1 Introduction

More than 100 years ago, the noted medical pathologist Virchow (1860) portrayed the skin as a protective covering for more delicate and functionally sophisticated internal viscera. At that time, the skin was primarily treated as a passive barrier to fluid loss and mechanical injury. The modern approach is to consider the skin as a highly complex organ in which precisely regulated cellular and molecular interactions govern many crucial responses to environmental changes.

The skin has many functions and apart perhaps from the liver, it could be said to have the most diverse range of ‘duties’ of all the major organs. Each of these functions is involved either individually or with others in the pathogenesis of skin disease (Table 1.1). The skin plays a major role in:

Table 1.1 The major functions of the skin that affect dermatological health

In addition, the skin provides a means of identification and individual recognition. Embryologically the skin is modified to create specialist structures such as the cornea and the hoof.

The cosmetic appearance of the skin is important both for individual recognition and in some cases for the function of the domesticated horse. Under normal conditions a healthy equine skin is lustrous and non-greasy. The mane and tail hairs are lustrous, long, strong and very flexible. In winter the body hair coat is longer, somewhat greasier to the touch and often lacks lustre. The mane and tail hairs do not alter between summer and winter.

Cosmetic problems often cause more concern to owners than some more serious diseases. This means that owners may overlook serious conditions while over-emphasizing some trivial ones.

Dermatological disease is one of the commonest clinical presentations in equine practice. This is possibly due to the fact that skin is the largest organ system, it may be altered by a number of exogenous and endogenous factors, and owners usually recognize cutaneous lesions easily. It is easy to overlook the fact that the hoof, ergots, chestnuts and cornea are modifications of the skin and their diseases could justifiably be included in dermatology. However, it is also true to say that many cutaneous diseases are overlooked, trivialized or belittled as being ‘cosmetic’ nuisances whilst they are more often significant than not. There are many cutaneous diseases that have systemic effects and many systemic disorders that have significant and diagnostically helpful cutaneous manifestations; in some cases the skin signs are both the earliest evidence of disease and indeed the most obvious. This makes differentiation between primary and secondary skin disease a significant aspect of the diagnostic process and it remains disappointing that the skin is often overlooked during clinical investigations.

Obvious lesions in the skin are usually easily identified but subtle changes in skin temperature, thickness, colour, hair density and sensitivity can sometimes be difficult to locate and investigate in horses. Deviations from normal may reflect primary skin disease, for example viral, bacterial or fungal infections or insect hypersensitivity, and/or secondary manifestations of primary systemic disease, such as the cutaneous photosensitization manifestations of advanced liver failure. The latter are relatively common. Also, the skin may act as a significant indicator of other systemic disease and may reflect the horse’s general health status. Clinicians and owners often report ‘a staring harsh coat quality’ in horses with significant systemic diseases. The same signs could be induced by measures applied by the owner also; for example repeated washing in severe degreasing shampoos, detergents and soaps can result in a grossly abnormal skin appearance and texture.

The key to successful treatment is accurate diagnosis. The basis of disease diagnosis must, by necessity, be guided by a thorough knowledge of what may be regarded as normal. This is usually a skill acquired by regular and careful scrutiny of many ostensibly normal horses so that subtle (possibly early) abnormalities can be identified quickly. Late diagnosis may sometimes make the investigation far easier – the lesions are advanced and therefore may be very typical for any particular condition. However, in these late stages there may be secondary changes that may confuse a diagnosis even if specialized tests are applied. Early lesions may be very subtle and this can introduce diagnostic and therapeutic problems. Furthermore, early diagnosis is often difficult because of the limited number of ways in which skin can react to the full range of infectious and non-infectious challenges; different diseases can have remarkably similar overt appearances (Fig. 1.1).

Figure 1.1 Four different periorbital alopecic and flaking disorders. They have a broadly similar appearance but there are very different implications for diagnosis, treatment and prognosis. (A) alopecia areata; (B) pemphigus foliaceus; (C) dermatophytosis/ringworm; (D) mixed sarcoid.

