side-effects, the patients who

need them most are those most likely to be sensi-

tized by them, so they are preferably avoided.

The sedative antihistamines, e.g. hydroxyzine,

promethazine  and  alimemazine,  are  preferred,

with  appropriate  warnings  about  drowsiness,

driving, etc., and are especially useful at night,

when   their   sedative   effect   is   beneficial   in

preventing  restlessness  and  scratching  during

sleep. A particular advantage of hydroxyzine is its

anxiolytic action.

Because the antipruritic effect tends to accom-

pany sedation, the newer, non-sedating anti-

histamines may be less useful for this purpose.

However,  these  effects  are  relative  and  non-

sedating antihistamines are often used during

the day and sedating ones at night. It should be

noted that although the newer antihistamines

are relatively non-sedating, e.g. acrivastine, fexo-

fenadine and mizolastine this does not mean that

they are safe under all circumstances and they

may not be suitable for use in children.

They have antimuscarinic effects and must be

used cautiously in patients with prostatic hyper-

trophy, urinary retention and glaucoma, all of

which tend to be common in the elderly. They

may also cause severe hypersensitivity reactions.

These drugs should be avoided if there is signifi-

cant hepatic impairment, hypokalaemia or other

electrolyte disturbance. Further, many antihista-

mines must not be used with anti-arrhythmic

agents, e.g. amiodarone, disopyramide, procaina-

mide and quinidine, because serious arrhythmias

have   occurred             (see   the   BNF   and   manu-

facturers’   literature).   Syncope           (fainting)   in

patients taking these antihistamines may indi-

cate an arrhythmia and should be investigated.

Broken and weeping skin

The best initial treatment is still the traditional

astringent, mildly antiseptic, potassium perman-

ganate soaks (1/8000). Unfortunately, the skin

and clothing will be stained brown and some

patients  find  this  cosmetically  unacceptable.

Once the skin starts to heal, other medications

can be applied. Alternatively, physiological saline

soaks may be useful. If the area is infected,

systemic antibiotics will be required: like the

antihistamines,   most   topical   antibiotics   are

liable to cause skin sensitization and should be

avoided.

Non-adherent  dressings  should  be  used  if

the area needs to be covered, and oily prepa-

rations, e.g. compound zinc oxide creams and

ointments,  are  preferred  on  weeping  skin  to

avoid crusting and the adherence of dressings:

this  is  an  exception  to  the  normal ‘wet  on

wet’ rule.

There is a large range available of new breath-

able dressings with good adherence and flexi-

bility.  These  protect  the  area,  allow  oxygen

penetration and control moisture loss, so they

can be left in place for long periods. They are

very useful for incipient pressure sores, though

good nursing care will avoid their occurrence.

Routes of administration

Topical treatment

Topical treatments are only of value in superfi-

cial (epidermal) dermatoses. If lesions are deep-

seated, any agent applied to the surface that

reaches the dermis will be removed rapidly in the circulation. Consequently, dermal disorders require systemic therapy.

Although topical corticosteroids have revolu-

tionized the treatment of many skin diseases the

older products still have a place in the first-line

treatment of mild to moderate disease. Thus coal

tar products are still used in the management of

mild psoriasis, e.g. 5% crude coal tar in a suitable

base, or tar paint (pp. 843-4) and may also be

helpful in chronic atopic eczema (p. 852), e.g.

15% coal tar solution in emulsifying ointment

applied before bathing. However, newer prod-

ucts are more acceptable cosmetically. Commer-

cial products are more elegantly formulated than

the equivalent official formulary ones and so are

usually more acceptable to patients. A coal tar

salicylic acid     sulfur    coconut oil ointment is

very useful in treating scalp psoriasis, although

it is very greasy.

Intertrigo, i.e. dermatitis of the skin folds

under the breasts or in the axillae, often macer-

ated  and  infected  with  Candida  albicans,  is

treated  with  dry,  non-staining  antimicrobial

agents, e.g. an imidazole gel, which are prefer-

able  and  more  acceptable  cosmetically  than

creams. The site is occluded by the opposing skin

folds, so it may be necessary to separate infected

skin  folds  with  an  antimicrobial-impregnated

dressing, to promote healing. Care must be taken

that patients are not sensitive to the products,

notably   iodine,   because   patients   with   skin

problems tend to be more liable to develop skin

sensitization than the general population. In all

situations, the simplest treatments are best and

safest, especially if there is any doubt.

Systemic treatment

This may be required in a variety of situations:

•  If there are associated systemic symptoms,

            e.g. psoriatic arthropathy.

•  To control serious conditions, e.g. erythro-

            derma (p. 824) and angioedema (a severe

urticarial reaction; p. 864).

•  When local treatment might cause skin sensi-

            tization,  e.g.  antibiotics  or  antihistamines.

•  When topical treatment is ineffective or inap-

propriate, e.g. the use of systemic cytotoxic drugs, corticosteroids, antibiotics and some retinoids.

Corticosteroids

Topical corticosteroids are widely used in derma-

tology. This merits special consideration because their indications, cautions, side-effects, etc. differ in important respects from those experienced

with systemic corticosteroid use.

Topical use

Selection

This depends primarily on four considerations:

•  The severity of the condition: clearly, the

            more  severe  the  damage  the  greater  the

potency needed, but this must be tempered

by the knowledge that the greater the damage

or  inflammation,  the  greater  will  be  the         Potency

systemic absorption through that site.     These products are classified in the BNF into four

•  The site of application: sites particularly sensi-

            tive to their side-effects are the axillae, under

the breasts, behind the ears and the genital

area, i.e. wherever there are skin folds and

delicate skin. It should be clear that greater care needs to be exercised if the face or other exposed areas are to be treated, because any side-effects (see below) will then be obvious and very important to the patient.

•  The nature of the condition, e.g. they are

            contra-indicated in rosacea, perioral dermatitis

and  untreated  bacterial,  fungal  and  viral infections,  because  they  are  likely  to  be exacerbated.

•  Patient characteristics, e.g. the very young

            and very old.

different potency groups (Table 13.11). However,

this classification must be regarded as approxi-

mate because formulation has a considerable

influence  on  potency.  Further,  percutaneous

absorption will be greater with a more extensive

area  of  application,  a  greater  degree  of  skin

inflammation and with occlusion of the site.

The concentration of drug used will influence

the relative potency. Prescribers frequently order

dilutions of commercial products, but the advan-

tages of this are questionable, because it should be

possible to choose a properly formulated product

of lower potency. Further, extemporaneous dilu-

tion has several disadvantages: the product is no

longer sterile, it may not be adequately preserved,

and injudicious manipulation may impair the

uniformity of a carefully formulated and manu-

factured  product.  For  example,  some  potent corticosteroid  ointments  are  dispersions  of  a propylene glycol solution of drug in the base, and excessive   manipulation   or   warming   of   the product may cause the dispersed droplets to

coalesce. A non-uniform product results, even though the correct diluent is used.

Side-effects

These will vary with the potency, the amount

applied, the area covered, frequency of applica-

tion and whether the site is inflamed, occluded

or particularly sensitive. Side-effects may be local

or systemic and are often related to the cytostatic

properties of steroids. Repeated application of

potent steroids leads to wasting of SC tissue, due

to inhibition of fibroblast maturation and conse-

quent failure of collagen repair in the dermis,

similar to what happens in the normal ageing

process. This results in thinning of the skin and

telangiectasis, i.e. a reddening resulting from

the disclosure and expansion of the small blood

vessels in the dermis, because they are no longer

adqeuately supported (Plate 16). If this effect is

severe, the larger vessels will also become promi-

nent and the capillaries will become fragile, so

that minor trauma leads to substantial bruising

(ecchymosis).  A  similar  underlying  process

may also produce striae, permanent disfiguring

stretch marks as the dermis and SC tissues lose

elasticity.

Suppression  of  local  non-specific  defence

mechanisms (see Chapter 2) by corticosteroids

may occur due to inhibition of macrophage and

neutrophil activity, resulting in delayed healing

and the aggravation of skin infections, notably

herpes  simplex.  Topical  corticosteroids  are

therefore contra-indicated if there is any suspi-

cion of bacterial, viral or fungal infection unless

formulated or used with an effective antimicro-

bial agent. The combination of their cytostatic

effects  and  the  suppression  of  local  defence

mechanisms means that they are usually contra-

indicated for the management of skin ulcers,

because they may delay healing and promote

infection.

Use of the more potent synthetic steroids may

result  in  local  erythema,  contact  dermatitis

(Plate 12) and perioral dermatitis (Plate 3). It is

not clear whether the latter condition is due to a

true sensitivity to the drug, whether the steroid

triggers a latent erythematous tendency or is a

variant of rosacea (p. 863). Corticosteroids will

aggravate rosacea and, being comedogenic, may

exacerbate acne (p. 856). Mild skin depigmenta-

tion may also occur, due to depressed melanocyte

activity.

Systemic   absorption   may   be   significant,

depending  on  the  factors  mentioned  above.

Thin skin areas, e.g. behind the ears, and the

genitalia,   hairy   areas   and   inflamed   and

damaged skin permit greater drug penetration

than normal skin. Occlusion of a treated area,

by folds of skin or dressings also enhances pene-

tration.  The  potent  and  very  potent  products

(see Table 13.11) are all capable of producing

significant  percutaneous  adrenal  suppression,

so they must be used with great care, especially

in children, whose skin is thinner and whose

surface area to body weight ratio is greater than

that of adults. Absorbed steroid may also cause

some  degree  of  immunosuppression  due  to

inhibition  of  lymphocyte  multiplication  and

maturation.

Patients must therefore be counselled carefully

on how to use these products, the major criteria

being that they are applied sparingly to the

specific lesions and usually not massaged into

the skin or occluded. The approximate amounts

of products needed for application to various

parts of the body are given in Table 13.7. Patients

must also be warned that these products are

prescribed   for   treatment   of   the   condition

presented, and must not be hoarded to use as

panaceas  for  all  skin  ailments,  or  loaned  to

friends or relatives.

Both patients and some prescribers are wary of

steroid use, so that the preparations used may be

too weak to control symptoms adequately. A

short burst of a potent agent is usually quite safe:

it will often be more effective, and safer in the

long run, to control symptoms rapidly with a

potent  agent  and  then  reduce  the  potency,

rather than to titrate the dose upwards.

Precisely placed intralesional  injections  of

poorly soluble forms may be more effective than

potent  topical  products  for  severe  localized

lesions,  e.g.  keloid  scars (fibrous,  raised  and

enlarging).

Systemic use     In the occasional very frail elderly patient, an

anabolic steroid, e.g. nandrolone, may be appro-

The best estimate of oral corticosteroid usage in theUKis that there are about 250 000 patients, taking an average of 8 mg/day of prednisolone, though most of this is not dermatological. Most users are in the 60- to 80-year age group.

In dermatological practice, systemic steroids

are  indicated  only  for  severe  dermatoses.  The

normal  rules  for  steroid  therapy  should  be

followed,  i.e.  the  minimum  dose  needed  to

control the condition should be used, and this

should be reduced as rapidly as possible on a

sliding scale to the minimum maintenance dose

required, preferably nil. However, daily doses of

prednisolone     7.5 mg, or the equivalent of other

products,  are  unlikely  to  produce  significant

adrenal suppression and other major side-effects

in  adults.  If  adrenal  suppression  does  occur

during long-term therapy it may be prolonged

after the cessation of treatment, so corticosteroids

must never be withdrawn abruptly after 3 weeks

or more of continuous use. Because the physio-

logical demand for corticosteroid is increased in

stressful situations, e.g. serious illness, accidents

and   major   surgery,   the   dose   needs   to   be

increased in these circumstances. Patients using

long-term corticosteroids need to learn how to

manage their dose in these conditions.

Injudicious use of corticosteroids may perma-

nently stunt children’s growth. At the other end

of  life,  perimenopausal  and  postmenopausal

women, and some elderly men, are at risk of

osteoporosis, the physiological bone loss being

increased in proportion to the cumulative dose

of corticosteroid. This may lead to peripheral

bone  fractures  following  falls,  particularly  of

the  neck  of  femur  and  wrist,  and  vertebral

crush  fractures.  Only  about 14%  of  patients

receive preventative treatment, which should be

based on bone density measurement. In post-

menopausal   women,   hormone   replacement

therapy (HRT) manages the symptoms of the

climacteric as well as the osteoporosis, but has

fallen out of favour because of the associated

cancer risk. Otherwise, the best strategy is to

ensure   an   adequate   calcium   intake (about

1.5 g/day), with vitamin D if sun exposure is

limited, plus a bisphosphonate, e.g. alendronate, cyclical etidronate or strontium ranelate.

priate because it has beneficial effects on both bone density and muscle, but has many side-

effects and the deep IM injection of its oily

solution may be poorly tolerated.

Retinoids

These  compounds  are  related  chemically  to vitamin A (retinol). The vitamin derived from natural sources is a mixture of isomers of which the  most  active  is  all-trans-retinol,  the  form produced synthetically.

Retinol is essential for normal skin formation

and keratinization and for proper cell maturation

and  differentiation  generally.  However,  it  has

only a moderate activity and an unfavourable

therapeutic ratio, high doses causing serious side-

effects on the skin, mucous membranes, liver and

CNS. The synthetic retinoids are more potent and

have a better therapeutic ratio, though they are

still rather toxic compounds with an extensive

list  of  side-effects (Table 13.12).  Synthetic

retinoids  should  be  used  only  if  there  are

adequate  haematological,  hepatic  and  other

monitoring facilities available.

The   more   recently   developed          ‘second-

generation’ compounds, e.g. acitretin, tend to have less serious side-effects, especially neuro-

logical and hepatic. ‘Third-generation’ polyaro-

matic agents, the arotinoids, e.g. arotinoid ethyl ester, are some 100-1000 times as potent, but none of these is yet available.

Mode of action

Retinoids  bind  to  inducible  nuclear  retinoic

acid receptors (RARs; vitamin A receptors) that

interact with the promoter regions of specific

nuclear genes that control the maturation and

development of a variety of tissue cells and so

regulate their transcription. Three types of RAR

are known, only two of which (RAR-alpha, RAR-

gamma) are expressed in human skin. RAR-alpha

is present primarily in the basal layer, and its

concentration  declines  progressively  as  the

cells migrate towards the surface. Conversely,

RAR-gamma predominates in the granular layer.

