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NEUTROPHILIC DERMATOSES

This comprises a group of disorders, with some overlapping clinical and histologic features, which are characterized by a predominantly perivascular neutrophilic infiltrate that may exhibit leukocytoclasis (fragmented nuclear remnants in the tissues) and some endothelial swelling, but most do not have a true vasculitis.

    These disorders are important for several reasons. They often have rather dramatic clinical features, are often accompanied by systemic malaise and neutrophilia, and many of them may be associated with significant internal disease. In some instances, such as rheumatoid neutrophilic dermatosis (which is not discussed further here), the internal association is with a specific disease entity. More commonly, the reaction does not identify a specific cause but raises the suspicion of one of several internal disorders. In particular, many of this group of neutrophilic dermatoses are associated with leukemia and other hematologic malignancies; in this context, they can even occur during periods of therapeutic granulocytopenia.

Acute febrile neutrophilic dermatosis (Sweet syndrome)

Etiology and pathogenesis

This disorder was described in 1964. It is characterized histologically by a predominantly neutrophilic infiltrate, classically without vasculitis, although this has been demonstrated in some cases. Associated disorders include the following.

Clinical features

The eruption is of acute onset, often with associated fever and neutrophilia (as suggested by the name), although these are not invariably present; the neutrophilia may be limited to the tissue infiltrate. Women are most commonly affected. The lesions are well-demarcated, elevated, inflammatory plaques, usually multiple, which may be studded with pustules or yellowish papules termed pseudopustules (Figs 14.50–14.56). The neck, trunk, and upper limbs are the most frequent sites. There may be associated conjunctivitis. Non-specific features such as malaise, elevated ESR, and elevated C-reactive protein are common but constitute only minor diagnostic criteria. Biopsy confirmation is often appropriate, and underlying disorders should be sought with appropriate investigations. This is particularly important in the small minority who get chronic lesions or recurrences. In any patient with neutrophilia, it is useful to check a convalescent blood count to ensure that this has resolved and does not represent a leukemic process. Occasionally in leukemia-associated Sweet disease, there may be atypical granulocytes in the skin biopsy.

Figure 14.50 Sweet syndrome. Discrete, very inflammatory plaques on the upper back.

Figure 14.51 Sweet syndrome: a case with rather more confluent lesions, which may be confused with erythema multiforme. This patient had thyroid disease, which is associated with Sweet syndrome.

Figure 14.52 A minority of patients with Sweet syndrome have recurrent episodes or chronic lesions, as in this patient. Treatment with dapsone was administered.

Figure 14.53 Frank pustular lesions may occur in Sweet syndrome, although some authors would view this acral pattern as a specific variant of pustular vasculitis. These lesions may leave a rather rippled pattern of scarring.

Figure 14.54 Sweet disease in a patient with myelodysplasia; sometimes in hematologic disease, there may be bullous lesions and an overlap with the appearances of pyoderma gangrenosum.

Figure 14.55 Ocular inflammatory changes may occur as part of the spectrum of Sweet syndrome, in this case in a patient with exophthalmos due to thyrotoxicosis.

Figure 14.56 Pseudopustular lesions representing part of the spectrum of neutrophilic dermatoses, in a patient with exacerbation of inflammatory bowel disease. The lesions resembled pustules but were solid and sterile; the yellowish color was due to the intense neutrophilic infiltrate.

In some instances, lesions may essentially be confined to the backs of the hands. Such lesions may ulcerate, may resemble a vasculitis or pyoderma gangrenosum, and may leave scarring when they resolve. This disorder has a neutrophilic infiltrate and may show more necrotic vascular changes than are typical of Sweet syndrome; it has been termed pustular vasculitis of the dorsal hands but is probably a variant of Sweet disease and should be managed accordingly (usually with prednisolone or dapsone).

Differential diagnosis

This includes the following.