Careful and critical assessment of presenting clinical signs and an understanding of their significance in relation to a disease process, combined with a basic understanding of skin morphology and function, allow the clinician to categorize skin disease into broad groups such as nodules, alopecia, change in hair/skin colour. This categorization allows a clinician to reach an accurate diagnosis more easily and accurately than if attempts are made to guess a diagnosis without knowing all the facts. However, in practical circumstances, there are few cases in which a single category/syndrome is strictly applicable because most skin diseases either have multiple presenting signs or are complicated by secondary changes that mask the underlying primary condition. Also, categorizing skin diseases into defined syndromes as opposed to identifying the primary cause of the condition carries dangers. Significantly different diseases can be remarkably similar to the casual observer (Fig. 1.1).

A single term for the clinical appearance of a cutaneous lesion may be very descriptive but subtle variations may perhaps not then be clearly identifiable. A broad categorization of a type of lesion is also not usually helpful. For this reason terms such as ‘eczema’ and dermatitis should be avoided as far as possible even though owners will often be satisfied with such an approach simply because these terms are commonly used in humans. For example, a diagnosis of ‘nodular skin disease’ could cover several distinctly different clinical entities and each of these would surely require very different therapy (Fig. 1.2 and Table 1.2).

Figure 1.2 The seven skin nodules shown here are very different diseases, they have different prognoses and each requires a very different treatment. (A) subconjunctival squamous cell carcinoma; (B) fly bite reactions; (C) cutaneous melanoma; (D) urticaria; (E) viral papilloma; (F) malignant melanoma; G sarcoid.

Table 1.2 Examples of some skin nodules illustrating the differences in treatment and prognosis

The written description of various skin lesions can be both poorly understood and poorly used, and the specialized vocabulary of the dermatologist may be daunting. Familiarity with the dermatological vocabulary allows a rational scientific dialogue between veterinary practitioners at all levels and dermatopathologists, reducing confusion and materially improving diagnostic accuracy. These terms and descriptions make the description of well-recognized lesions more universally understood by both dermatopathologists and clinicians. A short glossary of the common terms and expressions is included at the end of this chapter (p. 21). Their use serves to reduce confusion in written reports and dialogue and increases understanding of skin conditions but can lead to oversimplification. Although specific descriptive terms can sometimes be open to misinterpretation, regular usage will minimize this risk.

Normal equine skin

The normal anatomical structure of equine skin broadly follows the classical descriptions shown in many textbooks of anatomy (Fig. 1.3). However, there have been fewer studies on equine skin than for many other species and so significantly less is known about its particular function, the cutaneous blood supply and particular cellular behaviour patterns. Extrapolation from the other species seems an unreliable way to understand the skin of a highly adapted species but until more research is supported equine dermatology will remain behind that of other species in this respect.

Figure 1.3 Structure of normal skin. (Adapted from Boon N A et al, 2006, Davidson’s Principles and Practice of Medicine, 20th edn. Churchill Livingstone, Edinburgh; with permission.)

Skin structure varies greatly at different sites and among the different equine species. There are some significant differences, however, in the horse. For example, the skin is particularly well endowed with sweat glands and the horse sweats more easily and in different patterns from most other species. In addition there are specialized skin structures such as the eyelashes, the sensory or tylotrich hairs and the ergots and chestnuts.

Evolutionary adaptations have had a significant effect on the structure and function of equine skin. There are significant differences in the skin of the various members of the equidae, with the donkey in particular being particularly well adapted to extremes of heat and dryness. Without skin adaptations the donkey could not survive in the climates where its relationship to man is crucial. The donkey survives the rigours of extreme climates by having the ability to increase its body core temperature by 1–2°C without harmful effects and its mechanisms for thermoregulation through sweating are highly efficient, involving minimal water loss for maximal cooling effects. Even within the horse species there are significant differences in skin thickness and hair coat growth patterns that may have an influence on the prevalence of some of the disorders. In most horses, however, the natural periodicity of hair coat growth is adapted for the circumstances the horse is in. In hot climates, even the winter coat is short and thin whereas in cold climates the same horse would grow a long, dense, protective and warming hair coat. Even the use of rugs and blankets can have a profound effect on hair growth patterns.

Seasonality of coat character is an area that is poorly understood in the horse, but the changes are very predictable both in extent and type. The growth patterns of the hair coat have a seasonal relationship that is strongly and predictably dependent upon the daylight hours but also significantly affected by other factors such as temperature.

Colour patterns and the position of hair whorls are used widely as forms of identification but there are some important variations. For example, a foal may be born ostensibly chestnut or bay and then turn grey and some breeds such as the Appaloosa may change the patterning and clarity of their skin colour spots with age.