Binding  of  retinoids  to  these  RARs  produces

specific actions on keratinocyte differentiation.

They also possess antiproliferative and anti-

inflammatory  actions.  They  thus  have  four therapeutic actions:

•  Promotion of normal keratinocyte differentia-

            tion in the epidermis.

•  Blockade of excessive cell proliferation and

            epidermal   growth   by   down-regulation   of

ornithine decarboxylase, which is involved in hyperplasia and hyperproliferation.

•  Suppression of excessive sebum production.

•  Anti-inflammatory, due to inhibition of PG

synthesis and the consequent production of pro-inflammatory agents, e.g. HLA-DR and lipoxygenase products and interleukin-6, and modification of both humoral and cellular

immune responses.

Apart from their effects on the epidermis, these

drugs have powerful effects on general cell matu-

ration.  In  acute  promyelocytic  leukaemia  (see

Chapter 10) there is a failure of promyelocytes to

differentiate into mature granulocytes. Tretinoin

and other retinoids cause dose-dependent rapid

maturation  of  these  immature  cells  and  may

be  used  as  maintenance  treatment  following

cytotoxic chemotherapy to induce remission.

Pharmacokinetics          completely protein-bound, but to serum albumin

and not to RBP.

The retinoids are lipophilic and have a relatively low oral bioavailability, so oral dosage forms should be taken with meals to enhance absorp-

tion. The currently available compounds cross the placenta and are highly teratogenic. They

are excreted in breast milk and cause skeletal

abnormalities in breastfed infants.

Etretinate  is   a   highly   lipophilic   aromatic

retinoid. There is a large interpatient variation in

bioavailability after oral use and it has a very

long persistence because it is stored in body fat.

The  effective  terminal  half-life (t1/2)  is  about

90 days. Although the blood levels of etretinate

after  stopping  are  therapeutically  inadequate,

they  may  still  be  teratogenic:  it  is  detectable

in plasma up to 2-3 years after chronic dosing

has ceased. Acitretin, a metabolite of etretinate,

has  a  t1/2 of  only  2 days  and  does  not  accu-

mulate  in  the  tissues.  However,  because  it  is

esterified to etretinate in the liver this benefit is

partly nullified.

Isotretinoin is an isomer of tretinoin, the acid

form of vitamin A, and has a bioavailability of

about 25% following oral administration. Peak

blood levels are reached in 1-4 h and the elimi-

nation t1/2  following chronic dosing is of the

order of 10-20 h, steady-state blood levels being

reached in 3-4 days. Its major active metabolite,

4-oxo-isotretinoin,  has  a  similar  terminal  t1/2

because its formation is rate limited. The shorter

t1/2 of isotretinoin makes it safer than etretinate.

Acitretin and isotretinoin should be used system-

ically only under the supervision of a consultant dermatologist. Prescribing of acitretin is limited to consultants and it is available to hospital and

named community pharmacies only.

Tazarotene is an esterified prodrug of the active

agent, tazarotenic acid, to which it is hydrolysed

in the skin. Although used topically, it penetrates

skin significantly. In short-term topical use the

t1/2 is about 18 h. End metabolism of tazarotenic

acid yields inactive compounds and appears to be

autoinducible: peak plasma levels after 3 months

are about 10% of those seen after 13 days.

In the epidermis, all of these compounds bind to both RAR-alpha and RAR-gamma. Vitamin A is transported in the blood by a specific retinol

binding  protein (RBP).  Isotretinoin  is  almost

The  potent  aromatic  retinoid,  etretin,  is  a

major metabolite of etretinate and has interesting

pharmacokinetics. Although its terminal t1/2  is

about 50 h, so that it persists as long as etretinate,

isomerization to its inactive cis-analogue occurs

readily. Thus it is very unstable and very difficult

to formulate, and aromatic retinoids have not

yet produced useful therapeutic agents.

Adapalene is a synthetic polycyclic, lipophilic retinoid derived from naphthoic acid. Although structurally unrelated to other current retinoids, adapalene is somewhat similar in structure to the arotinoids, and is very stable. It binds preferen-

tially  to  epidermal  RAR-gamma  and,  because skin penetration is very low, it is undetectable in plasma, urine and faeces.

Indications

The retinoids are a potent and interesting group of drugs with great potential. Although there are currently only a few licensed indications, they are known to have beneficial effects in other

diseases (Table 13.13) and there are many more for which there is evidence of potential benefit. Further development of this group of drugs may have a profound influence on our understanding of skin diseases and their treatment and of cell maturation processes in general.

Acne.   Tretinoin and isotretinoin are used topi-

cally  for  all  grades.  Isotretinoin  is  licensed  for

the treatment of both inflammatory and non-

inflammatory  lesions.  Adapalene  is  a  topical

treatment  for  mild  to  moderate  acne.  Oral

isotretinoin is used for severe, refractory disease.

Psoriasis.   Tazarotene is used topically to treat mild to moderate disease limited in area. Acitretin is used orally for the treatment of severe, resis-

tant or complicated psoriasis and for some other disorders of keratinization.

Photodamage.   Topical  tretinoin  gives  slow

improvement   over       3-4 months   of   hyper-

pigmented,  wrinkled  skin  caused  by  chronic excessive sun exposure.

Other uses.   Because of toxicity, oral tretinoin is no longer used for the treatment of psoriasis that, although disfiguring, is rarely life-threatening. However,  it  is  used  as  a  first-line  treatment to  induce  remission  in  acute  promyelocytic leukaemia, after relapse and in resistance to stan-

dard chemotherapy. Low-dose acitretin has also been reported to reduce skin cancer incidence in renal transplant patients who are on long-term immunosuppressive treatment.

Further details relevant to specific treatment are discussed under the diseases concerned.

The side-effects are dealt with Table 13.12.

Psoriasis

Psoriasis is a hereditary chronic skin disorder, usually   characterized   by   scaly   plaques   or papules, and often distributed on areas exposed to frequent minor trauma.

Pathology

Psoriasis is characterized by increased turnover of

the  basal  skin  cells.  Their  doubling  time  is

reduced from some 20-30 days to about 2-3 days,

and there is an increased growth fraction (see

Chapter 10). Further, the three lowest layers of

the epidermis are involved in cell germination

instead of the normal, single basal layer. Because

the   resultant   cell   production   considerably

exceeds  the  rate  of  cell  differentiation,  the

epidermis is thickened (Figure 13.5) and nucle-

ated cells are present throughout the entire thick-

ness, i.e. the normal granular layer is absent. Even

the horny layer contains cells with degenerate

nuclei instead of being composed of amorphous

keratin.

This  increased  metabolism  causes  a  full-

thickness inflammation of the skin. There is

infiltration of neutrophils and activated lympho-

cytes that release growth-stimulating cytokines.

Dilated, tortuous capillaries are present high in

the dermis and these occur even in the appar-

ently  normal  skin  of  patients  with  psoriasis.

Psoriatic arthropathy (Plate 8) is the conse-

quence of a synovitis that, though very similar to that of RA (see Chapter 12), is believed to be a distinct entity. The condition affects about 7% of patients with psoriasis.

One current theory is that there is an inherited

defect of keratinization resulting in abnormal

keratinocyte surface antigens. If immunocytes

encounter   these,   e.g.   following   minor   skin

trauma, an immunological response is triggered,

with consequent stimulation of the basal layer.

This is supported by the finding that initiation of

psoriasis is accompanied by an influx of CD4

(helper) T cells into lesions (see Chapter 2).

Further, CD8    T cells (cytotoxic) are responsible

for the maintenance of lesions. It has also been

suggested that there are genetically abnormal

fibroblasts that fail to control keratinocyte pro-

liferation.  There  is  overexpression  of  trans-

forming growth factors alpha and beta and levels

of TNF alpha are also raised, the latter being a

potent proinflammatory agent (see Chapter 2).

Aetiology

The precise cause of these changes is not clear.

However, there is a polygenic inherited tendency

to develop psoriasis. There is an association with

certain  histocompatibility  antigens (HLA-B13,

B17, Bw57 and Cw6). HLA-DR7 is associated with

both skin and joint disease and HLA-DR4 with

the latter only (see Chapter 12). HLA-B27, which

is strongly associated with (seronegative) AS (see

Chapter  12),  is  also  linked  to  psoriatic  joint

disease and the severe pustular form of psoriasis.

HLA-B28 is associated with a particularly severe

form of psoriatic arthritis.

Environmental factors are implicated in addi-

tion to the strong genetic component. Psoriasis occurs more frequently in colder climates in the winter. Known trigger factors include:

•  Trauma: skin laceration, pressure from belts,

            brassieres, etc.

•  Infections: streptococcal tonsillitis, especially

            in children; HIV.

•  Stress, e.g. marital, bereavement.

•  Hormone status: there is an increased inci-

            dence in pregnancy and at puberty and the

            menopause.

•  Sunburn or excessive exposure to the sun is

            harmful   in        10%   of   patients,   although

sunshine may benefit others, and its lack

predisposes to attacks.

•  Drugs: alcohol, antimalarials, beta-blockers,

            chlorpropamide, lithium, smoking.

Infants may develop napkin psoriasis, which usually responds readily to treatment.

Epidemiology

Psoriasis is very common and affects about 2%

of Caucasians, though many more have mild

disease for which they do not seek medical treat-

ment. About 30% of patients have a first-degree

relative  who  is  also  affected.  Siblings  have  a

17% risk, and patients’ children have a 25-50%

risk  if  one  or  both  parents  respectively  are

sufferers.  Identical  twins  have  a  concordance

rate of about 50%, so environmental factors are

clearly important.

The incidence is similar in both sexes. About

75% of cases occur between the ages of 15 and

25 years, but it is unusual for lesions to appear

before the age of 10. The condition tends to

appear earlier in females than in males. The

potential   to   develop   the   disease   persists

throughout life, though the skin may appear

normal,  so  children  may  develop  symptoms

before   these   appear   in   their   parents.   The

remaining 25%  develop  symptoms  in  their

mid-fifties.

The disease is less common among Asians,

Blacks and Eskimos, and is almost unknown in

Native Americans. The situation with Eskimos

has been taken as circumstantial evidence for an

important role of essential fatty acids, present in

fish oils, in maintaining epidermal integrity.

Clinical features and diagnosis

Onset of psoriasis is usually gradual. In classical

plaque   psoriasis  the  skin  lesions  are  well

defined, raised, reddish (‘salmon pink’), slightly

itchy plaques of tissue which are covered with

large amounts of loose, silvery scales (Plates 9

and 10),  surrounded  by  completely  normal-

looking skin. In dark-skinned people the under-

lying colour may be much darker, even purplish.

Acute attacks occur most often in childhood

and may be triggered by streptococcal tonsillitis.

They often start as evenly scattered small discoid

lesions (guttate  psoriasis) that tend to clear

spontaneously within 4 months. This is erythro-

dermic psoriasis  (see below). A few of these

patients   develop   chronic   disease   at   about

5-7 years  of  age,  when  it  occurs  as  large,

symmetrically  located  plaques,  e.g.  affecting

both knees or elbows, though it may spread to

affect 80% of the skin surface. The lesions some-

times heal spontaneously, starting in the centre,

and may thus be confused with ringworm.

In pustular psoriasis sterile, yellow pustules

occur, often at the edges of plaques in severe

disease, but sometimes associated with flexural

lesions. This form is often very resistant to treat-

ment and is potentially life-threatening if wide-

spread,   because   fluid   loss   and   temperature

control  are  compromised.  Chronic  brownish

pustules on the palms and soles are strongly

associated with smoking.

The  most  common  sites,  in  approximate

descending order of frequency, are the elbows,

knees, scalp, lower back, chest, face, abdomen

and genitalia: all areas exposed to mild trauma

from clothing and physical activity. Scalp psori-

asis (Plate 10) may easily be mistaken for severe

dandruff if mild, or for seborrhoeic dermatitis

(see  below).  Diagnostic  features  are  that  the

plaques on the scalp are raised, as on other areas,

and usually isolated, so the margins are palpable

and  well-defined:  the  lesions  tend  to  spread somewhat beyond the hair line.

The  course  of  the  disease  is  very  variable.

Psoriasis is normally a chronic, mildly irritant

condition. Some patients have a single episode

followed by complete and prolonged remission.

Otherwise  it  is  usually  non-progressive,  with

occasional unpredictable exacerbations. Severity

may either increase or decrease with time.

The  combination  of  ‘thimble’  nail  pitting,

distal interphalangeal (DIP) arthropathy and nail

discoloration (see below) is pathognomonic. If

the scales are scratched off, the underlying skin

is inflamed and they leave small bleeding points,

because the capillaries are near the surface. This

sign is very strongly suggestive for the condition.

Complications

The nails are affected, usually symmetrically, in about 25% of cases (Plate 8), usually in long-

standing   psoriasis.   They   show   thimble-like pitting and later thickening, ridging and separa-

tion from the nail bed (onycholysis). An orange to  brown  discoloration  of  the  distal  lateral margins of the nail bed is characteristic and may be mistaken for tobacco stains.

Joint pain, i.e. psoriatic arthropathy, occurs in

about 7% of patients. This tends to be asymmet-

rical, affecting the larger joints and the DIP finger

joints (see Chapter 12, Figure 8.5) adjacent to

affected nails. Psoriatic arthropathy is seronega-

tive (see Chapter 12) and may precede or follow

the skin changes. In contrast, RA usually spares

these joints and is characteristically symmetrical

and  seropositive (see  Chapter 12).  Psoriatic

arthropathy  occasionally  leads  to  severe  joint

damage and disability.

Erythrodermic  psoriasis  is  a  severe,  wide-

spread, inflammatory form of the disease. The

cause is usually unknown, but it may be trig-

gered  by  injudicious  treatment  with  potent

steroids. If the condition is extensive, serious

and possibly life-threatening hypothermia and

dehydration may result, because there may be a

loss of 90-95% of the normal horny layer. High-

output cardiac failure (see Chapter 4) may be

precipitated in patients with compensated heart

failure, owing to the extensive skin inflamma-

tion  and  consequent  increased  dermal  blood

flow.

