Neutrophilic dermatoses

Clinics in Dermatology (2006) 24, 470 – 481

Neutrophilic dermatoses Arturo P. Saavedra, MDa,b,*, Susanne Christine Kovacs, MDc,d, Samuel L. Moschella, MDa,d a

Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115, USA c Department of Dermatology, Tufts University School of Medicine, Boston, MA 01805, USA d Department of Dermatology, Lahey Clinic, Burlington, MA 01805, USA b

Abstract Neutrophils may infiltrate all layers of the skin and consequently may cause different disorders, each with its own characteristic clinical and laboratory findings. We discuss how these disorders present and how they are diagnosed and treated. In addition, important associations with internal diseases are discussed to assist clinicians in evaluating for a concurrent illness. Because treatment of these disorders may often require systemic therapy, the potential short-term and long-term effects of commonly used medications are discussed. Finally, treatment of recalcitrant diseases, mostly by use of therapies published in the form of small case series or reports, is also included to guide clinicians in dealing with the more challenging cases. D 2006 Elsevier Inc. All rights reserved.

Introduction The neutrophilic dermatoses comprise a group of disorders characterized by recruitment of polymorphonuclear leukocytes to various layers of the skin. A disseminated disease is more likely to present with systemic symptoms, including arthralgias, fever, malaise, and weight loss, whereas a localized disease most often assumes a chronically recurrent and remitting course. In addition, associations with systemic diseases, which may often guide further diagnostic testing, are important to recognize. Histopathologic findings are helpful in making a diagnosis and localizing the predominant area of infiltration, which includes subcorneal, intraepidermal,

* Corresponding author. Tel.: +1 617 732 6510. E-mail addresses: [email protected] (A.P. Saavedra)8 [email protected] (S.C. Kovacs)8 samuel _ l _ [email protected] (S.L. Moschella). 0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2006.07.009

dermal, and panniculitic diseases.1 Because systemic therapy may be necessary in recalcitrant diseases, it is important to think about comorbidities in patients and side effects that may arise during and after treatment.

Acute febrile dermatosis (Sweet’s syndrome) Also known as acute febrile dermatosis, Sweet’s syndrome is an idiopathic disorder that is commonly associated with systemic diseases. Although it has no racial predilection, it appears to be more common in women than in men, with a 4:1 predilection. There is a trend toward a higher prevalence in Japan, and cases have been reported in children and adults. Criteria that rest primarily on the abrupt onset of cutaneous lesions and consistent histopathology, in addition to prompt response to corticosteroid therapy, have been developed for diagnosis.2 On presentation, patients may

Neutrophilic dermatoses complain of fever with a temperature of up to 398C, arthralgias, and myalgias, which are likely the result of dysregulation and secretion of cytokines. Tender erythematous plaques and papules that are classically nonpruritic are noted on physical examination (Fig. 1). Some plaques may exhibit yellowish discoloration and a pseudovesicular or mamillated surface caused by tissue edema and neutrophilic infiltration into the subcutis. As edema further accumulates, the lesions of Sweet’s syndrome may progress to vesicles and bulla formation. Pustules can also be seen. Lesions may occur anywhere on the body; however, they mostly appear on the neck, upper trunk or extremities, as well as at the site of trauma and often heal without scarring. In early stages, cutaneous findings may resemble erythema multiforme. Interestingly, this disorder can involve extracutaneous tissue as well. Pulmonary disease in the form of alveolitis can present a diagnostic and therapeutic dilemma as infectious etiologies must be excluded before initiating therapy. Patients present with cough or dyspnea and with evidence of air space disease on chest roentgenogram or computed tomography. Multifocal sterile osteomyelitis as well as infiltration of abdominal viscera (liver, kidney, pancreas), the heart and striated muscles, the eyes (conjunctivitis, episcleritis, and iridocyclitis), and the central nervous system are important to identify.3-5 Specifically, leptomeningeal disease often delays diagnosis because alternative explanations may be sought before initiating treatment with corticosteroids. Musculoskeletal manifestations have been reported in 12% to 59% of cases.6 Arthralgias are common, and, infrequently, a transient oligoarthritis occurs. The arthritis can involve the upper and lower extremities, and joint manifestations may occur before, during, or after the onset of the skin lesions.7 Various associations have been made to Sweet’s syndrome, which has led to the subclassification of this disorder according to the setting in which it arises. Paraneoplastic Sweet’s syndrome presents mostly in the face (particularly cheeks) and mucosal surfaces. Mucosal findings should raise suspicion for malignancy, although disseminated diseases have also been reported in paraneoplastic Sweet’s syndrome. Hematologic malignancies, including acute myelogenous leukemia, lymphoma, and dysproteinemia, comprise most cases, but adenocarcinomas of the lung, breast, and colon are also important to rule out in addition to testicular, ovarian, bladder, and prostatic malignancies. Acute febrile dermatosis has been reported before, during, and after the diagnosis of malignancy is made.8,9 Drug-induced cases constitute a second subtype, which occurs mostly in women. Drugs commonly implicated include granulocyte-macrophage colony-stimulating factor, furosemide, hydralazine, trimethoprim-sulfamethoxazole, minocycline, nitrofurantoin, co-trimoxazole, carbamazepine, diazepam, isotretinoin, levonorgestrel/ethinyl estradiol, and all-trans retinoic acid.10 In keeping with an overall higher incidence in women, Sweet’s syndrome has also been described in pregnancy. A fourth subtype occurs in association with inflammatory bowel