The mane and tail have a different type of hair – both have thicker, stronger and longer hair. Disease may affect one or more components of the skin/hair types on a horse; the mane may be spared while the body hair is badly affected or the legs may be spared while the body and mane can be severely diseased. White-skinned limbs have a deserved reputation for greater susceptibility to some photoactivated and some infectious disorders but the reasons for this are not known; the physiology and microscopic structure of the white skin is indistinguishable from pigmented skin apart from the obvious lack of melanocytes.

The skin is continuous with mucous membranes at the body openings and this is a common site for subtle dermatological signs to develop. The same can be said of specialized skin junctions such as the coronary band.

Gross and histological anatomy of the skin

The skin consists of epidermis, dermis, hair follicles, sebaceous glands, sweat glands and digital appendages, for example chestnuts, ergots and hooves. One of the most difficult aspects of dermatological investigation facing the veterinarian is establishing what is normal for an individual horse. Within the species there are also significant breed and even individual differences in hair coat density and quality and even distribution and so it is important that the breed, season and colour are always considered. An apparent dermatological disorder could in fact be normal for that animal and whilst most ‘genetically’ based changes are present from birth there are some that develop in later life.

Note

• The haired skin is thickest over the dorsum and lateral aspect of limbs and is thinnest on the eyelids, ventrum and medial aspect of the thighs.

• The subcutis or panniculus connects epidermis and dermis with the underlying fascia and musculature.

There is increasing evidence that all the cells that comprise the skin including the keratinocytes have active roles as well as passive ones.

Epidermis

The epidermis is an avascular stratified squamous epithelium and is firmly attached to the dermis by a complex basement membrane (Fig. 1.3). This structure is important in some well-recognized skin diseases such as the pemphigus complex.

Keratinocytes comprise over 95% of the epidermal cells. They are attached to each other by complex adhesion proteins known as desmosomes. They synthesize insoluble proteins called keratins of two main basic types. These are conventionally described as ‘basic (type 1)’ and ‘acidic (type 2)’. Individual keratins of each type pair up to form filaments which provide the basic structure to the skin (cytoskeleton). They also synthesize lipid-rich cornified material primarily responsible for the protective barrier and waterproofing functions of skin. They are derived from stem cells in the basal layer of the epidermis and move outwards, gradually losing their shape (becoming flatter). The nucleus degenerates and they become degenerate flattened anuclear cells in the most superficial horny layer of the skin where they are surrounded by the lipid-rich hydrophobic material that ‘cements’ them together. Finally the cells are sloughed/shed from the surface as fine scales (dander/dandruff/scale). Some pathological conditions are characterized by excessive scaling and flaking but a continuous low level of shedding of defunct keratinocytes, keratin strands and lipid is a normal physiological function of skin. A slightly scurfy skin character is normal on horses.

Classically the epidermis is divided into defined layers although this is a gradual change rather than a defined, abrupt one.

• The stratum corneum is the outermost epidermal layer and comprises many sheets of flat keratinized (anuclear) cells (keratinocytes) that eventually slough from the surface. Non-haired skin tends to have more layers in the stratum corneum than haired skin. This layer varies markedly in many disease conditions, being either excessively thick or abnormally thin.

• The stratum lucidum is absent in haired areas and is a thin layer of compacted, flattened, fully keratinized cells covering the granular layer or stratum granulosum. It consists of effete cells with basophilic keratohyalin granules. The stratum granulosum is absent or minimal in haired skin but prominent in hairless (glabrous) skin.

• Beneath these layers is the stratum spinosum, which consists of a zone of polyhedral cells attached by desmosomes; these intercellular bridges can be recognized histologically as ‘spines’. The innermost layer of the skin is the germinal layer or stratum basale, consisting of a single layer of mitotically active cuboidal to columnar cells resting on the basement membrane. There are abundant stem cells distributed in the stratum basale.

Intermixed in the basal cell layer are melanocytes, Langerhans cells and Merkel cells.

• Melanocytes synthesize melanin pigment from tyrosine, package it in the intracellular melanosomes and transfer the pigment to surrounding keratinocytes and hair bulbs via their dendritic processes, thereby imparting colour to the skin and hair. They are also present in the basal layers of the stratum spinosum.