Management

The two prime objectives are to:

•           Produce a complete clearing of the affected

areas: if this is attained, the disease-free inter-

vals between relapses are increased, even in very chronic conditions.

•           Reduce distress: if lesions are visible, the disfig-

urement is particularly distressing to juveniles

and young adults because it is interpreted by the lay public as a serious and highly infectious disease. However, it is benign except in its severest forms and is certainly not transmis-

sible. Thus, it is important to reduce stress and to reassure patients: a willingness to touch the plaques helps to convince the sufferers of the harmless nature of their condition.

The specific treatment aims are to:

•           Promote  normal  maturation  of  epidermal

cells, with vitamin D derivatives and retinoids.

•           Reduce epidermal cell turnover, using cyto-

toxic   or   cytostatic   agents,   e.g.   dithranol,

corticosteroids,   methotrexate,   phototherapy and retinoids.

•           Reduce  inflammation,  with  corticosteroids

and immunosuppressants.

•           Remove scale using keratolytics, e.g. salicylic

acid, coal tar.

•           Hydrate  the  skin  and  reduce  itch,  with

emollients.

While  this  treatment  classification  is  con-

venient,   there   is   an   inevitable   overlap

between  the  classes  of  drugs  used.  Cytotoxic

or cytostatic drugs are also anti-inflammatory,

e.g.   methotrexate,   and   corticosteroids   are

anti-inflammatory,   immunosuppressive   and

cytostatic.

Factors influencing treatment selection are:

•  Age.

•  Form of psoriasis, i.e. plaque, guttate, pustular

            or erythrodermic.

•  Site and extent (localized or generalized) of

            skin involvement.

Psoriasis           841

•  Prior successful and unsuccessful treatment. •  Concurrent disease, e.g. HIV.

Although the course of the disease is highly

unpredictable and relapses are common, modern

treatments may be very effective and so an opti-

mistic,  sympathetic  attitude  should  be  main-

tained. Mild psoriasis may need only the liberal

use of emollients and the patient should be reas-

sured that it is a benign condition. Many patients

will  need  long-term  maintenance  medication

with occasional intensive treatment for exacer-

bations.  However,  there  is  considerable  varia-

tion in response to different treatments, and in

one  patient  at  different  times  with  the  same

treatment.

Widespread unstable plaque psoriasis, and the guttate   or   erythrodermic   forms,   should   be managed by a dermatological consultant.

A general outline of treatment of psoriasis is

given  in  Table 13.14.  Careful  counselling  is

necessary  for  all  patients,  regardless  of  the

treatment  mode,  to  ensure  that  they  under-

stand  the  lifelong  nature  of  their  condition,

how  to  use  the  treatment,  the  side-effects  of

treatment, and what to do in an exacerbation

and if side-effects are troublesome. Carers and

family members need to be fully involved, to

ensure that they understand the problems and

to  apply  products  to  lesions  that  are  not

accessible to the patient.

Topical pharmacotherapy

Tar preparations, dithranol and salicylic acid have been used safely and successfully for many years, but have largely been replaced by the vitamin D analogues and retinoids, which do not smell or stain skin and clothing.

Promotion of normal cell maturation

Vitamin D analogues

Calcipotriol  (calcipotriene)   and   tacalcitol  are

vitamin   D   analogues   that   reduce   excessive

epidermal  cell  proliferation,  improve  cellular

differentiation and strongly inhibit T cell activa-

tion by interleukin-1. Unlike vitamin D itself,

these  agents  do  not  usually  affect  calcium

metabolism   significantly.   Nevertheless,   they

should be used cautiously in patients with disor-

ders  of  calcium  metabolism.  Caution  is  also

necessary in pregnancy and if they are used to

treat   patients   with   generalized   pustular   or

erythrodermic psoriasis, because the widespread

inflammation in these latter conditions allows

greater skin penetration, so they are more likely

to cause hypercalcaemia. Similarly, they should

not   be   used   under   occlusive   dressings.   In

common with most drugs, hepatic impairment

reduces   the   metabolism   of   the   vitamin   D

analogues and renal impairment reduces their

elimination, so patients with these conditions

are at greater risk of hypercalcaemia. Because the

ratio of skin surface to body weight is greater in

children, and their skin is thinner than in adults,

there is a greater risk of local reactions and

systemic absorption, and so of hypercalcaemia

and abnormal bone formation. They are unsuit-

able for use in young children.

They  are  as  effective  as  betamethasone  in

clearing mild to moderate plaque psoriasis. They

are less likely to cause skin irritation than other

forms of vitamin D, and seem to be relatively

free from significant side-effects, especially tacal-

citol, and are more acceptable to patients than

short-contact  dithranol (see  below).  However,

they should not be used for the more inflamma-

tory forms of psoriasis, nor during an inflamma-

tory exacerbation of otherwise stable disease,

because of the increased risk of systemic absorp-

tion. They may exacerbate the psoriasis, but this

is rare. It is important to wash the hands thor-

oughly after use, to avoid transfer to the eyes and

other sensitive areas.

Calcipotriol and tacalcitol are licensed in the UK

for treating any grade of plaque psoriasis, but

only if affecting not more than 35-40% of the skin surface. They should be used under the

supervision of a dermatological unit and treated areas should not be occluded, though this may be difficult to achieve.

Calcipotriol is available as a cream, ointment

and scalp lotion. The manufacturers advise liberal

application once or twice daily, avoiding the face.

However, the maximum weekly dose is limited to

5 mg of calcipotriol in adults, in any mixture of the

three  products.  Because  absorption  is  greater

through the scalp, the amounts of the scalp lotion

are less than those of the cream and ointment.

Suitable amounts in adolescents 12-18 years are

about 75% of the adult dose and this is reduced to

about 50% in children aged 6-12 years. It is not

recommended for use in younger children.

There is also a calcipotriol-betamethasone oint-

ment for use in adults only. The betamethasone is

present in a low concentration to minimize irri-

tation by the calcipotriol, but see the comments

on the use of corticosteroids in psoriasis below.

Calcitriol (1, 25-dihydroxycholecalciferol) is an

active form of vitamin D that is licensed for use

in mild to moderate plaque psoriasis. Because of

its greater potency it is more likely than the

products described above to cause side-effects,

but the ointment has a much lower concentra-

tion of drug than is used with calcipotriol. The

maximum dose of the ointment equates to about

one tenth of the weekly dose of calcipotriol. It

should be used with caution in hepatic or renal

impairment and in pregnancy and breastfeeding.

Tacalcitol  ointment is used similarly to the

calcitriol product, but is applied once daily at

night, avoiding the eyes (maximum 10 g daily

because of its greater potency). If used with UV

radiation (see below), the UV exposure should be

given in the morning and the tacalcitol ointment

applied at night.

All vitamin D analogues may cause hypercal-

caemia, so they should not be used if there is any abnormality of calcium metabolism, nor if there is sufficient inflammation or skin damage to

permit excessive absorption of the drug. They must be used with caution in pregnancy.

Retinoids

Tazarotene is used for the topical treatment of

mild to moderate plaque psoriasis affecting up to

Psoriasis           843

10% of the skin surface (see Table 13.7) in adults

(over 18 years). There are insufficient data on the

treatment of younger patients and larger areas.

This topical drug reduces basal cell hyperplasia via RAR-alpha binding and promotes normal

basal cell maturation and progression to granular cells. Improvement may be seen within a week and a good response occurs in 65% of patients after 12 weeks. The benefit may be maintained for at least 12 weeks after stopping, so pulsed treatment may be appropriate.

As with other retinoids (p.  835), tazarotene

must be used with great care and is suitable

primarily for the non-intertriginous areas of the

trunk and limbs, provided that the skin is not

inflamed, eczematous or covered with hair. In

hairy areas, skin penetration is enhanced via the

hair follicles. Exposure to the sun, UV light or

solaria  must  be  strictly  limited.  Other  pre-

cautions  include  washing  hands  immediately

after use, avoidance of contact with the eyes,

face, scalp and eczematous or inflamed skin.

Pregnancy   and   breastfeeding   are   absolute

contra-indications, because of teratogenicity.

The  common  side-effects,  which  occur  in

10-20% of patients, are skin irritation, erythema,

burning, contact dermatitis, skin pain and wors-

ening of psoriasis, and are related to concentra-

tion and duration of treatment. If severe, these

should be managed by cessation of therapy and

use of emollients. Irritation can be avoided by

applying the ointment sparingly and carefully to

the plaques only, avoiding unaffected skin, and

emollients and cosmetics should not be applied

within one hour of product application.

Tazarotene is unsuitable for treating pustular and erythrodermic psoriasis.

Keratolytics, antipruritics and skin hydration

Salicylic acid

Creams and ointments containing 2% of salicylic acid are used primarily as mild keratolytic agents to remove excessive skin scales. It also helps to stabilize dithranol and can be used to remove dithranol staining (see below).

Coal tar

This   has   mild   keratolytic,   antimitotic   and

antipruritic  actions  and  is  thus  effective  only in  mild  cases.  Although  tar  is  a  recognized

carcinogen, there are no reports of associated

skin tumours over more than 40 years of phar-

maceutical use. The crude forms of tar are more

effective than refined ones, especially as anti-

pruritics,  but  the  latter  and  the  numerous

commercial  preparations  are  more  acceptable

cosmetically and cause less staining. Coal tar is

used in the form of creams, ointments, pastes,

lotions  and  bath  emollients  in  a  range  of

concentrations,  often  prepared  from  coal  tar

solutions. Some older tar preparations may be

unsuitable for use on the scalp or face where

they may be irritant or cause folliculitis, and

specially formulated commercial shampoos are

available. Tar preparations should not be applied

to infected areas.

Coal tar is sometimes combined with salicylic

acid  or hydrocortisone, adding additional kera-

tolytic and anti-inflammatory effects. It may also

be used with UVB radiation (see also PUVA,

below), when it presumably acts as a skin sensi-

tizer.  Coal  tar  and  salicylic  acid  ointment  has

been used for many years. Because this is cosmet-

ically unattractive and difficult to prepare, it has

largely been replaced by commercial products.

Propylene  glycol  (50%  aqueous  solution)  is

also mildly keratolytic. Further information on

emollients  and  antipruritics  is  given  above

(p. 830).

Reducing cell turnover

Dithranol (anthralin)

This is a synthetic agent that has been a main-

stay of psoriasis treatment for over 80 years.

Although effective, it is now giving way to less irritant and more cosmetically acceptable drugs, e.g. the vitamin D analogues.

Its mode of action is not known precisely, but

dithranol inhibits thymidine incorporation into

DNA, mitochondrial DNA replication and repair,

and ATP supply in epidermal cells. It also uncou-

ples oxidative phosphorylation. The combined

effects of these leads to inhibition of cell growth.

The principal side-effects are a local burning

sensation, discomfort, soreness and moistness,

which may need discontinuation of treatment.

Contra-indications to dithranol treatment are

spreading of a lesion which is anything other

than gradual and it must not be used immediately following topical steroids.

If reactions occur, a bland emollient prepara-

tion, should be used for 14 days before recom-

mencing treatment with a lower concentration of

dithranol and building up slowly once more to the

highest  tolerated  concentration.  A  moderate-

potency corticosteroid, e.g. betamethasone valerate

0.025% cream, may be used for dithranol burns.

Reactions following corticosteroid use (p. 834) are

similarly managed with weaning and emollients.

Major problems with dithranol are that it is

very irritant and chemically unstable, so the

extemporaneous preparation of pastes and oint-

ments   is   unwise.   Further,   without   suitable

milling equipment it is difficult to prepare the

very fine dispersions that are required for low

irritancy, though hospital manufacturing units

are usually suitably equipped. Poor dispersions

result in highly localized irritation from large

particles. Production staff must be made aware

of the hazards involved in handling dithranol

powder, especially if it gets into the eyes. They

must wear suitable protective clothing and wash

thoroughly after use.

Dithranol  is  readily  oxidized  to  brown  or

purplish  pigments,  especially  under  alkaline

conditions, which stain skin and fabrics and are

difficult to remove. Salicylic acid has been used

for  stain  removal.  This  chemical  instability

means that concentrations less than 0.05% are

not normally practicable, due to significant loss

of potency. The triacetate ester is more stable,

because the hydroxyl groups are protected by

esterification,  the  ester  being  hydrolysed  to

dithranol in the skin. The ester is used occasion-

ally, being less irritant than dithranol but also less

active.

Commercial products provide well-formulated,

stable  preparations  that  are  cosmetically  very

acceptable to patients. This has the additional

benefit of encouraging patient compliance, thus

improving control and hastening the response.

Phototherapy

Both natural (sunlight) and artificial UV radiation

may be beneficial and are often used after tar or

psoralen   baths.   UVB,   i.e.   short   wavelength,

290-320 nm radiation, responsible for sunburn, is

used either alone or with emollients as required.

Alternatively  UVA,  i.e.  longer  wavelength, 320-365 nm, is used with a psoralen: this is

photochemotherapy (PUVA).

Once the lesions have cleared, mild UV expo-

sure may prolong the period of remission, but

over-exposure and burning must be avoided.

Patients are usually tested for UV sensitivity by

graduated  exposure.  Although  sunlight  helps

some patients it may trigger attacks in others.

Further, hot climates often exacerbate the condi-

tion because sweating readily leads to skin macer-

ation. The procedure aggravates erythrodermic

and pustular disease.

Anti-inflammatory treatment

Corticosteroids  are  potent  anti-inflammatory

agents and have cytostatic effects that reduce cell

proliferation in the basal layer, but they have

only a limited role in the treatment of psoriasis.

Although there is an inflammatory element in

psoriasis, and potent steroids may produce a

dramatically rapid symptomatic improvement,

there may be a substantial rebound effect on

withdrawal and subsequent difficulties in treat-

ment. If used as a first-line treatment, cortico-

steroids may so modify symptoms as to make a

definitive diagnosis very difficult. If rebound

occurs  there  may  need  to  be  a  prolonged

weaning period, using progressively less potent

preparations and finally an emollient. This may

take from 4-8 weeks, depending on the severity

of the symptoms, during which time dithranol

must not be used.

