The skin has a range of pattern reactions which usually remain true to type but may be mixed; they are provoked by every conceivable toxin including drugs, systemic bacterial and virus infections, reticuloses, malignant neoplastic disease and as part of auto-immune reactions. The margins of definition are blurred, yet it is useful to define the separate reactions, as the commoner cause varies in each and the prognosis varies accordingly.
This eruption is acute in onset, the extent of the lesions varies greatly, but the sites usually affected are the face, the flexor aspect of the forearms, hands in either aspect and knees. In very severe eruptions the whole body may be involved. As the name implies the lesions are polymorphic; pink papules and slightly raised discs usually form some of the elements. The characteristic lesions are described as erythema iris and consist of annular red lesions with a purple centre which in time develops a play of colours similar to a bruise. When severe the centre of this target lesion consists of a vesicle or rarely a sizable bulla so that this is one of the causes of a blistering eruption.
The other characteristic of this reaction is involvement of the mucosae, usually the mouth only. The buccal mucosa is shed leaving a raw red surface to which shreds of mucosa still adhere; the tongue and red margin of the lips may be similarly affected, the lips rapidly becoming crusted by serous exudate. Similar changes can occur in the vulva and there may be urethritis. Involvement of the eyes may cause conjunctivitis, which can be sufficiently severe to produce adhesion between palpebral and bulbar conjunctivae; alternatively when precipitated by virus infection phlyctenular conjunctivitis can occur. Mucosal involvement of this type can occur in all three sites with no or very little involvement of the skin but is more common in severe reactions with a profuse eruption, pyrexia and profound constitutional disturbance. Various synonyms, including Stevens-Johnson syndrome, have been given to this wide range of reactions but they are better thought of as one entity.
Whether the attack is mild or severe it lasts for about 10 days, at the end of which time the lesions subside rapidly, though repair of the buccal mucosa is slower.
The commonest cause is a virus infection and in one-third of cases this is herpes simplex. There is an interval of about 10 days between the attack of herpes and the eruption of erythema multiforme, so that if mild the herpes may be forgotten unless a special enquiry is made, or if severe the mouth lesions of the toxic eruption may obscure the remains of the herpes. Herpes simplex being commonly recurrent the accompanying erythema multiforme may recur in greater or lesser degree with each attack though usually after a year or two the tendency to produce this toxic eruption subsides, even though the herpes continues to recur. Less commonly other virus infections such as virus pneumonia may precipitate this reaction and occasionally it may be seen in the prodromal stage of the exanthemata. Str. haemolylicus is an occasional cause, usually as finger pulp infection rather than tonsillitis, and Mycoplasma pneumoniae has been recovered from blister fluid in a small number of cases.
Drugs, in particular barbiturates and sulphonamides, are almost as common a cause as herpes simplex, giving rise to the complete clinical picture with mucosal involvement and they are the commonest cause of very severe attacks with constitutional disturbance. Some of the widespread fixed drug eruptions bear a close resemblance to erythema multiforme. Toxic epidermal necrolysis (Lyell’s syndrome) resembles severe erythema multiforme.
Other rare systemic diseases such as leukaemia and disseminated lupus erythematosus may give rise to erythema multiforme, so that if the cause is not obvious the patient should be investigated with such entities in mind.
Treatment. Those cases due to virus infection are often mild and the only treatment necessary is rest for a few days to enable an antipruritic lotion such as calamine lotion with I per cent phenol to be applied. If itching is troublesome, antihistamines may relieve this but will do nothing to shorten the course of the disease. In recurrent outbreaks precipitated by herpes simplex early treatment of the infection with idoxuridine (page 77) may prevent or modify the subsequent erythema multiforme.
Severe attacks are often the result of drug sensitivity which must be recognised and its administration stopped; but once triggered off this seems to be an ‘all or none’ reaction and does not begin to improve until it has run its course of about 10 days.
Systemic steroid therapy has little or no effect in shortening the attack but is indicated if there is severe constitutional disturbance with pyrexia and signs of collapse with lowered blood pressure. In such a case prednisolone 30 mg should be given each day until the condition is controlled, then gradually diminished and stopped. An antipruritic lotion is sufficient application except in those patients with large bullae. If tense, these should be pricked to allow the serum out in order to retain the roof as a cover for the erosion and an antibiotic cream applied to prevent secondary sepsis.