• Langerhans cells are dendritic cells derived from bone marrow that circulate between the epidermis and the local lymph nodes. They act primarily as immune surveillance cells and are the major antigen-presenting cells of the skin. Antigens are presented to T lymphocytes and may be vital in viral and bacterial infection and in tumour cell recognition. It is possible to stain for these cells specifically but they cannot be identified on normal haematoxylin and eosin stained sections.

• Merkel cells are neuroendocrine cells and function as slowly adapting mechanoreceptors for touch sensation. A few Merkel cells are also found in the basal layer of the epidermis.

• Intra-epidermal lymphocytes are known to be T cells in the mouse and human (and likely to be similar in horses). They monitor the skin surface for extraneous potentially harming antigens.

Dermo-epidermal junction and basement membrane

The basement membrane acts as an anchoring system for the epidermis but it still allows the relatively free movement of cells and nutrients between the dermis and the epidermis. In the horse, the basement membrane zone is thick and relatively easy to define histologically. This is typically straight in hirsute animal skin due to the extra anchoring function of the hair follicles. The structure of the basement membrane is identifiable by electron microscopy and is typical of all basement membranes under epithelia. It attaches to the basal cell layer of the epidermis by hemidesmosomes.

Dermis

The dermis is the vascular part of the skin that structurally and nutritionally supports the epidermis. It also supports blood vessels, nerves and adnexal structures including the hair follicles and sweat glands. It is divided into superficial and deep layers; the superficial dermis has finer, loosely arranged collagen fibres while the deeper dermis has a denser collagen fibre arrangement. Its thickness varies at different anatomic sites and this accounts for the main differences in the physical nature of the different sites on the body. In the horse, the dermis is thinnest in the eyelids, the medial thigh and axillae. In the neck, gluteal and sacral regions a deeper third layer is present, which is composed of fine collagenous fibres interwoven with fine elastic and reticular fibres.

Fibroblasts comprise the majority of the cellular components of the dermis; fibroblasts synthesize the extracellular matrix fibres and the ground substance. Mast cells, mononuclear phagocytes (macrophages), lymphocytes and Langerhans cells are distributed throughout. Eosinophil and neutrophil leukocytes are occasionally distributed in normal dermis.

The dermis consists mainly of collagen (type I and type III) and elastic fibres (elastin and reticulin) in a ground substance largely containing glycosaminoglycan, hyaluronic acid and dermatan sulphate, all of which are synthesized by fibroblasts. The production and catabolism can be influenced by endocrine factors although these are probably less obvious in the horse than in other species.

Cutaneous arteries give rise to three intercommunicating vascular plexuses. The deep plexus is located at the subcutaneous-dermal junction, the middle plexus lies at the level of the sebaceous glands and the superficial plexus sends capillary loops to the dermo-epidermal junction. Lymphatics are present in the superficial dermis and around adnexae. The rich supply of nerves to the epidermis and dermis consists largely of general somatic, afferent, myelinated and non-myelinated fibres.

Adnexae

The adnexal structures such as hair, sweat glands and hoof are in effect specialized epithelial structures with embryonic ectodermal origins. They develop during gestation so that at birth all the major skin appendages apart from the hair shafts are present in adult form. The hair types vary; the mane and tail hair is thicker and longer than body hair. Seasonal shedding of hair affects only body and limb hair.

Mane and tail hair are less influenced by endocrine factors but are more affected by insults that affect keratin such as selenium toxicity. This is a partial explanation at least of the different responses that occur in different diseases.

Hair follicles

Forms of hair follicles vary in different animals. The hair follicles of the horse are simple; single hair follicles of different sizes are evenly distributed. Simple follicles are deeply rooted in the dermis, and usually have a single hair shaft, sebaceous and sweat glands and arrector pili muscles. The hairs themselves consist of the internal root sheath, external root sheath, dermal papilla and hair matrix. The root of the hair has a terminal bulb which attaches to the dermal papilla. The hair shaft has an outer cortex (cuticle) of densely packed keratinized cells containing most of the pigment that imparts the characteristic colour. The inner medulla is a looser mass of cuboidal or flattened cells.