However, a low- or medium-potency product

with low toxicity, e.g. hydrocortisone or clobetasone

butyrate creams, are useful under careful supervi-

sion on sensitive sites such as the flexures, ears,

face and genital areas, where many other agents

are too irritant. Treatment should be short-term

and  more  potent  products  avoided,  because

permanent skin damage may occur rapidly. Scalp

lotions may also be useful for short-term treat-

ment if coal tar or coal tar-salicylic acid shampoos

are  ineffective,  or  if  the  scalp  preparations

referred to above are not cosmetically acceptable.

There  are  combined  preparations  in  which

coal tar is occasionally combined with dithranol

(anthralin).  However,  they  are  incompatible:

the dithranol reacts with tar bases and undergoes

Psoriasis           845

a  rapid  free  radical  oxidation.  Nonetheless,

there  is  one  commercial  tar  ointment  that

contains  both  dithranol  and  salicylic  acid:

presumably,  the  dithranol  is  protected  by  the

non-aqueous environment and the salicylic acid.

Topical treatment modes

Scale removal

If the scaling is very thick, e.g. on the elbows and

knees, it will hinder the penetration of drugs, so

it may be helpful initially to remove excess scale

by using 2% salicylic acid ointment on its own

for a week or so. Propylene glycol is also used.

Coal tar

Provided that the psoriasis is mild and not too

extensive, a correspondingly mild therapeutic

approach is appropriate. Ointments or creams

containing coal tar may be used, in association

with tar baths, until the lesions have cleared.

Treatment should be started with the weaker

preparations, probably those including salicylic

acid to help remove excess scale. However, the

vitamin D analogues are simpler to use and

cosmetically more acceptable than coal tar, but

are considerably more expensive and are POM

products. Tar preparations are available OTC, but

the formulary products are increasingly difficult

to obtain.

Scaling on the scalp may be especially thick, so

this area can be treated with the coal tar and sali-

cylic acid ointment, which may be applied once or

twice daily, usually for 1 h and shampooed out.

This is very greasy and many patients do not

find  this  cosmetically  acceptable.  A  similar

commercial product (Cocois) is available OTC

and is used daily initially, if the scaling is severe,

and is then used once weekly. These treatments

are unsuitable for young children and children

6-12  years  using  this  should  be  supervised

medically. The commercial coal tar shampoos are

also  very  useful.  Calcipotriol  scalp  solution  is

cosmetically more acceptable, but is not recom-

mended for children under 12 and there is a

restricted total weekly dose (see above).

The Goeckerman regimen involves the use

of  topical  tar  preparations,  especially  baths,

followed by UVB radiation. Coal tar may also be

used in conjunction with dithranol (the Ingram regimen, see below), though retinoids are prob-

ably the single agent of choice for most patients.

Dithranol

Dithranol has often been used as a first choice, with excellent results, especially if the condition is mild to moderate. It is also used if coal tar

treatment has not been successful.

The older preparations were rather messy oint-

ments or, for more severe cases, consisted of

dithranol  in Lassar’s paste. The purpose of the

latter is to provide a stiff vehicle that prevents

dithranol spreading from the site of application

onto surrounding skin, because it stains and irri-

tates normal skin. This formulation also contains

salicylic  acid,  which  helps  to  minimize  oxida-

tion  of  the  dithranol.  The  dithranol  concentra-

tion  used  normally  varies  between 0.1%  and

0.5%,  depending  on  the  tolerance  of  the

patient’s skin (fair skins are more sensitive) and

the  response.  Although  concentrations  in  the

range 0.05% to 4%, even up to 10%, have been

used, the higher concentrations require inpatient

day  care  management,  at  least  initially.

The paste is applied precisely to the areas of

the lesions, usually by a trained nurse using a

spatula. Treatment commences with the lowest

concentration and the contact time is increased

every 3-4 days  if  there  is  a  response  and

there are no significant side-effects. If a response

is not obtained, a higher strength is used. The

approach is to find the contact time/strength

balance   that   gives   a   satisfactory   response

without burning the skin.

This  procedure  normally  produces  some

response  within 1 week,  and  many  patients

will  be  completely  clear,  i.e.  no  palpable

lesions,  in 2-3 weeks,  though  chronic  cases

may  take 6 weeks.  The  purple-brown  skin

staining that develops indicates that the lesions

are  responding  to  the  medication.  This  does

not require treatment because it usually clears

spontaneously  within  a  further 2 weeks,  to

leave ‘normal’ skin, though the psoriatic poten-

tial  remains.  Patients  need  to  be  counselled

about  this.  Dithranol  products  are  generally

unsuitable for application to sensitive areas, i.e.

the  face,  ears,  flexures  and  near  the  genitalia

(but see below). These areas are often treated

with steroid creams, with or without coal tar.

Clearly, pastes are unsuitable for application to the hair.

The  Ingram  regimen  is  a  common  proce-

dure often used in severe cases as an intensive inpatient routine. It involves:

•  Initial patch testing with 0.1% dithranol in

            Lassar’s paste, to determine skin tolerance.

•  Soaking in a bath containing coal tar (coal tar

solution   or   a   commercial   equivalent)   to remove scale and sensitize the lesions.

•  Exposure to UVB radiation to give a slight

erythema, i.e. a dose that mildly damages the basal layer.

•  Application of dithranol in Lassar’s paste at the

            desired   concentration,   leaving   for    24 h,

removing with oil and bathing as before. The paste is normally powdered over with talc and covered with a tubular bandage. A top-up

may be necessary after 8-12 h.

Dithranol creams are more acceptable cosmet-

ically than pastes or ointments and are gener-

ally less irritant, though they act more slowly.

They are more suitable for use by patients at

home and can be used on the scalp. Because the

scalp skin is very thin and sensitive, all products

used  there  have  a  limited  contact  time.  The

product has to be washed of with copious warm

water  and  soap  must  not  be  used  because  it

enhances skin penetration.

Intensive short contact time regimens have

been the major advance in dithranol treatment,

i.e. ‘30-minute  therapy’,  rather  than  the  24 h

of  the  Ingram  regimen.  These  involve  the

application  of  higher  concentration  dithranol

creams  before  bathing  at  night.  This  has

proved  to  be  similarly  effective  to  conven-

tional treatment, though the lesions may take

slightly  longer  to  clear,  up  to  one  month  as

against 3 weeks. However, there are substantial

advantages:

•  Less interference with the patient’s life.

•  Better patient acceptability and compliance.

•  No need for hospital inpatient or day care

treatment.

•  Less staining of clothes and bed linen.

Higher concentrations of dithranol have been

introduced in commercial preparations to suit

the short contact time approach, with up to 2%

being used in the community. Concentrations up to 8% are sometimes used in hospital.

The lower-strength creams are also suitable for

application to delicate areas such as the flexures,

provided that no burning or undue local reaction

occurs. Shorter contact times may be preferred

here. The apparently normal skin at scalp margins

and behind the ears must be avoided, because it is

very sensitive. Concentrations other than those

prepared by the manufacturers are sometimes

requested by prescribers, but commercial prepa-

rations should not be diluted without careful

inquiry because the precise formulation may be

critical. Rather than attempt extemporaneous

preparation  it  is  preferable  to  use  a  weaker

preparation for a longer contact time or a more

concentrated one for a shorter time, depending

on patient tolerance.

Phototherapies

PUVA treatment is used for widespread involve-

ment of the trunk. This involves treating the

patient with methoxsalen (8-methoxypsoralen), a phytochemical photosensitizing agent. Patients bathe in a solution of the drug before irradiation in a cabinet with a bank of UVA tubes; alterna-

tively an oral dose is taken 2 h before UVA irra-

diation. Higher UV doses (longer exposure times) are more effective than lower ones, but cause

increased side-effects (see below).

This  approach  is  more  effective  than  the

Ingram    regimen.    Trioxysalen            (trioxsalen,

4,5 , 8-methoxypsoralen) is a similar drug that is

not licensed in the UK but is used in North

America.

Dark goggles should be worn during the treat-

ment and for a further 8 h, to minimize the risk of cataract formation.

Combination treatment with a retinoid (Re-

PUVA) has been used for resistant psoriasis, and

is probably the most effective modality. However,

the UVA dose must be very carefully controlled.

Many patients will experience long periods of

remission with PUVA regimens. The methods are

technically simple and can readily be used on an

outpatient basis, usually twice weekly for about

5 weeks. They are liked by patients because they avoid the use of messy topical products.

Some  patients  experience  nausea  and  head-

aches, and burns may occur, even with careful

Psoriasis           847

calculation of the UV dose. In the long term,

there  is  premature  skin  ageing  and  a  slightly

increased  risk  of  skin  malignancies,  especially

squamous cell carcinoma, so patients under 40

should not be treated unless other approaches are

ineffective. Most consultants use PUVA routinely,

though it is usually confined to specialist centres

in the UK.

Narrow band UVB phototherapy appears to be as effective as PUVA and avoids the need for psoralens.

Systemic pharmacotherapy

Acitretin

This retinoid, a metabolite of etretinate (p. 837),

is the only member of this group licensed in the

UK for the systemic treatment of severe psoriasis

unresponsive to other treatments. It is especially

useful for pustular disease. Because of its toxicity,

acitretin is reserved for use under the supervision

of hospital consultants. Acitretin interacts with

both RAR alpha and RAR gamma receptors (see

above).

There is considerable interpatient variation in

absorption and metabolism, so the dose must

be individualized for each patient. Acitretin  is

usually given with other treatments and is some-

times given in one year cycles comprising nine

months of treatment followed by a three month

rest period. Some dermatologists use the drug in

low dosage as an adjunct to dithranol or PUVA

treatments, if these give inadequate control.

Mucocutaneous  side-effects  of  acitretin  are

common, e.g. dryness of the skin, cracked lips

and dry eyes. Generalized pruritus, nail prob-

lems, nosebleeds and hepatotoxicity may occur,

as  does  slight  transient  alopecia.  Acitretin  can

cause a rise in plasma lipids and serum triglyc-

erides, and may exacerbate diabetes mellitus, so

they must be monitored regularly. Concurrent

use   with   vitamin   A,   tetracyclines   and

methotrexate must be avoided, because of cumu-

lative toxicity. Because acitretin is highly terato-

genic,   meticulous   contraception   must   be

initiated  for 1 month  before  treatment  and

maintained throughout, and for at least 2 years

after stopping treatment. Those taking acitretin

must not donate blood for 1 year after treatment

cessation  because  of  the  possibility  of  terato-

genicity  in  pregnant  recipients.  Hepatic  and renal impairment are other contra-indications. The drug is rarely used in children because it

may cause growth impairment, due to prema-

ture closure of the epiphyses, the growth plates at the ends of the bones.

There is a long list of other side-effects and precautions and the BNF and the manufacturer’s literature should be consulted.

Immunosuppressants, immunomodulators and cytotoxics

These potentially very toxic agents are used in

psoriasis in lower doses than are used to treat

neoplastic disease (see Chapter 10) and to prevent

rejection of organ transplants (see Chapter 14).

Because skin diseases are rarely life-threatening

there must be careful individualized evaluation of

the risk-benefit balance before these drugs are

prescribed.

Methotrexate

Methotrexate is a very effective antifolate agent but is reserved for the treatment of severe exacer-

bations or intractable cases because of poten-

tially serious side-effects. Methotrexate must be used extremely carefully in the elderly, is unsuit-

able for children, and is therefore restricted to use by specialists only.

In psoriasis, methotrexate is usually given orally in low dosage, i.e. 10-25 mg once weekly. This dosage frequency must be strictly adhered to: there have been serious blood dyscrasias, liver cirrhosis and even death, with more frequent

dosing. The UK’s CSM has advised that:

•  A full blood count and renal and liver func-

            tion tests be carried out before starting treat-

ment, and repeated weekly until therapy is

stabilized. Patients should then be monitored carefully every 2-3 months.

•  Patients should be told to report all symptoms

            and   events   occurring   during   treatment,

especially sore throat.

Blood  dyscrasias  may  occur  abruptly  and

calcium folinate rescue (see Chapter 10) may be

required. Abnormal liver function tests are a

contra-indication to starting or continuing treat-

ment, and liver biopsies should be taken if liver

function tests (see Chapter 3) fail to return to

normal after stopping methotrexate treatment.

Renal function tests (see Chapter 14) are also required because methotrexate is nephrotoxic and accumulates in renal failure.

Analgesics reduce the excretion of methotrexate

and death has occurred with concurrent use of

NSAIDs, so such combinations are preferably

avoided in psoriatic arthropathy and patients

warned  about  the  risks  of  self-medication

with products containing NSAIDs. This is not

an absolute contra-indication, but special care

is  needed  if  a  patient  needs  analgesic  anti-

inflammatory  treatment.  Other  drugs  which

may   increase   toxicity   include   penicillins,

phenytoin,   pyrimethamine        (antimalarial)   and

trimethoprim (another antifolate agent).

Methotrexate  is teratogenic and is absolutely contra-indicated   in   pregnancy   and   during breastfeeding. Conception should be avoided for at least 6 months after use in either sex.

Hydroxycarbamide (0.5-1 g daily) has been used in patients who are intolerant of methotrexate or in whom the latter is contra-indicated, but it is also myelosuppressive.

Ciclosporin

This  is  a  calcineurin  inhibitor  that  was  origi-

nally introduced to prevent rejection of kidney

transplants (see Chapter 14). It has been used

for   the   treatment   of   psoriasis         (low-dose;

2.5 mg/kg daily, rising to 5 mg/kg daily) unre-

sponsive to other treatments, and a very high

proportion of patients respond. It is also very

useful for erythrodermic disease.

However,  the  renal  toxicity  of  ciclosporin

means  that  it  should  only  be  used  under

expert supervision and patients must be moni-

tored  for  renal  function  and  hypertension.

Exposure  to  UV  radiation,  e.g.  UVB  or  PUVA

(see above), and excessive exposure to sunlight

should be avoided. Its potent immunosuppres-

sant effects mean that special care is required

if infections or neoplastic disease are present,

or  possible,  and  no  alternative  treatment  is

suitable.

The  antirheumatoid  drug,  leflunomide  (see Chapter 12),  is  also  used  for  treating  active psoriatic arthritis (see Chapter 12).