471 disease, although segregation with several autoimmune disorders should also be noted. Behc¸et’s disease, rheumatoid arthritis,11 systemic lupus erythematosus,12-15 Sjfgren’s syndrome,16 relapsing polychondritis,17 Still’s disease,18 and sarcoidosis have also been associated with this syndrome. Vasculitis is not a major feature of Sweet’s syndrome. There have been several cases reported, including a young child with Takayasu’s arteritis.19 Finally, when a specific etiologic agent cannot be specified and in the absence of a comorbid disease, one may diagnose idiopathic acute febrile dermatosis, which is responsible for roughly half of cases. Low-grade infections often precede this subtype, most commonly caused by Staphylococcus and Streptococcus species, but gastrointestinal pathogens such as Yersinia are also important. Rare cases of preceding atypical mycobacterial disease, hepatitis virus, HIV, cytomegalovirus, and vaccinations have been reported.20 Laboratory tests, although helpful, are not diagnostic. Findings include leukocytosis (up to 20,000 cells/mm3 or higher) with neutrophilia and elevated erythrocyte sedimentation rate or C-reactive protein (nonspecific markers of inflammation). Particularly in cases in which Sweet’s syndrome is associated with malignancy, leukopenia, lymphopenia, and thrombocytopenia have been reported and anemia may suggest adverse prognosis. Abnormal renal function has been reported in up to 50% of patients.21 Histopathologic findings are often suggestive but not diagnostic. Evidence of edema in the dermal papillae with occasional spongiotic changes in the epidermis (although in most cases the epidermis is largely unaffected) may fortify the diagnosis. Although early lesions may show lymphocytic infiltration, reticular-dermal neutrophils are most commonly observed and often aggregate in a perivascular distribution. They can extend to the panniculus and may involve the epidermis and cause subcorneal abscesses.20 Traditionally, most lesions lack vasculitis, although reactive leukocytoclasis in the absence of fibrinoid necrosis is not rare. In addition, endothelial cell swelling and red cell extravasation may be observed. Immunofluorescence studies are noncontributory, and tissue is often sent for culture, Gram stain, and periodic acid–Schiff stain to exclude infection. Treatment is aimed at controlling inflammatory symptoms once infection has been excluded. Microbiologic cultures may be obtained as guided by a review of systems. These may include, but are not limited to, blood cultures and sputum, urine, and stool samples. Corticosteroids can be used in doses approximating 1 mg/kg for a period of at least 4 to 6 weeks while the drug is tapered slowly. Cutaneous and extracutaneous features tend to improve within the first 72 hours of therapy. Although this disease may spontaneously resolve if untreated after 6 to 8 weeks, recurrences are more common if patients are not treated initially. Prompt treatment prevents morbidity, but side effects of therapy, such as acute infection, reactivation of mycobacterial infection, hyperglycemia, hypertension, rise in intraocular pressures, and neuropsychiatric effects, must be monitored.

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Fig. 1

Sweet’s syndrome.

Long-term sequelae in adults are usually not observed in this setting, but bone demineralization and ulcer disease should also be considered relative contraindications to systemic therapy in the absence of calcium supplementation or prophylaxis against ulcer disease. Side effects are most often seen in patients with recurrent diseases driven by neoplastic disorders that require chronic low-dose suppressive therapy. In addition to systemic steroid treatment, topical and intralesional regimens may be used in limited cutaneous diseases. Steroid-sparing agents may play a role in systemic diseases and include potassium iodide (30-300 mg thrice a day), dapsone (200 mg per day), colchicine (1-1.5 mg per day), and nonsteroidal antiinflammatory drugs. Cyclosporine (4 mg/kg per day), mycophenolate mofetil, thalidomide, clofazimine, methotrexate, and interferon a combined with hydroxyurea and chlorambucil can also be used. Case reports have established successful use of doxycycline and metronidazole in monotherapy.10 More importantly, the successful use of tumor necrosis factor a inhibitors such as infliximab has been documented and reviewed.22