Mouth lesions are always uncomfortable and may necessitate a semifluid diet. The application of chlortetracy cline 250 mg in 10 ml of water as a paint gives some relief.
The onset of erythema nodosum is usually sudden and in all except the mildest attacks the patient is pyrexial and suffers flitting joint pains and sometimes joint swellings which are often erroneously supposed to be rheumatic. The lesions characteristically appear on the shins as red nodules, about 3—4. cm in diameter. They are initially bright red and shining, but with the passage of time they may assume the same play of colours as a bruise and fade leaving bruise marks behind. Painful and throbbing when erupting they are very tender to touch. Oedema of the legs rapidly accompanies the nodules and can be severe if the patient persists in remaining ambulant. Usually the nodules are symmetrical and a few scattered smaller lesions may also appear on the thighs and extensor aspect of the arms. Occasionally the first lesion is unilateral and forms an extensive plaque of tender erythema which can be mistaken for cellulitis. Rarely lesions of erythema multiforme accompany this eruption.
There are two important causes in Britain, streptococcal infection and sarcoidosis. Their proportions vary according to the age and domicile of the patient.
In Sheffield, 75 per cent of cases in adults are precipitated by a streptococcal sore throat or tonsillitis 10-14 days before the onset of lesions. In children, the number due to primary tuberculous infection is now very small in Britain but is still significant in many other countries. In these cases the lesions appear at or shortly after the time at which sensitivity to tuberculin has been demonstrated to change from negative to positive. In children the majority of cases are caused by streptococcal infection, but it must not be assumed that the history of a preceding sore throat rules out tuberculosis as it is also found in cases of erythema nodosum of definite tuberculous aetiology. In the adult, the number of cases of tuberculous aetiology is very small.
Sarcoidosis shows such a wide range of incidence in different localities that it can be found to be responsible for one-third of adult cases in Buckinghamshire and for less than 10 per cent in Yorkshire.
Other causes are rare and consist of drug reactions, particularly to sulphathiazole; similar nodules may occur in meningococcal septicaemia though usually smaller; leprosy, especially when under treatment with dapsone, may produce these lesions as a reaction; coccidioidomycosis in areas in South West United States where it is endemic can give rise to similar lesions.
Investigation of the patient reveals a slight rise in the total white cell count with insignificant changes in the differential count. The sedimentation rate is markedly elevated and takes from 2—6 months to return to normal. In sarcoidosis the chest x-ray can help by showing bilateral hilar node enlargement or there may be miliary, linear or nodular infiltration of the lung fields. The Mantoux test should be performed with 1:10,000 tuberculin as in primary tuberculosis the reaction may be severe; in sarcoidosis lower dilutions provoke no reaction in 50 per cent of patients. The antistreptolysin titre will be raised in cases of streptococcal origin and repeated rising titres provide additional support for the diagnosis. The presence or absence of haemolytic streptococci in throat swabs is not useful evidence, since at the stage of this sensitisation reaction they may have been dispersed by antibiotics and secondly, positive cultures have been obtained from the throats of patients with erythema nodosum who have a definite tuberculous infection. Biopsy of the lesions is of no help in deciding the aetiology and shows a perivasculitis in the upper portion of the subcutaneous tissue with an infiltrate of neutrophils and lymphocytes, these also invade the vessel walls of larger veins and there is marked endothelial proliferation. Older lesions also contain giant cells and foci of epithelioid cells. Sarcoidosis may be also present with additional papular lesions in the skin and biopsy of these is more helpful in showing typical histology of dermal clumps of epithelioid cells.
Treatment. The general management of the patient depends on the aetiology which these investigations establish but as far as the skin lesions themselves are concerned, the course of the disease is similar. Individual lesions last less than 2 weeks; the time during which new lesions recur depends on whether the patient is at rest, and if put to bed, new lesions usually cease within 2 weeks. If however the patient has not sought advice and remains ambulant, fresh crops of lesions may appear for a month or more, if lesions recur for more than 6 weeks the diagnosis should be reconsidered. Sometimes, even when at rest in bed, the temperature is slow to settle to normal; we have observed this in several patients with previous histories of rheumatic fever but in none was there any evidence of reactivation of rheumatism.
Rest in bed with a cradle to take the weight of the bed clothes off the lesions and analgesics if necessary is the treatment of choice. The patient should remain in bed until the lesions have resolved, as too early mobility can provoke another crop. Corticosteroid therapy is, in our opinion, unnecessary and undesirable.