Biological agents

Efalizumab, etanercept and infliximab are licensed

for use in psoriasis. Efalizumab is a monoclonal

antibody that inhibits T cell activation and so

the production of pro-inflammatory cytokines

(see Chapter 2). It is licensed for the treatment

of moderate to severe chronic plaque psoriasis,

in  patients  who  have  not  responded  to  at

least two other systemic treatments and photo-

chemotherapy (PUVA), or who are intolerant of

such therapy. It is given weekly by SC injection.

Side-effects include exacerbation of psoriasis

and the possible development of other forms,

e.g. psoriatic arthritis, and if this occurs treat-

ment must be stopped. Treatment should also be

stopped if there is no response after 12 weeks.

Other side-effects are influenza-like symptoms,

joint pain, leucocytosis and, more rarely, throm-

bocytopenia and injection-site reactions. These

reactions make it unsuitable for treating children

and adolescents, but these rarely suffer psoriasis.

It should be used with caution in hepatic or

renal  impairment  and  in  patients  with  low

platelet counts. The latter should be checked

before treatment commences, then monthly for

three months and, if the condition responds,

three monthly.

Contra-indications    include    immunodefi-

ciency, severe infections, active TB, a history of

neoplastic disease, pregnancy and breastfeeding.

The TNFa  antagonists  etanercept  and inflix-

imab have evidence of benefit and have been

used to treat moderate to severe chronic plaque

psoriasis. These are also licensed for psoriatic

arthritis (see  Chapters 2  and 12).  They  are

contra-indicated  in  pregnancy  and  in  breast-

feeding  women.  They  should  be  used  with

caution in immunosuppressed individuals, in

those   exposed   to   varicella-zoster   infection,

patients with a history of cardiovascular disor-

ders, ischaemic syndromes, renal impairment,

seizures, demyelinating diseases, e.g. multiple

sclerosis and Guillain-Barré syndrome, dyspnoea

and bone fracture.

Further information on the biological agents is given in Chapter 12.

Antipruritics

Oral  antihistamines  are  occasionally  used  if

itching is troublesome, the sedating side-effects

Eczema and dermatitis  849

of the older drugs being useful at night. Anxi-

olytics may also be useful in some patients to

relieve associated stress and anxiety, so hydrox-

yzine, which has sedative, anxiolytic and antihis-

taminic properties, is often used. However, the

most effective approach is adequate counselling

and reassurance and effective treatment of the

psoriasis.

Other treatments

Corticosteroids   are   sometimes   injected   into lesions, to control chronic plaques resistant to other treatments.

Experimental treatments

There is limited evidence that dimethylfumaric

acid and monoethylfumaric acid improve chronic

plaque psoriasis, but there was a high rate of

withdrawal due to flushing and gastrointestinal

effects. There is no evidence on their suitability

for long-term maintenance treatment, so routine

use of these agents requires further evidence of

efficacy and safety.

Improvements in psoriasis have been reported

in patients treated with IFN alfa and the anti-

arrhythmic drug amiodarone. The somatostatin

analogue,   octreotide,   also   has   anti-psoriatic

activity,    possibly    because    the    increased

epidermal cell growth is influenced by human

growth hormone. However, it is too early to say

whether any of these will find a place in routine

therapy.

Treatments combining two of the widely used modalities described earlier have been used, but there  is  insufficient  evidence  to  justify  their routine use. There are likely to be increased side-

effects due to a summation of the side-effects of the regimens used.

Rarely, surgical removal of troublesome plaques has been used and has produced a local cure.

Eczema and dermatitis

Definition and classification

Eczema  is   an   inflammatory,   highly   itchy, usually chronic, eruption of the epidermis and outer dermal layers.

The terms eczema and dermatitis are often

used  synonymously,  but  it  has  been  conven-

tional  to  use  the  term  dermatitis  to  describe

skin  reactions  due  to  external  agents,  and

eczema for reactions to endogenous factors in

atopic individuals. However, this is an artificial

distinction because in many of these conditions

there  is  an  interaction  between  genetic  and

environmental factors. Current British practice

tends to use the term dermatitis plus a quali-

fying adjective, e.g. atopic dermatitis and sebor-

rhoeic dermatitis. A classification and some of

the  characteristics  of  dermatitis  are  given  in

Figure 13.6.

This group of diseases comprises the largest single group seen in skin clinics and is respon-

sible for about 25% of all dermatological referrals to consultants.

Aetiology and pathology

Essential fatty acid metabolism

An interesting discovery has been that essential

fatty acids (EFAs) are important in the mainten-

ance of epidermal integrity (an example of their

nomenclature is arachidonic acid, which is a

20:4n-6 acid, i.e. it consists of a 20-carbon chain

with four double bonds, the first of which links

carbons 6-7). The composition of the plasma

phospholipids   is   significantly   changed   in

patients with atopic dermatitis compared with

controls,  the  level  of  cis-linoleic  acid  being

increased,   whereas   those   of   its   metabolites

(including  arachidonic  acid)  are  substantially

reduced.  Because  linoleic  acid  is  the  major

dietary  n-6-EFA,  this  points  to  a  metabolic

defect, probably a reduced activity of delta-6-

desaturase. This enzyme converts linoleic acid to

gamma-linolenic acid, a rate-limiting step. There

is also a reduction of alpha-linoleic acid metabo-

lite concentrations in atopic respiratory disease

and   the   same   enzyme   may   be   involved.

However, the oral administration of linoleic acid

and gamolenic acid in the form of evening prim-

rose oil is not regarded as beneficial, but this is

available as an emollient cream via the UK NHS.

Modification of n-3 metabolite levels would

require  the  administration  of  fish  oils,  and

circumstantial evidence from the study of Eskimo

populations indicates that this may be beneficial

in some skin diseases, notably psoriasis. However,

it is likely that the benefit of halibut liver oil is

due to its vitamin A content, which is important

for epidermal maturation (see retinoids; p. 835).

Because abnormal levels of serum fatty acids have also been observed in patients with allergic respiratory   disease   it   seems   possible   that abnormal  fatty  acid  metabolism  is  a  funda-

mental feature of atopy, though whether this is a cause or effect remains to be elucidated.

Reactions to environmental agents

Dermatitis is inflammation of the epidermis.

Contact (irritant, toxic) dermatitis is usually

the result of mechanical or chemical disruption

of the horny layer of the skin. Sensitivity varies

greatly, and dermatitis is more likely in individ-

Eczema and dermatitis  851

uals with an excessively dry skin, in the elderly,

and after childbirth. Atopic subjects have drier

skin than normal, even if there is no active

dermatitis. However, almost anyone can develop

this form of dermatitis if the insult is sufficiently

severe or prolonged. An indication of a tendency

to develop such reactions is given by the pres-

ence of thin dry skin showing numerous fine

furrows on the palms and palmar surfaces of the

fingers (hyperlinearity, Plate 11), which is a mild

reaction to chronic irritants.

In some patients there is a more severe reac-

tion, with erythema, severe irritation, swelling,

vesicle formation and exudation. This may be

due to allergic dermatitis (Plate 12, Figure 13.6),

in which external agents penetrate the horny

layer through minute abrasions or the hair folli-

cles and ducts of the sweat glands. This skin

penetration may be allowed by low levels of IgA

(surface-protective  antibody;  Chapter 2).  The

allergens bind to antigen-presenting Langerhans

cells in the middle layer of the epidermis, which

then migrate to the local lymph nodes and acti-

vate T cells. Because these activated TH2 cells

migrate to all areas of the body via the blood, the

entire skin surface becomes sensitive. After a

very variable period (days to years), and usually

after repeated reinforcement, subsequent contact

with the same agent elicits a type IV (delayed)

hypersensitivity reaction that may take 24-72 h

to develop (see Chapter 2).

Almost any substance can sensitize the skin, but the most common agents include:

•  Irritants:

-  Soaps   and   detergents,   the   commonest

            cause of hand dermatitis.

-  Plants: e.g. Compositae, primulas.

-  Solvents, e.g. lubricating oils and petrol,

which remove protective lipids and may contain irritant additives.

-  Plasticizers  in  rubber  and  plastics,  e.g.

            rubber gloves.

•  Allergens and haptens (see Chapter 2):

            -  Dyes: e.g. hair dyes and in clothing and

shoes.

-  Fragrances and preservatives, now included

            widely in household products.

-  Medicines: e.g. antibiotics, topical antihist-

            amines and anaesthetics, wool alcohols,

preservatives and antioxidants and some corticosteroids.

•  Metals: e.g. nickel, chromium and cobalt, e.g.

            in jewellery.

Endogenous reactions

In atopic eczema (Figure 13.6) there is a skin

reaction  to  presumed  systemic  antigens.  This

occurs only in genetically predisposed (atopic)

subjects  and  is  associated  with  a  personal  or

family  history  of  atopy,  i.e.  allergic  rhinitis

(perennial or seasonal), asthma and, occasionally,

urticaria and migraine. It has been estimated that

some 10% of the population is susceptible to this

form of dermatitis, though only about half of

these  actually  develop  the  skin  reaction.  The

fundamental mechanism appears to be a reduced

T-suppressor cell activity, and levels of circulating

IgE may be increased 10-fold. This results in a

type I (immediate type) hypersensitivity reaction

when  the  antigen  is  encountered.  Levels  of

surface-protective antibody (IgA) are low, and

this may account for the ability of allergenic

substances to penetrate mucous membranes and

produce systemic sensitization.

It is possible that in skin carriers of Staphylo-

coccus aureus the bacteria produce superantigens that activate large numbers of T cells and so

cause the widespread release of inflammatory cytokines and excessive IgE production.

About 10% of sufferers also have a tendency to

develop chronic lichen  simplex. This causes

well-defined  areas  of  dry,  roughened,  itchy,

hyperpigmented skin. The problem starts with

attacks of itching provoked by minor stimuli.

Scratching causes lichenification and the area

becomes very liable to itch, thus provoking a

reflex itch-scratch-itch cycle, often leading to

excoriation. Infection of the damaged skin is

then common. The back of the neck, legs, outer

forearms, groin, anal and genital areas are most

frequently involved.

Food allergies are commonly blamed, though

these are far less common than is popularly

believed.  Such  allergies  cannot  be  tested  for

simply, so the only approach is the use of a rigid,

often unacceptable, exclusion diet with gradual

replacement of individual foods or food compo-

nents.  This  requires  dedicated  persistence  by

clinician, nutritionist and patient over a long

period. Breastfeeding reduces the incidence of the disease, though it is unclear whether this

results from the delayed introduction of artificial foods or is a consequence of the protective effect of maternal antibodies.

Clinical features

Contact and allergic dermatitis

The affected area is always itchy and there may be anything from mild inflammation to severe swelling and vesiculation. In contact dermatitis (Plate 11) the reaction is initially confined to the area exposed to the damaging agent, but limited local spread may occur. With chronic insult the horny layer disintegrates and the skin becomes thickened, dry and scaly. This leads to loss of the water-retaining property of the skin.

In   allergic   dermatitis   the   reaction   is

initially similarly confined to the contact area and is sharply demarcated (Plate 12), but the

reaction may spread widely from the original

site, especially in the chronic condition.

Continuing exposure, excoriation or infection

may result in the establishment of a chronic state

in  both  conditions,  which  are  very  common.

They affect 10-20% of occupationally exposed

workers, and occur in twice as many women as

men.

Atopic eczema

This  is  a  genetically  determined  allergic  skin

condition that often starts in the first year of life

(about 75% of cases; Plate 13), usually in the third

or fourth months. However, it may appear for the

first time in older children or adults. In infants it

usually  affects  the  face,  scalp  and  extensor

surfaces of the limbs, but in later years it may

become more localized and chronic (Plate 14).

Lesions always itch, often severely. The course is

unpredictable, with occasional or frequent exacer-

bations and remissions up to 30-40 years of age,

or sometimes throughout life, because atopy is

determined genetically. In about 50% of children

there is a slow improvement throughout child-

hood,  with  complete  remission  by  puberty.

There is usually a personal or family history of hay fever, urticaria (see below) or asthma, i.e. other  forms  of  atopy.  In  some  unfortunate individuals all four conditions may coexist.

Older children and adults often have localized, cracked areas in the flexures behind the knees, elbows, on the eyelids, neck and wrists. The skin tends  to  be  very  dry  in  most  patients,  and scratching may lead to chronic lichen simplex, i.e. thickened, rough skin confined to areas of scratching, and infection. Severe scratching leads to   weeping   lesions (excoriation),   frequently aggravated by bacterial infection.

The condition follows a relapsing/remitting

course and infantile eczema tends to clear in

3-5 years and a small proportion may recover

within 18 months. Exacerbations may be caused

by primary irritants, stress, climatic changes and

clothing, especially wool. There is an increased

susceptibility to skin infections, notably warts

and   dermatomycoses,   and   herpes   simplex

infections may cause serious generalized illness.

Long-standing sufferers tend to develop cataracts

in early adult life.

Seborrhoeic dermatitis (seborrhoeic eczema)

This is an acute or chronic eruption that princi-

pally affects the scalp, face and the skin over the

sternum and between the shoulder blades, i.e. the

areas with large numbers of sebaceous glands. It

may also affect intertriginous areas, i.e. armpits,

navel, groin and below the breasts. Despite its

name, there is no clear association with sebum

flow. This is a genetically determined condition

that predisposes the skin to respond with sebor-

rhoeic  reactions  to  almost  any  form  of  skin

damage.

It occurs in two quite distinct age groups. In infants this occurs as cradle cap (Plate 15), with thick, yellowish, encrusted lesions on the scalp and a papular, red eruption of the face. It may also affect the napkin area.

The adult form appears to be unrelated to the

infantile  one.  Onset  is  gradual  with  grey  to

yellowish scaly lesions and dandruff. It may be

otherwise asymptomatic, though there is often a

varying degree of itch. The rash occurs mainly on

the trunk, but in severe cases the perinasal area,

hair line, similar to Plate 10, and sternal area may

Eczema and dermatitis  853

be affected. Facial lesions mostly occur in men. Very  rarely  the  condition  may  become  more generalized and this form has been ascribed to poor diet and hygiene. Eruptions may be associ-

ated with upper respiratory tract and pyogenic infections (see Chapter 8).

Seborrhoeic dermatitis can be distinguished

from atopic eczema in difficult cases because IgE

levels and the RAST test are usually normal in

seborrhoeic  dermatitis  and  raised  in  atopic

eczema.