Pyoderma gangrenosum Pyoderma gangrenosum occurs worldwide, with an overrepresentation in women aged between 30 and 60 years. It is a chronic disease that may occur in isolation of systemic diseases 50% of the time. Its important associations include inflammatory bowel disease (ulcerative colitis and Crohn’s disease), arthritic disorders such as rheumatoid arthritis and seronegative arthritis, as well as myeloproliferative disease, myelodysplasia, and leukemia. In addition, chronic hepatitis, diabetes, thyroid disease, sarcoidosis, hidradenitis suppurativa, Behc¸et’s disease, Takayasu’s arteritis, and antineutrophil cytoplasmic antibody–positive vasculidites have also been reported in association with pyoderma gangrenosum.22-25 When associated with cystic acne and pyogenic septic arthritis, pyoderma gangrenosum completes the diagnosis of PAPA syndrome, which appears to be autosomally

dominant.26 In this syndrome, joint disease tends to precede the onset of skin involvement and onset in puberty is common.27 Drug-induced pyoderma gangrenosum can be caused by agents that curiously have often been used to treat the disease, including potassium iodide, granulocyte-macrophage colony-stimulating factor, and interferon. Particularly, granulocyte-macrophage colony-stimulating factor has also been reported as an important culprit of drug-induced neutrophilic dermatoses, such as Sweet’s syndrome. Patients typically present initially with follicular papules and pustules that form ulcers with a violaceous undermined border that are tender and rapidly enlarge (Fig. 2). Some pustules may be hemorrhagic and are surrounded by erythema. Central ulceration is the result of tissue necrosis, which heals as atrophic scars, unlike the lesions of Sweet’s syndrome, which often heal without scarring. Pyoderma gangrenosum may arise in areas of trauma that recapitulate a disease or exacerbate a preexisting disease, a phenomenon termed pathergy. Most lesions are observed in the extremities, but truncal and mucosal distribution has also been reported. In children, predilection for the face or perineal locations may occur. Finally, after tissue resection for colitis or malignancy, the disease may arise in peristomal sites.28,29 Similar to the case in Sweet’s syndrome, extracutaneous disease may involve the lung, bone, the abdominal viscera, the genitals, and the eyes in the form of ulcerative keratitis.5 Various rheumatologic entities have been identified in association with pyoderma gangrenosum30-32; these include (1) an acute oligoarticular lower-extremity predominantly nonerosive inflammatory arthritis associated with inflammatory bowel disease, (2) a systemic inflammatory arthritis that resembles rheumatoid arthritis that can be either positive or negative for rheumatoid factor, (3) a destructive erosive arthritis similar to psoriatic arthritis or reactive arthritis,31,33 and (4) seronegative spondyloarthritis.34 The synovial fluid analysis reveals sterile low-viscosity inflammatory effusions similar to those found in rheumatoid arthritis. Variants of pyoderma gangrenosum include vesiculobullous, pustular, and granulomatous forms. Vesiculobullous disease is often related to hematologic disease and

Fig. 2

Pyoderma gangrenosum.