Treatment

Underlying conditions should be treated as required. The lesions may respond to strong topical corticosteroids, although a short course of oral corticosteroids is often helpful to treat the associated fever and malaise (usually at moderate 10–20 mg doses). Dapsone may be required in more persistent cases. Doxycycline, ciclosporin, colchicine, and potassium iodide have all been used.

Pyoderma gangrenosum

Etiology and pathogenesis

Pyoderma gangrenosum (PG) is important as, although it can occur in isolation, it is strongly associated with underlying medical disorders. The three main groups are:

Pyoderma gangrenosum occurs in 1–2% of patients with ulcerative colitis (UC), and is five times as common in UC compared with in Crohn disease; IBD accounts for about 50% of cases of PG. The other important causes are hematologic malignancies (leukemias and myeloproliferative disorders, myelofibrosis, and paraproteinemias), but a few cases occur in patients with inflammatory joint disease such as rheumatoid arthritis. Other rare gastrointestinal associations include chronic active hepatitis and carcinoid tumor. Although it may parallel the course and severity of the gastrointestinal disease, PG may occur in patients without contemporary gastrointestinal symptoms. The fact that it has been reported up to 10 years after panproctocolectomy is clear evidence that a diseased bowel does not need to be present for PG to occur, and suggests that this disorder is related to the colitis phenotype itself.

Clinical features

The characteristic lesion of PG is a rapidly evolving, tender, inflammatory skin ulcer (Figs 14.57–14.63). This may initially appear as a pustule or small nodule, but rapidly breaks down to form a necrotic ulcer that typically has a bluish, undermined ulcer edge and surrounding inflammation. Lesions may occur at any site, but the commonest is the lower leg. Lesions at less common sites may cause diagnostic uncertainty; PG of the face or scalp is particularly difficult to diagnose with confidence.

Pyoderma gangrenosum should always be considered in cases of peristomal ulceration, even if the stoma was not as a consequence of IBD, although this is much the most frequent association.

Ulcers of PG are usually solitary but may be multiple. They often occur at sites of minor injury (a process known as pathergy). Less commonly, verrucous, pustular, or punched-out necrotic areas may be the dominant lesion.

Figure 14.57 Typical ragged inflammatory ulceration of pyoderma gangrenosum.

Figure 14.58 Pustular macerated lesions are typical of rapidly progressing lesions of pyoderma gangrenosum, shown here (a) on the hand and (b) on the leg.

Figure 14.59 A bolstered blue border around a painful and progressive ulcer is very suggestive of pyoderma gangrenosum.

Figure 14.60 Lesions of pyoderma gangrenosum may occur at sites of tissue injury (pathergic response), in this case at sites of stripping of varicose veins.

Figure 14.61 A chronically inflamed area of pyoderma gangrenosum with discharging areas. Clinically, this could be an area of panniculitis, as the discharge has the oily appearance that occurs with liquefied fat.

Figure 14.62 Cribriform scarring is typical of pyoderma gangrenosum. The scar has small perforations or pits, resembling a colander.

Figure 14.63 Peristomal pyoderma gangrenosum in a patient with ulcerative colitis; this is a difficult management problem, and may initially be misdiagnosed as a dehisced or infected wound.

Differential diagnosis

The main differentials are as follows:

Treatment

Gentle debridement of the ulcer may be helpful, but attempts at excisional surgery should be avoided in any form or site of PG, as it typically exhibits a pathergic response and recurs.

Some lesions respond to strong topical or intralesional steroid injection, or to topical tacrolimus, but systemic therapy is often required. The choice of systemic therapy may depend on the treatment required for any underlying disorder, as this may lead to resolution of PG; for example, if the patient has severe active IBD that requires infliximab infusions, then this is likely to heal the PG. In some cases, combining systemic and topical therapy, or combining systemic agents with a different spectrum of side effects (Ch. 4), can be useful to limit doses. Systemic treatment options include the following.