Dandruff is a mild form, associated with colo-

nization   with   the   yeast   Pityrosporum (Pity-

rosporon) ovale, though whether this is causative or is an opportunistic invader of damaged skin is unclear. However, eradication of the yeast

improves the condition.

Discoid (nummular) eczema

In this relatively uncommon condition, chronic, widespread discoid lesions occur, consisting of confluent vesicles, which ooze and crust. Lesions are more common on the extensor aspects of the arms and legs and on the buttocks.

Pompholyx

This is sometimes called dishydrotic dermatitis or

vesicular  palmar  eczema.  As  the  latter  name

implies, the condition has a restricted skin distri-

bution, affecting only the hands (80%) and feet,

primarily the palms, sides of the fingers and

soles. The term ‘dishydrotic’ is misleading because

there  is  no  abnormality  of  the  sweat  glands.

Pompholyx usually occurs in young adults aged

12-40 years and may be acute, with no previous

history of atopy or skin conditions, chronic or

recurrent. Some cases are due to an allergic reac-

tion to active skin disease elsewhere on the body,

e.g. tinea pedis and scabies, with which it may be

confused.

Initially there is an intensely itchy or burning

vesicular rash. If untreated, the vesicles coalesce

to form large, fluid-filled bullae (blisters) that may

rupture and become infected, causing pain and

possibly  cellulitis  and  lymphadenopathy.  The

chronic condition is marked by crusts and dry,

cracked skin. Heat or emotion, causing sweating,

and hot, humid weather may precipitate attacks.

‘Varicose eczema’

This is also known as stasis, gravitational or

asteatotic eczema. It is not a true eczema, because

the underlying condition is neither allergic nor

irritant, but due to poor peripheral circulation

causing pooling of the blood in the lower legs,

with  resultant  oedema.  This  causes  capillary

damage, pericapillary deposition of fibrin and

poor  tissue  perfusion.  The  poorly  nourished

skin is hyperpigmented and is very friable and

readily liable to damage by contact irritants or

minor trauma. Varicose dermatitis is essentially a

problem of elderly patients and, because smoking

impairs  the  peripheral  circulation,  these  are

mostly men.

The condition responds poorly to treatment,

especially because the circulation in the area is so

poor.  Steroids  are  largely  ineffective,  support

stockings and occlusive tar bandages or modern

absorptive or ‘breathable’ dressings are usually

more useful. Bioengineered skin is now available

and gives good healing. There is a tendency to

chronic ulceration and infection. If poor circula-

tion is due to atheroma of the femoral or iliac

arteries, angioplasty or arterial by-pass grafting

may improve the circulation substantially, and

with it the skin condition.

Complications

Apart from the hazard of opportunistic infec-

tion, the most serious complication of dermatitis

is exfoliative (erythrodermic) dermatitis, in

which there is a gradual onset of widespread

inflammation and scaling. This occurs mainly in

middle-aged men. Patients feel generally unwell

with  hypothermia  and  rigors  due  to  impair-

ment of temperature regulation consequent on

extensive skin damage.

Diagnosis

The diagnosis is usually made clinically. A careful

history and examination (p. 819) is essential to

identify any possible allergen or irritant. Patch

tests may be used to identify or confirm contact

allergens in allergic dermatitis. Intradermal prick

tests with suspected allergens and, especially, the

RAST procedure (see Chapter 5, Figure 5.16), to

determine IgE levels, may help in doubtful cases

but patients are often allergic to multiple agents.

Because of the limited repertoire of skin reac-

tions there is a possibility of confusion with

other skin diseases and, especially, with reactions

to serious systemic conditions (p. 825; Table

13.6) such as lymphomas, SLE (see Chapter 12) and skin infestations, e.g. scabies.

Management

Aims

The aims of management are:

•  Patient education and reassurance.

•  Avoidance  of  identifiable  precipitating  or

aggravating   factors   and   prevention   of

recurrence and chronicity.

•  Relief of troublesome symptoms, e.g. itch, dry

            and  fissuring  skin,  moist  or  weeping  and

infected lesions, sleep loss.

•  Control of the disease process.

General principles and pharmacotherapy

Patient education and reassurance

Because there is no specific, curative pharma-

cotherapy patients have to learn to manage their

symptoms over a long period. A positive, encour-

aging outlook on the part of the doctor, nurse

and pharmacist is important. Patients should

also be made aware that a tendency for atopic

reactions to recur persists throughout life and of

what it is reasonable to expect from treatment.

Avoidance of precipitants

These include especially soaps and detergents,

airborne  allergens,  plants,  medicaments  and

occupational triggers. Vigorous washing in hot

water, which dries the skin by removing sebum

lipids should be minimized: patients should wash

and bathe in warm water using an emollient, e.g.

aqueous cream or emulsifying ointment as a soap

replacement (see Table 13.9). Complete avoid-

ance is often difficult or impossible, but career

choice,  e.g.  avoiding  hairdressing,  nursing  or

contact with lubricating oils, may be important.

Finding a suitable emollient and using it freely is the cornerstone of dermatitis management,

and will minimize the need for corticosteroids. An emollient alone, used freely, may be adequate in mild disease.

Control itching

The liberal use of emollients (see Table 13.9) is

fundamental to management, especially for dry

skin, and systemic antihistamines, e.g. hydrox-

yzine, which is also sedative and helps with sleep

problems. Bland topical antipruritics (p. 830)

may also help.

Moist or weeping lesions

Astringent (drying) lotions, e.g. 0.01% potassium

permanganate  solution  or  aluminium  acetate

lotion.  If  large  areas  are  affected,  potassium

permanganate baths can be used (see Table 13.8).

However, most patients find potassium permanga-

nate unacceptable because of the brown staining

of the skin.

Control inflammation

Use the mildest possible product. Coal tar is used

occasionally. However, topical corticosteroids (p.

833) form the essential component of active

dermatitis treatment, used in the most appro-

priate pharmaceutical dosage form, i.e. cream,

gel, lotion or ointment, for the shortest possible

time.  A  potent  preparation  may  be  needed

initially (see Table 13.11) and is safe for short-

term use, e.g. 7-10 days, but must not be used on

the face or in the flexures, i.e. the groin, armpits

and under the breasts. In these situations appo-

sition of the skin surfaces causes occlusion of the

site, causing increased absorption of the steroid

and skin damage. Only mild preparations are

suitable for application to these areas. Potent

corticosteroids  are  also  unsuitable  for  use  in

young children.

Once the symptoms have come under control

the potency should be reduced gradually to the

mildest that will control symptoms. Exacerba-

tions may need a return to the potent product

used initially, and patients should be given guide-

lines  on  self-management  of  their  condition.

Corticosteroids  should  be  applied  only  to

inflamed  areas  and  not  to  uninvolved  skin.

Eczema and dermatitis  855

However, it should be remembered that signifi-

cant systemic absorption may occur if there are large areas of inflamed skin, so widespread corti-

costeroid treatment may cause adrenal suppres-

sion, especially with potent preparations. Liberal emollient use should be continued.

In severe disease with marked systemic symp-

toms, high doses of oral corticosteroids may be

required for a short time to gain control rapidly.

The treatment can then be stopped abruptly if it

has been used for less than 3 weeks and relapse is

unlikely. Alternatively, the dose can be stepped

down rapidly to about 7.5 mg prednisolone (or its

equivalent) daily and then more slowly. Careful

supervision is needed to avoid relapse. The objec-

tive is to move progressively to minimal use of

a mild  topical  corticosteroid,  or  to  complete

discontinuation  if  symptoms  are  episodic.  If

treatment has been more prolonged, follows a

longer course within the preceding year or doses

greater than 40 mg prednisolone daily have been

used, more gradual dosage reduction is necessary.

If withdrawal is too abrupt, acute glucocorticoid

insufficiency (Addison’s disease) may result.

High-dose corticosteroid use may precipitate

post-primary TB, which may be prevented by

suitable prophylactic treatment, or shingles (see

Chapter 8). The latter may be interpreted as an

exacerbation of the eczema and inappropriate

use of corticosteroid creams will cause wide-

spread skin lesions that need prompt treatment

with oral aciclovir, famciclovir or valaciclovir (see

Chapter 8).

The immunomodulator ciclosporin (see above

and Chapter 14) is licensed for short-term use,

i.e.        8 weeks, in severe atopic dermatitis when

conventional therapy has been ineffective or is

contra-indicated. At least two full dermatological

and physical examinations are required before

initiating treatment, including blood pressure

and renal function tests. It is contra-indicated if

renal function is abnormal, if there is malig-

nancy and if hypertension or any infections,

especially herpes simplex, are not under control.

The serum creatinine level should be monitored

fortnightly during therapy (see Chapter 14).

Pimecrolimus and tacrolimus are used topically

if maximal topical corticosteroid therapy has not

given adequate control or has caused severe side-

effects. They should not be used near the eyes

and mucous membranes and excessive exposure

to sunlight or UV radiation should be avoided.

NICE  has  recommended  that  pimecrolimus

cream is appropriate for the (short-term) control

of  mild  to  moderate  atopic  eczema  and  to

prevent or treat exacerbations of disease. It has

also been used in children aged 2-16 y. Topical

tacrolimus is licensed for treating moderate to

severe disease in adults (0.1% ointment) and

children aged 2-15 years (0.03% ointment).

These agents are still under evaluation for

safety and therapeutic role and should not be

used as first-line agents unless there are specific reasons against the use of topical corticosteroids. They should be used under the supervision of dermatological consultants.

Unlicensed   treatments   for   severe   refrac-

tory  dermatitis  include  the  systemic  use  of azathioprine or mycophenolate mofetil.

Infection control

Skin  hygiene requires  careful  attention.  Infec-

tions  should  be  controlled  promptly  with

systemic antibiotics, after taking swabs for sensi-

tivity   testing.   Multi-resistant   Staphylococcus

aureus (MRSA;   see   Chapter            8)   and   beta-

haemolytic streptococci may be implicated. An

antiviral  agent (see  above)  is  necessary  for

herpes simplex infections, which may be severe.

Other treatments

It  is  difficult  to  be  more  precise  about  treat-

ment, because patients vary very widely in their

symptoms and in the ways in which they react

to  medication.  Most  patients  with  chronic

disease  eventually  settle  down  to  a  particular

regimen  of  emollients  and  topical  cortico-

steroids  that  they  find  suits  them  best,  more

vigorous treatment being used to treat exacerba-

tions, as appropriate. A lithium/zinc ointment is

available  for  the  treatment  of  seborrhoeic

dermatitis and appears to be effective, largely

non-irritant and suitable for facial use. However,

it must not be used near the eyes or on mucous

membranes.

Second- and third-line therapies include:

•  Hospital admission for intensive or systemic

            therapies.

•  Phototherapy or PUVA (see p. 847).

•  Use  of  the  immunomodulators  mentioned

            above. Other antagonists of proinflammatory

cytokines, e.g. etanercept, have not found a place in this context.

Gamolenic  acid,  used  orally,  is  no  longer considered to have a role, but may possibly be beneficial in a few patients at any stage as an

adjunct to other therapy, but this is controver-

sial. It is not without side-effects, e.g. headache and gastrointestinal discomfort, and may even cause pruritus, and must be used cautiously in pregnancy and if there is a history of epilepsy. It is used in one emollient cream.

Exfoliative dermatitis

This is a life-threatening complication. Rest, a

high-protein diet to replace the serum proteins

lost through the extensively damaged skin, and

the use of high-dose systemic steroids comprise

the normal treatment mode, plus the specific

management of any underlying cause, if one can

be identified. All nonessential drugs should be

withdrawn.

It may also complicate psoriasis, lymphomas and leukaemias.

Acne

Definition

Acne is a hormone-associated disorder of the

pilosebaceous (hair) follicles and is characterized

by  excessive  sebum  production,  comedones

(blackheads), papules and pustules (whiteheads).

The lesions occur primarily on the face, but the

upper chest, back and arms, etc. may be affected

in severe cases, i.e. any area where pilosebaceous

follicles occur. Only the palms and soles are

spared completely.

Epidemiology

Acne affects adolescents in industrialized soci-

eties, females being affected at a slightly earlier

age (10-17 years) than males (14-19 years). The

condition is rare in infancy, but the incidence

rises sharply with the onset of puberty, and about

80% of the 12-18-year age group is affected to

some extent. Some 70% of cases remit sponta-

neously  after  about  5 years,  and  most  of  the

remainder improve slowly thereafter. However,

acne occasionally persists into late adulthood,

affecting five times as many women (5%) as men,

though men tend to be more severely affected

because of their higher androgen levels. Hirsute

females are more liable than other women to

suffer acne and this should provoke a search for

an endocrine abnormality.

Although it is more common in cold climates and industrialized areas, acne may be aggravated by hot, humid conditions once established.

Pathology and aetiology

The underlying problem seems to be an exagger-

ated  response  of  the  pilosebaceous  units  to normal levels of circulating androgens, causing increased production of a modified sebum.

Because  the  composition  of  the  sebum  is

altered, there is hyperkeratosis in the mouth of

the  follicular  duct  and  outflow  of  sebum  is

Acne    857

blocked, causing gross enlargement of the piloseb-

aceous follicles. Saprophytic bacteria, notably

Propionibacterium acnes, are trapped in the follicle

and their metabolism produces inflammatory

substances from the sebum, so that the follicles

become surrounded by inflammatory (polymor-

phonuclear   and   lymphoid)   cells.   Excessive

production of free fatty acids in the sebum may

initiate blockage of the follicles and maintain

the inflammatory response.

Oxidation of tyrosine at the surface of the

trapped   sebum   by   oxygen   and   tyrosinase

produces melanin, staining the sebum to give

the characteristic black comedone: ‘blackheads’

are not due to dirty skin. Although bacterial

activity exacerbates the condition there is no

evidence that acne is infective in origin. In some

cases   rupture   of   comedones   releases   their

contents into the underlying tissues, causes an

intense dermal inflammation (cystic acne).

There  is  a  genetic  predisposition  with  a

familial association, and the condition is aggra-

vated by stress, hormones (premenstrually) and a

hot climate. Certain drugs may aggravate acne or

cause  an  acneiform  reaction  as  a  side-effect

(Table 13.15). An environmental or iatrogenic

cause is probable whenever acne occurs in an

older patient or in an unusual facial distribution.