In very mild cases where bed rest is impossible for social reasons, adhesive clastic bandaging may be applied, with the adhesive side outwards, from the toes to the knees then covered with a bandage. This can be left in place for a week at a time and enables the patient to be ambulant without producing oedema of the legs, nevertheless, as much rest as possible should be advised. Recurrences are not uncommon in the streptococcal group if a fresh infection is acquired.
Erythema induratum (Bazin’s disease)
This is a rare disease which is important because its most common cause is active tuberculosis. It occurs on the lower calves in the area of erythrocyanosis; this chilblain-type of circulation provides a sufficiently sluggish circulation for the deposition of tubercle bacilli which have frequently been isolated from lesions. Young women are predominantly the sufferers.
The lesions consist of deeply infiltrated plaques and nodules, cyanotic in colour, cold to touch and symmetrically situated on cold blue areas of the calves. Some of the lesions ulcerate forming deep punched out ulcers about 1-2 cm in diameter. Chilblains may occur on a similar site but the nodules and plaques which they produce are superficial and do not produce the brawny induration of erythema induratum; if they ulcerate, they do so very shallowly producing little more than a break in the epidermis.
In some cases there is a history of tuberculous infection but in others a systematic search may have to be made to trace the site of active disease which may be in the lungs, abdominal lymph nodes, kidneys or bones. Pyrexia, a high sedimentation rate, a strongly positive Mantoux test, and raised gamma globulin are the usual findings in such cases. Chronic streptococcal infection has been incriminated in some cases but so high is the incidence of tuberculosis as the cause of this disease that even if the focus of infection cannot be traced it is advisable to treat the patient with a full antituberculous regime.
This is an allergic reaction to infection, the most commonly traceable cause being streptococcal. Occasionally drugs such as penicillin may be incriminated but it is difficult to dissociate antibiotic drugs from the infection for which they were prescribed. The protean manifestations of the disease are due to the fact that the basic lesion is an inflammation of small blood vessels sometimes associated with fibrinoid necrosis of their walls, which can involve any organ but it is the appearance of skin lesions which establishes the diagnosis.
Anaphylactoid purpura may occur at any age, the classical sequence of streptococcal tonsillitis followed after 10—14 days by the skin lesions and other manifestations is commoner in children. In the adult, drugs causing immune complex disease and the dysproteinaemias such as macroglobulinaemia and cryoglobulinaemia may produce similar skin lesions.
Skin lesions are not necessarily the first manifestation; they consist of urticarial papules 0.5 to 1 cm in diameter into which is a varying degree of purpura, so that this may appear to be the basic lesion. It is therefore important to notice that these lesions are raised and palpable, unlike thrombocytopenic purpura which produces no alteration in the skin texture. If the degree of purpura is severe enough to produce an ecchymosis the centre of the papule may become necrotic and form a small circinate ulcer with a black slough; gravity increases the purpura and necrotic ulcers are therefore more common on the feet and legs.
The skin lesions may consist of only a few papules on the feet and legs which are of diagnostic help only to the observant, or can be profuse, in which case the thighs, buttocks, arms and extensor aspect of the upper arms are predominantly involved, though scattered lesions may affect the trunk. Hess’s test of capillary fragility is negative (except for an increase in purpura in the lesions). The skin lesions tend to recur in crops and in the attack two or three crops during about 6 weeks is the usual course.
Preceding or coinciding with the skin lesions the most common symptom is flitting joint pains sometimes with obvious hydrarthrosis. Any joint may be affected but commonly the wrists, ankles and knees. The patient is usually febrile. Abdominal pain may accompany melaena and in young people appendicitis may be diagnosed if the skin eruption is not noticed. Haematuria and albuminuria denote involvement of the kidneys but it is uncommon for the haematuria to be more than microscopic, despite the fact that kidney biopsy has established that some degree of renal involvement occurs in all cases. The usual lesion is a focal glomerulo-nephritis and the prognosis in these cases is good, two-thirds recover completely. Occasional patients show a florid diffuse proliferative glomerulo-nephritis and in these the risk of renal failure and death is greater. Pathological investigation also demonstrates a raised sedimentation rate in most cases and in many a rising antistreptolysin titre suggesting a recent streptococcal infection as the cause. In the adult the immunoglobulins and fibrinolytic activity should be studied and a search made for cryoglobulins.