PRACTICE POINTS

Behçet disease

Etiology and pathogenesis

Behçet disease is an uncommon multisystem disorder of uncertain etiology, which is most common in Japan and eastern Mediterranean countries. It is strongly associated with human leukocyte antigen (HLA)-B51, especially in areas of high prevalence or with high frequency of ocular disease in affected individuals (such as Japan and Turkey ). Early skin lesions have a perivascular neutrophilic tissue reaction or small-vessel vasculitis; later lesions may be lymphocytic. It may be best viewed as a disorder that lies between neutrophilic dermatoses and vasculitides.

Clinical features

The diagnosis of Behçet disease is clinical, as there are no specific laboratory tests. Diagnostic criteria are listed in Table 14.7. The development of lesions at the sites of needle prick injury (known as a positive pathergy test) is common in Turkish people but less so in the UK or USA . In some populations, the increased frequency of HLA-B51 is useful diagnostic support.

In most patients, the earliest feature is oral ulceration. Other features may take many years to become apparent. It is likely that milder cases also occur; for example, it is not uncommon to see individuals who have occasional aphthous ulcers, or a severe solitary episode of genital ulceration (even multiple episodes), but with no other features (see Ch.  20). Such patients do not meet the diagnostic criteria in Table 14.7, but perhaps these criteria suffer from the limitation that patients without oral lesions are excluded. Skin lesions include the ulcers discussed earlier, papulopustules and acneiform lesions, pseudofolliculitis, vasculitis (see Fig.20.5), and erythema nodosum.

Ocular features, typically iritis, occur in about 50% of patients and are most frequent in males; retinitis is the potentially most severe ocular feature, which may lead to blindness.

Arthritis is usually episodic and mono- or oligoarticular, usually affecting the knees.

(From International Study Group for Behçet's disease. Criteria for diagnosis of Behçet's disease. Lancet 1990; 335: 1078–80.)

Differential diagnosis

The differential includes various causes of oral and/or genital ulceration, including severe idiopathic (‘major') aphthous ulceration, herpangina, herpetic gingivostomatitis, Crohn disease, various sexually transmitted diseases, and artefactual ulceration.

Treatment

This varies according to disease severity. Topical agents that may be helpful for oral aphthae include various types of corticosteroid application (lozenges, pastes, and mouthwash) or sucralfate rinse. Topical steroids or local application of sucralfate can help genital lesions. Intralesional steroid injection can be very effective for localized oral or genital ulceration. In patients with vasculitis, immunosuppressive therapy is used and may include corticosteroids, azathioprine, ciclosporin, colchicine, dapsone, and others. Thalidomide is particularly useful for orogenital ulceration, but has the potentially irreversible side effect of peripheral neuropathy and is strictly contraindicated in pregnancy; it therefore requires monitoring by repeated nerve conduction studies and would not generally be considered a first-line treatment.

Other neutrophilic dermatoses

Bowel-associated dermatosis–arthritis syndrome

Although originally described as the bowel bypass syndrome, this entity is due to antigenic stimulus from bowel bacteria leading to immune complex formation, and occurs in other situations where there is bacterial overgrowth.

The clinical features are a purpuric and pustular skin eruption, with crops of lesions associated with arthralgia, arthritis, myalgia, fever, and malaise. Lesions resembling erythema nodosum (Fig.14.64), and ulceration (PG) may also be prominent. Raynaud phenomenon and nephritis may occur. Treatment is with appropriate antibiotics and resolution of the underlying bowel defect if possible; corticosteroids and immunosuppressive therapy may also be required (as for PG).

Subcorneal pustular dermatosis (Sneddon–Wilkinson disease)

This is a neutrophilic dermatosis but is not centered around vessels; it is clinically manifest as blistering and is thus discussed in Chapter 16.

Figure 14.64 Bowel-associated dermatitis– arthritis syndrome. Some lesions resemble erythema nodosum; the most inflammatory lesion has ulceration reminiscent of pyoderma gangrenosum.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.