It has been alleged that acne is due to a poor, fatty diet, but this is without foundation.

Clinical features

Acne is so common and usually has such a

characteristic appearance that the diagnosis is seldom  in  doubt.  Onset  is  gradual,  initially with blackheads and whiteheads, progressing to inflamed nodules. The skin and scalp are greasy and dandruff is usually present.

Pustules and deep cysts occur in some patients

if the condition is not controlled. Cysts cause

intense local inflammation and eventually heal

to  leave  permanent,  characteristic  depressed

scars. Cystic acne, which is aggravated by a hot

climate, may be very resistant to treatment and

improve only with a move to more temperate

conditions.

Because the onset usually coincides with the

period of increased sexual awareness, and the

lesions are visible and often unsightly, there is

always   emotional   and   psychological   distur-

bance,  sometimes  severe.  This  may  lead  to aggressive or reclusive behaviour.

Occasionally there may be confusion with:

•  Rosacea (see below).

•  Perioral   dermatitis   (Plate   3),   sometimes

caused by the inappropriate use of topical

steroids around the mouth, may also give an inflamed, pustular eruption but comedones and a greasy skin are absent.

•  Atopic dermatitis (p. 852).

•  Seborrhoeic dermatitis (p. 853).

Because the management of these differ from that of acne a firm diagnosis is essential.

Management

Aims

The aims of management are to:

•  Encourage an optimistic outlook and ensure

            perseverance and compliance with therapy.

•  Prevent disfiguring scarring.

•  Unblock the ducts of the sebaceous glands by:

-

Reducing sebum production.

-  Reducing keratinocyte activity in the duct.

-  Loosening    the    keratin    plugs,    thus

achieving a free flow of sebum.

•  Suppress the growth of bacteria that produce

            inflammatory substances.

General measures

The types of treatment used are outlined in Table

13.16, and a flow chart for the treatment of acne is given in Figure 13.7.

Acne    859

Patients should be advised sympathetically of

an optimistic outcome, because acne can be

treated very successfully, though not necessarily

cured, with safe medication. Complete healing

occurs in most cases. However, rapid improve-

ment must not be expected, and successful treat-

ment requires at least six months’ therapy. The

improvement rate is approximately as follows:

•           4-6 weeks, some improvement.

•           2-3 months, 40% improvement.

•           6 months, 75% improvement.

Patients  should  be  taught  appropriate  self-

management. Because most of them tend to

have rather sensitive skins, any new treatment should be initiated cautiously at the lowest avail-

able concentration. Detergent washes may help by reducing greasiness, but excessively frequent or  vigorous  treatment  is  undesirable.  Greasy make-up should be avoided.

Good compliance is essential for success, most

failures being associated with lack of persever-

ance or non-adherence to the correct method of

use of medication. Initially, once-daily use on

a restricted area for 4-5 days will detect the

possibility  of  a  severe  reaction,  before  using

twice-daily over the whole area. The intensity of

treatment can then be increased stepwise.

Patients should avoid squeezing comedones, because this may cause or exacerbate permanent scarring   by   forcing   infected   sebum   into surrounding tissue, causing intense inflamma-

tion. Exposure to sun and wind may be helpful, by promoting skin peeling, but may aggravate reactions to medications.

Topical pharmacotherapy

Skin reaction to treatment

Some  degree  of  inflammation  and  scaling  is inevitable with most treatments, except adapa-

lene, and is desirable because it indicates efficacy. However, inflammation should not be too severe and it is advisable to have a 1- to 2-day ‘drug

holiday’ after a moderate reaction, before recom-

mencing treatment. An area larger than that

currently affected should be treated, but the area around the eyes must be avoided.

Patients using benzoyl peroxide or the vitamin A

derivatives tretinoin or isotretinoin (gels or lotions

are preferable to creams because they are non-

greasy), should avoid bright sunshine and expo-

sure to UV ‘sun’ lamps, which may produce

photosensitive reactions, and there is a remote

possibility  of  an  increased  incidence  of  skin

tumours with topical retinoids. Both of these

retinoids  are  available  with  erythromycin (see

below).

The use of a retinoid in the morning and

benzoyl peroxide at night may be more effective,

but this is inappropriate if the benzoyl peroxide

produces significant peeling. Peeling due to the

prior use of benzoyl peroxide should be allowed to heal before using a topical retinoid.

Inflamed comedonal lesions

Benzoyl   peroxide.   This  mildly  bactericidal

keratolytic agent is one of the most effective

treatments for mild disease. It is available in a

variety  of  formulations  in  concentrations  of

2.5-10%. Patients with sensitive skins should

start with 2.5% once daily, otherwise the 5%

products are satisfactory: a test patch is desirable

before full area usage. The aim is to build up to

use of the 10% product twice daily, if tolerated.

The skin irritation is believed to be associated

with the activity of the drug and often subsides

as treatment proceeds.

No  benefit  has  been  shown  for  prepara-

tions with added sulfur, though products with

added antimicrobials, e.g. erythromycin, hydroxy-

quinoline, miconazole, are available (see below).

Patients should be warned that benzoyl peroxide may bleach clothing.

Azelaic  acid.   This very well-tolerated dicar-

boxylic acid appears to act by interfering with

the mitochondrial function in melanocytes and,

presumably, in other basal layer and piloseba-

ceous cells. It also has antimicrobial properties

and is similarly effective to benzoyl peroxide and,

additionally,  may  prevent  post-inflammatory

hyperpigmentation in dark-skinned patients.

It is not normally used in pregnant or breast-

feeding women, and should not be used near the

eyes.

Antibiotics.   Topical antimicrobial treatment is

popular because it avoids the problems associ-

ated with long-term systemic use. However, skin

sensitization may occur (neomycin is no longer

used for this reason) and they may encourage

the emergence of resistant strains. Because of

this, it is preferable to use benzoyl peroxide, azelaic

acid or adapalene first. Further, topical antimicro-

bials  are  not  usually  used  for  longer  than

10-12 weeks, though if a response occurs the

course may be repeated after a gap of 3-4 weeks,

to minimize resistance, which is an increasing

problem.   They   produce   reduction   of   local

inflammation by reducing infection and recruit-

ment of pro-inflammatory cells and by a mild cytotoxic effect.

Lotions containing erythromycin, clindamycin

and  tetracycline  are  useful  for  mild  to  moder-

ate   inflammatory   acne.   Combinations   of

erythromycin with benzoyl peroxide, retinoids or

zinc acetate  may help to minimize antibiotic

resistance.

Retinoids.   Adapalene is a retinoid-like topical

agent, formulated as a 3- to 10-lm microcrys-

talline suspension in a gel base. This particle size

gives good penetration into the pilosebaceous

follicles.  Adapalene  achieves  most  of  the  aims

of treatment, having four clinical effects: it is

comedolytic, it loosens the keratin plugs and

reduces sebum production and the inflamma-

tion caused by the irritant effect of sebum and

microbial action on damaged tissue. The speci-

ficity  of  adapalene  results  in  good  tolerance.

Although it seems to provide a faster response

than tretinoin, the overall outcomes of the two

drugs appear similar. The contra-indications are

similar to those for tretinoin. Treatment should

be stopped if it causes severe irritation.

Adapalene is licensed in the UK for treating mild to moderate acne.

An  important  advantage  of  retinoids  over

antibiotics is that retinoids do not induce Pr.

acnes  resistance.  Further,  adapalene  does  not

interact with other treatments and is very stable.

Mild to moderate comedonal acne

Because retinoids (p. 835) normalize develop-

ment of follicular keratinocytes, they are used

when there are numerous comedones. Tretinoin

is comedolytic and keratolytic and is available as

a cream, gel or lotion in concentrations of 0.01%

and 0.025%. The lower of these should be used

for patients with sensitive skins, or as a starter

dose.

Because it causes photosensitivity reactions, tretinoin should not be used with UV lamps, and exposure to sunlight should be minimized. Some patients do better by using this in the morning and benzoyl peroxide at night, but both products should not be applied simultaneously. If the

latter has been used for some time, causing skin peeling, topical retinoids should not be used

until the skin has healed completely.

Acne    861

Tretinoin  is   contra-indicated   in   pregnancy (contraceptive precautions should be taken in

women of child-bearing age), eczema, on broken or sunburned skin and if there is a history of

cutaneous malignancy.

Isotretinoin is an isomer of tretinoin with similar properties. It is available as a 0.05% gel, with or without erythromycin, and is also used systemi-

cally (see below).

Retinoids should not be used in severe acne

involving large areas. Contact must be avoided

with the eyes, mucous membranes, i.e. nostrils

and  mouth,  and  eczematous,  sunburned  or

damaged skin. They should be used with care on

sensitive skin, e.g. the neck and behind the ears,

and concentrations should not be allowed to

build up in the angles of the nose. Retinoids

should not be applied until the skin has recovered

fully from the effects of damaging treatments,

e.g. peeling agents, UV radiation, abrasive skin

cleansers, astringent lotions or cosmetics. Finally,

strict precautions should be taken to avoid expo-

sure to UV radiation or sunlight: high protection

factor sun creams or protective clothing should

be used.

Severe acne should be managed by consultant dermatologists.

Other topical treatments

Nicotinamide gel promotes skin peeling and may be useful. It tends to cause dryness and irritation, and  the  frequency  of  application  should  be reduced if these reactions are not tolerated.

UV radiation is occasionally used to promote

skin peeling in resistant acne, but it must be used

cautiously if there is any evidence of photosensi-

tivity; in addition, the eyes must be protected.

All topical treatments irritate the skin to some

extent and make it particularly UV sensitive.

Exfoliation  has  also  been  achieved  using glycolic acid or by swabbing with a solid carbon dioxide-acetone slush.

Corticosteroids are not recommended for use

in acne treatment because the fluorinated agents

aggravate the condition, and the more potent

steroids may cause irreversible skin damage (p.

834; Plate 16). Further, sulfur and salicylic acid

preparations, and debridement with mild abra-

sives,  are  not  considered  to  be  helpful  and

should no longer be used. However, the large

cysts that occur in severe acne may respond to intralesional injections of hydrocortisone sodium phosphate or sodium succinate.

Superficial facial damage has been treated

with exfoliating agents and laser therapy and

deeper scarring with injections of collagen, but a year should be allowed after comedone clearance before scars are assessed.

Systemic pharmacotherapy

This is required in moderate to severe acne unre-

sponsive to topical treatment and for difficult

to reach areas. It may be advisable to continue topical therapy for 1-2 years, concurrently with systemic treatment: exceptional cases may need continued topical therapy for some 10-12 years, though this should not be necessary if retinoids or full doses of antibiotics are used.

Antibiotics

If  topical  antibiotics  fail  to  give  significant improvement  after 2 months,  systemic  anti-

biotics are used.

For optimal effect, erythromycin, doxycycline or

other tetracyclines should be used at normal

antibiotic doses until the lesions have resolved

completely. This may take at least 6 months, the

dose then being tapered to zero over the ensuing

month or two (see Chapter 8). Although doses

lower than those used for normal antibiotic use

are common, they are less effective and run the

risk of failure due to resistance, although there is

less risk of side-effects. Antibiotics may occasion-

ally exacerbate acne due to colonization of the

lesions with resistant microorganisms, usually

Gram-negative   bacteria   or   Candida   albicans,

which need appropriate treatment (see Chapter

8). Repeat courses of antibiotics may be needed and do not appear to be commonly associated with problems of bacterial resistance or excessive side-effects (see Chapter 8).

Tetracyclines should be used with the usual

precautions regarding timing of doses in relation

to food and other medications. If compliance is

a problem, doxycycline (once-daily) or minocycline

(twice-daily) may be preferred; in fact, the latter

has been reported to be more effective than

tetracycline, possibly because of fewer resistance

problems.  However,  minocycline  may  cause  a

lupus-like syndrome and a bluish/brown skin

discoloration: the drug should be stopped imme-

diately if either of these reactions occurs. Tetra-

cyclines are unsuitable for children under 12

years of age because it is deposited in the teeth

and bones, causing undesirable tooth discolora-

tion, and may reduce tooth and bone growth.

If there is no response after 2 months, or if

there  is  deterioration  or  a  recurrence  during treatment, a change should be made to a second-

line antibiotic, e.g. clindamycin or trimethoprim. Alternatively,  if  treatment  has  been  initiated in community practice the patient should be

referred to a specialist clinic.

Hormone therapy

If an oral contraceptive is being used, a change to one with a higher oestrogen content may be helpful (if tolerated), on order to increase the

anti-androgenic activity.

Resistant acne in females may be treated with

co-cyprindiol, a cyproterone-ethinylestradiol combi-

nation, which reduces sebum secretion by 30%

and acts as a hormonal contraceptive. A clear

improvement is usually apparent after several

months. The product must not be used in males.

Isotretinoin

Patients with pustules or severe cystic acne, or

who are unresponsive after 2 months of antibi-

otic treatment, may need hospital referral. Late-

onset acne, at 30-50 years, is also usually resistant

to antibiotics. Acne unresponsive to other agents

usually responds dramatically to isotretinoin (p.

837), often with lasting improvement. Isotretinoin

causes  a  marked  inhibition  of  sebum  gland

activity and complete or nearly complete remis-

sion in about 12-16 weeks. Sebum production

may remain at low levels for up to a year or so

after stopping treatment. Consequently, many

acne patients experience long periods of remis-

sion with isotretinoin, though men under 25 years

of age are more likely to relapse. There is also a

secondary anti-inflammatory effect.

There is a long catalogue of side-effects associ-

ated with isotretinoin (see Table 13.12). Because

of its toxicity, long-term isotretinoin administra-

tion  may  be  unjustified  for  treating  a  minor

disease state such as acne, although the condi-

tion is admittedly potentially disfiguring. Repeat

courses are inadvisable. The oral form is available

in the UK only through hospital consultants, and

through them to named community pharmacies.