Growth of hair is seasonal in animals, with the time of growth and mitotic activity termed the anagen phase. Microscopically, anagen hair follicles have a roughly spindle-shaped dermal papilla wrapped over the hair matrix in the form of a ‘ball and claw’. A transitional phase, during which cellular proliferation ceases, is the catagen phase. The follicle then enters a resting state, the telogen phase, after which mitotic activity and new hair production resume and the old hair is shed.

Tactile hairs, which include sinus and tylotrich hairs, are also prominent at some anatomic locations on horses including the periorbital and facial skin. They are much heavier, coarser shafts and the follicles have a prominent nerve and blood supply. The former act as slow-adapting mechanoreceptors and generally are located on the muzzle, above the eyes and on the lips and throat. The latter function as rapid-adapting mechanoreceptors and are scattered among regular body hairs.

Sweat glands

There are two types of tubular glands in the skin: apocrine (paratrichial) glands associated with primary hair follicles and eccrine (atrichial) glands found on glabrous skin (e.g. hoof).

Apocrine gland activity is grossly visible in horses as they sweat after exercise or during high temperature. It is believed that the ability of the horse to sweat in limited regions is dependent on the local delivery of catecholamines. This can arise either because the blood has large amounts (as in excitement or exercise) or when the cutaneous blood supply is increased sufficiently. Increases in cutaneous blood supply in local areas occur in some autonomic disorders such as Horner’s syndrome when the affected side of the face/neck sweats significantly relative to the normal unaffected side. Grass sickness (equine dysautonomia) is an autonomic neuropathy characterized by patchy sweating over the body and neck in particular.

Sebaceous glands

These are holocrine glands derived from hair follicles and their ducts discharge sebum into the upper part of the hair follicle. The horse has large, branched sebaceous glands that are especially numerous on the lips and around the vulva and particularly large in the mane, prepuce and mammary gland areas. Secretion of sebum is governed by endocrine factors in most species but the mechanisms are not established in horses.

Arrector pili muscles

These are smooth muscles that extend from the connective tissue sheath of hair follicles to the superficial dermis. Muscle contraction causes erection of hairs and expression of sebaceous glands. These muscles are not well developed in horses.

Blood vessels and nerves

The equine skin is very well supplied by both blood vessels and nerves. The latter explains the considerable sensory and tactile nature of equine skin. The blood supply is controlled largely by autonomic nerves and can be locally variable; this accounts for the horse’s ability to sweat in patches. Patchy sweating is a normal equine phenomenon that relates more to the blood supply than to the overall concentration of catecholamines in the skin and this is why vasodilation results in sweating even in the absence of extra catecholamine. Autonomic nerve dysfunction can result in localized areas of continuous sweating – usually the affected areas are warmer than the adjacent normal skin and this can usually be palpated or can be confirmed using thermal imaging techniques.

Subcutis (hypodermis, panniculus)

Below the dermis is the subcutis (or hypodermis). It consists primarily of fat and loose connective tissue. The subcutis attaches the dermis to adjacent muscle or bone and comprises adipose tissue, collagen and elastic fibres. The former insulates against temperature variation, the latter provides flexibility. The subcutis is also an effective shock absorber for impact protection and cushions the more sensitive structures beneath.

In horses there are areas where subcutaneous fat accumulation is more obvious such as the sides of the body, buttocks and neck regions; only rarely can fat be found on the limbs or face. Deposition of subcutaneous fat is an important energy reservoir and its extent is used to provide an index of body condition. Deposition can occur irregularly in some areas and over-fat horses often have excessive subcutaneous fat deposits in the neck/crest region and over the buttocks and tail head. In some diseases there is an abnormal redistribution of fat. For example, in pituitary pars intermedia dysfunction (PPID/equine Cushing’s disease) there is a diagnostically significant pattern of fat deposition in which fat is laid down in the retrobulbar regions and in the abdomen at the expense of the neck and body wall.

Special appendages (hoof/ergot, chestnut)

There are several significant cornified/horny appendages including the hooves, the ergots and the chestnuts. These structures tend to be viewed as rather casual ‘skin appendages’ but not only can they reflect important clinical signs of disease (e.g. laminitic rings) and nutritional abnormalities (e.g. biotin and methionine deficiencies) or toxicity (e.g. selenium toxicosis) but they have significant implications for diagnosis of some important diseases. The margin between these structures and the adjacent skin is often a site where abnormality can be demonstrated in some significant autoimmune conditions. For example, in pemphigus foliaceus and some autoimmune coronitis disorders there may be marginal inflammation along the skin border and often much more extensive changes than in normal skinned regions. The chestnuts provide a good source of tissue for diagnostic pathology where the coronet cannot easily or safely be sampled.