In acute cases the patient should be kept at rest in bed until the skin lesions cease to appear and until haematuria, if present, has ceased. Systemic corticosteroid therapy should only be used if there is evidence of severe involvement of the kidneys; its effectiveness is doubtful as it has no effect on the skin lesions though it does control the joint symptoms. Continuous oral penicillin is a valuable prophylactic measure in children suffering recurrent attacks associated with tonsillitis.
Rarely the eruption continues in crops for months or years; obviously bed rest is out of the question in these cases but sometimes corticotropin therapy helps.
This is a further degree of hypersensitivity reaction than those already described; small arteries and arterioles throughout the body are involved in localised areas of inflammation, producing nodules. Circumstantial evidence points to drugs as the most common cause. In the skin all the eruptions of erythema multiforme, urticaria, purpura and anaphylactoid-type purpura and erythema nodosum may be produced, often in a polymorphic eruption. Nodules in the skin formed by involved arterioles are a useful diagnostic sign and confirmation can be established by biopsy of such a nodule.
In more chronic cases damage to skin arterioles produces broken areas of fixed livedo due to capillary stasis.
The acute form of the disease causes a severe febrile illness and the damage caused by involvement of the arterioles may affect any system, producing an endless variety of symptoms and signs which include peripheral neuritis, abdominal pain and melaena, haematuria and evidence of lung damage. Corticosteroids and immunosuppressant drugs may be combined in treatment.
Chronic discoid lupus erythematosus
This is a disease of unknown aetiology which occurs in the third and fourth decades of life in women more often than men. Usually the lesions occur on the face in the area of the nose and cheeks, forehead or preauricular area. Symmetry is uncommon and the classical distribution over the ‘butterfly’ area formed by nose and cheeks is rare.
The lesions are sharply demarkated discs of slightly scaly erythema. The degree of thickening and infiltration varies; long standing lesions are scarred in tha centre though they may still show active edges. On close examination the follicles are prominent owing to the formation of a keratin plug which is characteristic and can sometimes be demonstrated by peeling off a scale and showing the follicular plugs adhering to its under surface as a brush, of spikes. Telangiectases are usual in the lesion and it is important to notice that no translucent nodules are present when the blood is expressed with a glass slide, thus differentiating it from lupus vulgaris. Lesions may occur in the scalp producing loss of hair; when activity ceases a pale scarred area of permanent baldness remains. More widespread discs occur in some cases involving the dorsum or palmar aspect of the fingers. Exposure to sunlight aggravates the patches and can be such an important factor that activity occurs only in the summer months.
Haematological investigation of cases of chronic discoid lupus erythematosus reveals a raised sedimentation rate in about one-third of cases and presence of LE cells in approximately one-fifth; a few cases may show other abnormalities such as leukopenia, presence of anti DNA and antinuclear antibodies, rheumatoid factor and positive Coombs tests. In cases where the histological changes are equivocal the presence of immunoglobulins and complement in a basement membrane band can be demonstrated by immunofluorescent techniques. However, despite these findings less than 5 per cent of cases of typical discoid lupus progress to subacute or acute systemic lupus erythematosus; the vast majority of patients remain in good health apart from the skin lesions and even these tend to heal over the course of years regardless of treatment.
Treatment. There is no specific treatment of chronic discoid erythematosus since the aetiology is unknown. The lesions should be protected from direct sunlight by the wearing of a hat and the application of a light-barrier cream. The application of fluorinated steroid creams, of which clobetasol propionate (Dermovate) seems most successful, suppresses most lesions; maintenance application is necessary for months once the lesions have healed. If this is unsuccessful, infiltration of the lesion with triaminolone by injection is successful in those areas where such a measure is not too painful. Chloroquine sulphate 200 mg three times daily usually heals the lesion if local steroids fail but should be given only as the last resort and in courses which are broken in the winter months to avoid toxic effects on the eyes.
Systemic lupus erythematosus is too rare a disease to be described in detail here. Its main presenting features are of an acute or subacute pyrexial illness mainly affecting women in the reproductive period of life. Skin eruptions may be present and the most usual is a blotchy erythema of the face, neck, V area, hands and arms associated with oedema of the face. Toxic alopecia occurs in most cases. Associated with the skin lesion are a variety of systemic signs including polyarthritis, kidney damage, involvement of serous membranes and blood vessels. In addition to the LE cell phenomenon systemic lupus patients produce a number of abnormal serological reactions due to a variety of auto-antibodies which react with different components of body cells and tissues.