Sore eyes, cracked lips and dry, peeling skin are

common and can be managed with hypromellose

eye  drops  and  emollients,  respectively.  Kera-

tolytics (salicylic acid), abrasives and laser treat-

ment must be avoided. Because isotretinoin  is

highly  teratogenic,  fertile  women  must  take

strict contraceptive measures, starting 1 month

before initiating treatment and continuing for at

least 1 month  after  stopping.  Fertile  women

should be tested for pregnancy 2-3 days before

menstruation is expected and treatment started

on day 2 or 3 of the cycle.

Isotretinoin is contra-indicated if pregnancy is possible and in patients with hyperlipidaemia or abnormal liver function.

Other treatments

A small trial of the antigout drug colchicine in

antibiotic-resistant acne (unlicensed indication)

has  been  reported  to  produce  up  to 70%

improvement, especially in severe cystic nodular

disease. This is the subject of further trial, which

will need to demonstrate tolerance of this rather

toxic drug, notably the absence of diarrhoea.

Dapsone is used occasionally if other treatments fail (unlicensed indication). There are potentially severe side-effects, including dapsone syndrome, i.e.  rash  with  fever  and  eosinophilia,  which requires immediate cessation of treatment. Other blood dyscrasias also occur.

Rosacea

Definition and epidemiology

Rosacea  is  a  chronic  inflammatory  condition,

characterized by reddish, acneiform lesions of the

face and forehead and telangiectases, but without

comedones (see Plate 4). Although less common

than acne, rosacea affects about 1% of dermato-

logical outpatients in the UK. In contrast to acne,

rosacea  is  much  more  common  in  women,

especially during and after the menopause.

It is possible that perioral dermatitis (p. 823;

Plate 3) is a variant form of rosacea, although it

Rosacea           863

has also been ascribed to cosmetic allergy. It may

be  important  to  identify  which  of  these  is

causing a rash around the area of the mouth

because treatment is different. Corticosteroids

aggravate both rosacea and perioral dermatitis

(see below).

Aetiology and clinical features

The  pathology  of  rosacea  is  unknown,  but  it may be a familial condition. It is provoked by anything causing persistent flushing of the face. The flushing correlates with:

•  Perimenopausal incidence, especially if the

            climacteric is prolonged.

•  Ingestion of alcohol, hot drinks and spicy

            foods.

•  Exposure to bright sunshine and high winds

            (there is a high incidence in outdoor workers).

Flushing  usually  starts  on  the  forehead.

Unlike  acne,  rosacea  usually  affects  the  face

only and the  30-50-year  age  group.  Although

there  are  no  comedones,  there  are  closed

papules,  more  generalized  inflammation  and

the skin is dry, despite sebaceous gland hyper-

trophy.  The  latter  may  cause  rhinophyma,

with  a  disfiguring,  bulbous,  reddened  nose,

primarily  in  male  alcoholics.  The  ears  and

eyelids may occasionally be similarly affected.

New  facial  capillaries  develop  and  these  may

dilate  to  form  telangiectases.  Ocular  involve-

ment   is   a   serious   complication   requiring

specialist ophthalmological care.

Pharmacotherapy

Mild rosacea may not require treatment unless it  is  causing  psychological  distress.  Mild  to moderate  disease  is  treated  empirically  with topical metronidazole gel or cream, or any of the topical antibiotics used for acne. However, prepa-

rations  with  an  alcoholic  base  may  aggravate flushing. Emollients may be useful.

Moderate   to   severe   rosacea   and   resistant disease requires the use of high-dose antibiotics; e.g. 1-2 g/day of erythromycin, 1 g/day of tetra-

cycline  or 100-200 mg/day  of  minocycline,  for 3-6 months.   Topical   antibiotics   should   be

continued. The benefit of antibiotics is probably

due their mild toxicity to epidermal structures.

Severe disease unresponsive to antibiotics may

require   isotretinoin:      100-200 lg/kg   of   body

weight/day  is  normally  sufficient  but  higher

doses may be needed. Isotretinoin is a very toxic

drug  and  the  usual  precautions  and  contra-

indications must be observed (see above). This is

an unlicensed indication.

Antibiotics   may   be   ineffective   against

erythema and flushing: a beta-blocker can help

with the former and, paradoxically, 4% topical

nicotinamide with the latter, but this may be very

irritant. Low-dose clonidine, e.g. 25 lg twice-

daily,  may  also  help  to  control  flushing,  but

has   potentially   serious   side-effects,   notably

intractable,  severe  depression.  This  is  clearly

undesirable in a patient who is already depressed

because of their condition.

Ocular involvement requires specialist oph-

thalmological   management.   Rhinophyma   is dealt with by plastic surgery, nowadays usually by high-frequency diathermy or laser therapy, which may give long-term benefit.

Corticosteroids are contra-indicated in rosacea and perioral dermatitis. If the latter is thought to be due to an allergic reaction to cosmetics it

should be treated by cessation of use and oral antihistamines. If the rash is resistant to anti-

allergic therapy, it is likely that it is due to

perioral dermatitis, so the temptation to use

hydrocortisone cream, which may be requested by patients, should be resisted.

Urticaria

Definition

The condition involves transient, pruritic, chronic

or  recurrent  inflammatory  weals,  plaques  and

papules. It is also known as nettlerash and, mostly

in North America, as hives. The weals are raised,

oedematous lesions, that are very variable in size

and extent.

Hereditary  angioedema  (angioneurotic  oed-

ema) involves larger areas of the SC tissues and dermis, producing gross swelling.

There is an arbitrary distinction between acute and chronic urticaria. The acute form persists

for less than 30 days before remission occurs, with recurrences after variable periods, whereas chronic urticaria involves episodes lasting for longer than 30 days.

Pathology and aetiology

The condition can have various causes (Table

13.17):

•  Immunological,  mediated  by  IgE,  comple-

            ment components or immune complexes (see

Chapter 2).

•  Physical, caused by several external agents,

            including drugs.

Whatever the mechanism, the final result is

gross dilatation of the skin capillaries, allowing

the escape of fluid, and sometimes leucocytes

and less frequently erythrocytes, from the circu-

lation into the dermis, i.e. localized oedema. The

escape  of  erythrocytes  causes  a  purpuric  rash

(p. 826) that may leave residual pigmentation.

Acute  urticaria  is  usually  due  to  a  type  I (allergic)  reaction  in  atopic  subjects,  which releases  histamine  from  mast  cells.  Possible stimuli are given in Table 13.17.

The   underlying   mechanisms   in   chronic

urticaria are unknown in 80-90% of cases, but

may be:

•  Immune  complex  disease  (see  Chapter  2)

coupled   with   a   defective   complement

cascade, e.g. lack of inhibition of C3a by

carboxypeptidase   B   permits   an   ongoing

reaction.

•  Abnormalities   of   the   arachidonic   acid-

            eicosanoid   pathway    (see   Chapter   12),

evidenced  by  sensitivity  to  salicylates  and indometacin.

•  Chronic infection, e.g. H. pylori (see Chapter 3). •  Autoimmune disease:

•  IgG auto-antibody reacting with IgE cross-

            linked to receptor sites.

There is a linkage between autoimmune mast cell disease and autoimmune thyroid disease in about 15% of patients, so thyroid function tests may be indicated.

Some patients with SLE and Sjögren’s syn-

drome (see  Chapter 12)  have  an  urticarial

vasculitis.

Hereditary angioedema is a severe, episodic,

autosomal-dominant   inherited   disorder   that

affects the face, larynx, extremities and gut. It is

associated with an abnormal or deficient C1

esterase  inhibitor (see  Chapter 2),  allowing

excessive bradykinin formation. The condition is

sometimes associated with perivascular leucocy-

tosis and eosinophilia in the area of lesions.

Chronic urticaria may coexist with angioedema.

Clinical features and diagnosis

Acute urticaria is defined by the symptoms. There

are transient pruritic weals, possibly lasting for

hours, which may vary in size from 1-2 mm to

10-80 mm or be widespread; these may be oval,

annular  or  may  follow  bizarre  shapes  and

patterns.  The  weals  are  usually  pink,  though

larger lesions have a light central area with an

erythematous  margin,  somewhat  resembling

tinea. The weals occur commonly on pressure

areas, hands, feet and trunk, especially exposed

areas.

Hereditary  angioedema  affecting  the  lips,

tongue, larynx and neck, is one of the few derma-

tological emergencies because it may compro-

mise respiration. The weals characteristic of other

forms of urticaria do not occur, but tissue swelling

may be moderate to gross, and in some cases the

patient  becomes  completely  unrecognizable.

Abdominal  involvement  causes  severe  pain.

Chronic urticaria may coexist with angioedema.

About 25% of sufferers have chronic urticaria.

This occurs in the age range 10-50 years, most

commonly in the 20-40-year age group, and

about twice as many women as men are affected.

The symptoms are similar to those of the acute

form,  though  some  patients  have  symptoms

lasting 20 years or more. Patients tend to be

intolerant of salicylates and benzoates. Some

aetiologies   can   be   determined   by   simple

challenge tests:

•  Cold: application of an ice cube for 10 min

            gives a weal within 5 min of removal.

•  Solar: exposure to an UV or powerful sun

lamp for 30-120 s gives weals within 30 min.

•  Cholinergic: a hot shower produces weals on

the neck, limbs and trunk.

•  Pressure: firm pressure perpendicular to the

            skin, e.g. excessively tight clothing, gives a

persistent weal after 1-4 h.

Apart from pressure-related forms, these tend

to be associated with angioedema, so prompt emergency treatment needs to be available (see below).

Management

The management of urticaria involves:

•  Avoidance of known precipitants.

•  Oral antihistamines (both H1  and sometimes

H2 blockers), non-sedating during the day, e.g.

acrivastine,  cetirizine,  desloratadine,  fexofena-

dine or mizolastine, and a sedating antihista-

mine  at  night  (see  p.  831  for  side-effects),

e.g. alimemazine, hydroxyzine or promethazine.

Ranitidine,  an  H2 blocker,  may  also  help.

Doxepin  has both antihistaminic and anti-

depressant   properties   and   is   useful   for

patients depressed by their condition.

•  Corticosteroids:

-  A  moderate-potency  topical  steroid  for

            most patients (see Table 13.11).

-  Oral prednisolone: for severe reactions, espe-

            cially angioedema. The very severe throat

            swelling of those suffering from hereditary

angioedema needs IV hydrocortisone and SC adrenaline (epinephrine).

•  Severe resistant urticaria may respond to ciclo-

            sporin or to human normal immunoglobulin.

•  Danazol may be helpful for the long-term treat-

ment of hereditary angioedema (unlicensed indication in the UK).

•  Whole fresh plasma, C1 esterase inhibitors

            and   plasmapheresis:   these   methods   are

successful with the immune complex form of urticaria  because  they  remove  circulating antigen-antibody complexes.

Drug-induced skin disease

Skin eruptions are one of the most common

manifestations   of   systemic   or   topical   drug

therapy (Table 13.18). Probably every pharma-

ceutical  product  has  the  potential  to  cause

dermatoses, even topical steroids, though this is

very unlikely with hydrocortisone. The reactions

may be immunological in character and cover

the whole range of skin manifestations.

The systemic use of drugs may cause various types of lesions:

•  Bullous or vesicular, e.g. sulphonamides. •  Erythematous, e.g. antisera.

•  Lichenoid, e.g. antimalarials, gold, phenothia-

            zines.

•  Photosensitive,  e.g.  chlorpromazine, sulpho-

            namides.

•  Pruritic, e.g. tetracyclines.

•  Purpuric, e.g. barbiturates, chloramphenicol,

            aspirin.

•  Urticarial (see above).

One rather unusual type of response is the

fixed drug eruption, which is characterized by a

skin reaction in the same localized sites on each

occasion that the drug is taken. If the reaction

occurs   repeatedly,   there   may   be   persistent

pigmentation of the site, even in the absence of

the drug and of an overt skin reaction. Common

causes are barbiturates and phenolphthalein, but

phenobarbital is used nowadays only for the

treatment of epilepsy (see Chapter 6).

Serious  systemic  reactions  may  also  occur,

such  as  Stevens-Johnson  syndrome,  with  a

severe rash, high fever, joint pains and painful

involvement of the mucous membranes. This

needs expert diagnosis and management, using

rest, antibiotics and high-dose corticosteroids.

Reactions to topical treatments include any of those described on p. 851.

The skin as a route for systemic drug delivery

Transdermal (percutaneous) administration is a

technique  for  delivering  drugs  systemically  at

a  controlled  rate  over  a  relatively  prolonged

period: it is not used for the topical treatment of

skin diseases.

The principal barrier to drug penetration of

the  skin  is  the  horny  layer. ‘Shunt  routes’

through the hair follicles and sweat glands are

significant in the early stages after application,

but only for some electrolytes and highly polar

corticosteroids and antibiotics, which penetrate

keratin poorly. These shunt routes are important

because they are probably the principal routes

References and further reading  867

of penetration and systemic absorption of the

topical corticosteroids, though they contribute

only marginally to the steady-state flux across

the epidermis for many agents. Once past the

horny layer, the drug molecules rapidly pene-

trate the living tissues of the epidermis and

dermis and are swept away into the circulation.

The skin also acts as a drug reservoir, due to:

•  Binding  by  proteins  in  the  horny  layer,

            giving a persistence of up to 2-3 weeks after

application has ceased.

•  Concentration  of  lipophilic  agents  in  the

            fatty tissues in the dermis, from which they

leach gradually into the circulation. However,

this mechanism contributes little to any effect

that the product may have on most skin prob-

lems, which are generally epidermal in origin.

Factors relevant to penetration include:

•  Concentration of the drug.

•  Formulation of the product.

•  Mode of use (occlusion and greasy vehicles

            enhance skin penetration).

•  Contact time.

•  Site of application, e.g. the skin behind the

            ears is very thin and may be the preferred site,

and the presence of hair follicles and sweat glands.

•  Patient age: young children and the elderly

            have readily penetrable skin.

•  Features of the disease state, e.g. inflammation

            and excoriation enhance drug penetration.

Factors affecting the likelihood of side-effects are the skin type (fair-skinned people are more likely  to  suffer  an  adverse  reaction)  and  the potential  of  the  formulated  product  to  cause skin  problems,  e.g.  rashes  due  to  the  drug, preservatives, adhesives, plastics, etc.

Further  details  of  this  subject  concern  the formulation pharmacist and are not pertinent

here (see References and further reading).