In solipeds such as the horse, the hooves consist of the wall, sole and frog. The sole and wall are composed of keratin. The wall consists of three layers, the inner one of which interdigitates with the dermis and acts as an anchor. The deeper portion of the dermis blends with the periosteum of the third phalanx. The frog is a dense fibro-elastic structure that has a major shock-absorbing function. Both the walls/sole and the frog are subject to significant pathological changes. An excellent description of the anatomy of the foot is available in Pollitt (1995).

Hair growth patterns

Some months before birth hairs develop over the body. Premature or dysmature foals always have a poorly developed hair coat and this is used as one of the indices of gestational age. The character of the hoof is also significant – at birth the hoof is soft but is recognizably ‘hoof’. It hardens rapidly after birth. Premature foals have a soft rubbery hoof capsule often with finger-like extensions from the sole margin. The hair of a newborn foal is soft and is usually short; in some specific lines of some breeds a longer curly coat is present. This is a ‘normal’ trait in these animals.

Abnormal growth patterns do occur and the timing and nature of these are important diagnostic features. There are seasonal variations on the normal that may relate to breed and environment but some changes are regarded as pathological, for example seasonally related alopecic conditions. However, little is known about equine hair and its alterations in disease in horses.

The horse has four types of hair:

1. The temporary hair that is shed in cycles governed by changes in daylight length. This comprises the large majority of the body and limb hair.

2. The tylotrich hairs are distributed throughout the body hair. They are recognizably larger than normal body hair and have a sensory function.

3. The permanent hair of the mane and tail. This is not shed in a coordinated way and grows continuously at the rate of about 2–5 mm per month. Eyelashes (vibrissae) are also classified in this category but clearly these do not grow as fast and are inherently shorter.

4. Tactile/sinus hairs. These are larger and more isolated hairs mostly found on the face, eyelids and ears. They are associated with sensory nerve endings and play an important tactile role.

The hair coat of the horse varies with breed and with seasonal as well as environmental influences. Horses that live in cold conditions tend to have longer hair than those living in permanently hot conditions – although the moulting cycle still takes place. A horse that lives in the arid deserts of Africa does not grow a long hair coat at all and those living in very cold climates tend to have denser and longer coats at all stages in the year; both of course do still shed seasonally. Some breeds will grow very thick winter coats when in their natural environment of very cold conditions and this can be confused for abnormal hirsutism. Horses that move from one type of climate to another will adapt to the new circumstance over a few hair-shedding cycles.

Skin and hair alterations in disease states

The response the skin shows to insult or disease is reflected in changes in its physical appearance or texture. Alterations in the hair density or colour are also common signs of skin disease, but in some cases these occur in the absence of any apparent local disease process.

Changes in physical appearance might be very significant to the dermatologist but taken alone may serve to confuse the possible diagnosis and treatment. Although there are some pathognomonic changes in some diseases that make diagnosis relatively straightforward, there are many disorders that are almost indistinguishable clinically. This emphasizes the need for detailed history and clinical examination as well as the careful selection of further diagnostic procedures. Usually some pathological evidence can be obtained provided that the samples are truly representative of the abnormal condition. Possibly the most difficult change to detect and assess pathologically are the pigmentary changes in the absence of hair loss.

The skin can be an indicator of systemic disease; for example, a horse with generalized lymphoma may have obvious cutaneous nodules that may on their own resemble other conditions such as nodular sarcoid or melanoma. Liver disease may manifest as cutaneous jaundice or photosensitization affecting the white parts of the body. The cutaneous signs of equine systemic lupus erythematosus-like syndrome and equine sarcoidosis (generalized granulomatous disease) may be by far the most obvious visible evidence of the conditions but these cutaneous symptoms can resemble other conditions also and in many such cases the changes are subtle. There are also skin diseases with systemic implications; and it is therefore important again that a full clinical examination is performed when investigating a dermatological complaint.

Note

It is easy to overlook the skin when dealing with more ‘significant’ clinical signs but careful dermatological examination can be very helpful in identifying systemic disease and systemic signs of cutaneous disease can also be helpful diagnostically.

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