Lymphoma and myelosis
Lymphomas are a group of malignant tumours arising usually from multiple foci of the lymphoid reticular system. The lymphomas may be monomorphic and composed of stem cell, reticulum cell or lymphocytic series or they can be polymorphic as in Hodgkin’s disease and mycosis fungoides. Leukaemia may be present at some stage in these groups or it may never arise. Myelosis designates tumours of the myeloid system and is nearly always associated with myeloid leukaemia.
Just as the mode of presentation of these diseases varies greatly so do the cutaneous signs, many of which are shared between all groups. Determination of the type of cell involved rests with the pathologist.
Toxic symptoms produce the usual non-specific cutaneous patterns of pruriginous papules, erythema multiforme-like lesions and purpura. Generalised pruritus in the absence of any apparent cutaneous cause may precede signs of Hodgkins disease by months or years and, more rarely, occurs in lymphatic leukaemia. The persistence of such intractable itching in a young adult should be investigated at intervals for the development of lymphoma or hepatic disease.
Rarely Hodgkin’s disease gives rise to an acquired form of ichthyosis.
In those cases of generalised exfoliative dermatitis occurring without any history of previous skin disease it is important to exclude the possibility of underlying Hodgkin’s disease, lymphatic leukaemia or mycosis fungoides.
Interference with blood cell formation and resistance to infection produces another motley collection of signs. Purpura may be associated with thrombocytopenia, in which case Hess’s test will be positive. Furunculosis can be a presenting symptom especially in myeloid leukaemia, boils failing to heal because of infiltration with leukaemia cells so that painful ulcerated nodules are formed. Herpes zoster is a relatively frequent occurrence in the lymphomas, especially in Hodgkin’s disease and lymphatic leukaemia. In such cases a generalised chicken-pox like eruption accompanies the localised zoster and this development should be an indication for investigation for underlying disease.
Infiltrations of the skin occur in all groups and consist of nodules and plaques; the nature of the infiltrate can only be determined by biopsy. Infiltration of the skin is rare in Hodgkin’s disease and usually breaks down to produce painful intractable ulceration. Large nodules in elderly people are often due to reticulum cell lymphomata. Reddish brown profuse translucent nodules in those over 45 years of age may be due to lymphatic leukaemia, but in the same age group an identical appearance can be produced by carcinomatosis.
Mycosis fungoides is a cutaneous syndrome produced by a pleomorphic infiltrate similar to Hodgkin’s disease. Infiltration of the skin and tumour formation are the final stages of this lymphoma and are preceded by a variety of non-specific eczematous or psoriasiform eruptions whose severe itching and lack of response to treatment suggest the ultimate development of mycosis though this may not become apparent for years.
One pattern of eruption which is easier to identify as a possible precursor of mycosis fungoides is known as parapsoriasis en plaques. This presents in the adult as slightly brownish red macules which may be isolated, or coalesce into figurate patterns. Once formed they remain completely resistant to treatment and development into mycosis fungoides can take place after many years. The final pattern produced is a mixture of lesions of parapsoriasis, areas of infiltration of the skin and ulcerated exuding nodules 2-4 cm in diameter.
The commonest cutaneous lesions produced by internal carcinomata are nodules in the skin due to secondary deposits. Their nature may be guessed from the age and symptoms of the patient and determination of their source can usually be established by examination of biopsy material.
Rare toxic eruptions occur in association with carcinomata and can resemble pemphigoid in producing bullae, can mimic the fixed lesions of lupus erythematosus or produce a gyrate erythema on the trunk, therefore the possibility of underlying malignant disease should be considered in any unusual eruption in patients over 45 years of age. Dermatomyositis is also precipitated by malignant disease in about 20 per cent of cases above middle age, though it occurs without this association in younger age groups. The condition presents with muscle weakness and wasting caused by inflammatory changes in the muscles. Associated with this is an acute erythema of the light exposed areas of the face and arms, oedema of the face and especially of the eyelids which assume a characteristic violet colour, a streaky erythema over the tendons on the dorsum of the hands and telangiectasia of the nail beds.