Neutrophilic dermatoses may start as hemorrhagic pustules that quickly expand. These ulcers tend to be more superficial than in other subtypes, and the upper extremities and face are often involved.21 Pustular disease is more insidious and, when related to inflammatory conditions, often coincides with flaring disease. The patient is usually acutely and systemically ill. Granulomatous variants tend to occur superficially at the site of trauma or surgery, whereas vegetative disease may be expressed in mucosal membranes in the form of pyostomatitis vegetans.23,24,35 Laboratory tests are performed to evaluate for associated disorders rather than to establish a diagnosis of pyoderma gangrenosum. Deficiency of any hematopoietic lineage warrants workup for hematologic disorders, although it is important to note that isolated IgA monoclonal gammopathies may be observed in up to 20% of cases. In addition, IgG and IgM subtypes have also been reported. Interestingly, IgA monoclonal gammopathies are also observed in erythema elevatum diutinum and subcorneal pustular dermatosis, which have been associated with pyoderma gangrenosum.36 Serum and urine electrophoresis in addition to bone marrow examination may be obtained to test for paraproteinemias. Excluding infectious causes is important given that histopathologic examination of pyoderma gangrenosum is not diagnostic and often nonspecific. When the index of suspicion for mycobacterial or treponemal disease is high, polymerase chain reaction, a rapid plasma reagin test, and the VDRL (Venereal Disease Research Laboratory) test can be valuable adjuncts. In addition, stool studies for culture as well as ova and parasites are often sent. Histopathologic findings typically include neutrophilic aggregates with mononuclear cell infiltration and fibrotic reactions near the ulcer edge that extend into the dermis and subcutis. Giant cells may be observed in specimens obtained from patients with inflammatory bowel disease. Tissue stains for infectious organisms may reveal occasional colonization, but presence of organisms in the dermis should prompt treatment against infectious agents. A significant proportion of cases may show histology not traditionally associated with pyoderma gangrenosum, making this entity a clinical diagnosis.37 Like Sweet’s syndrome, pyoderma gangrenosum is treated with antiinflammatory agents. In mild cases, dressing changes, prevention of trauma, and supportive care may be sufficient for reepithelialization to occur. Steroids have been used with the greatest success in topical and systemic formulations. The role of intralesional therapy has also been exploited, particularly in localized diseases.38,39 Steroidsparing agents such as cyclosporine and dapsone have also been used with success. As with the case when using systemic steroids, screening for hypertension and renal disease is important before initiating cyclosporine therapy. In selective populations, assays for glucose-6-phosphate dehydrogenase activity are also indicated for those in whom dapsone is considered. Azathioprine, chlorambucil, and cyclophosphamide have been used in recalcitrant cases.

473 Case reports have documented the utility of colchicine, minocycline, clofazimine, thalidomide, nitrogen mustard, and immunomodulators such as pimecrolimus and tacrolimus. In addition, intravenous immunoglobulin is effective.40 Treatment geared toward associated disorders may ameliorate cutaneous disease but is not uniformly curative. Treatment of pyoderma gangrenosum in those with inflammatory bowel disease with infliximab infusions (5 mg/kg at 0, 2, and 8 weeks) is useful. Subcutaneous etanercept can also be used at 25 to 50 mg twice weekly. A severe recalcitrant disease had been treated with plasmapheresis.41,42 A primary surgical approach to pyoderma gangrenosum is contraindicated.

Neutrophilic eccrine hidradenitis Although it has often been considered as a result of excretion of chemotherapeutic drugs by eccrine glands, neutrophilic eccrine hidradenitis is included in this review because it is often in the differential diagnosis of neutrophilic dermatosis. In addition, mounting evidence suggest that this disorder may also arise in the setting of treatment for HIV or in the setting of malignancy previously untreated with chemotherapy.43 Neutrophilic eccrine hidradenitis presents as erythematous edematous plaques and papules, more commonly on the face and upper extremities. It has also been reported on the palms and soles. Although it may resolve spontaneously and heals without scarring, it can also recur. Patients may present with fever and arthritis, much like patients with Sweet’s syndrome; however, unlike other neutrophilic dermatoses, involvement of extracutaneous sites has not been reported for this disease. Neutrophilic eccrine hidradenitis is associated with lymphomas and leukemias, primarily chronic myelogenous variants before or as a result of treatment with chemotherapeutic agents such as cytarabine. Other drugs implicated in the development of neutrophilic eccrine hidradenitis include bleomycin, doxorubicin, chlorambucil, lomustine, mitoxantrone, and antiretrovirals such as zidovudine.43,44 In addition, a similar disease isolated to palms and soles has been linked to local pseudomonal infection.45 As a result, it is mandatory to exclude infection before making this diagnosis. On histopathology, neutrophilic infiltrates are noted surrounding and infiltrating the eccrine glands, with secondary necrosis of the eccrine epithelium, or inducing reactive metaplasia. There may also be degenerative vacuolar changes in secretory cells, but the acrosyringium is spared. Therapy is geared toward the primary disorder or discontinuation of the culprit drug, but supportive care with topical or oral steroids may be indicated. Lesions typically involute over 2 weeks to 1 month. A similar clinical entity in children, which presents with tender erythematous nodules and plaques in the absence of drug intake, has been termed idiopathic palmoplantar

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Fig. 3

Behc¸et’s disease and apthosis.

hidradenitis. Trauma has been postulated as an etiologic agent for this disease. On biopsy, nodular neutrophilic infiltrates of the sweat glands may be observed.46,47

Behc¸et’s disease A systemic multiorgan disease of unclear etiology, Behc¸et’s disease can involve virtually any organ in the body. Diagnostic criteria have been outlined.48 Etiologically, autoimmune and infectious mechanisms have been postulated, although the search for potential infectious culprits has been unrevealing.49,50 Patients should have evidence of apthous stomatitis, plus 2 other findings including genital ulcerations, skin lesions, ocular abnormalities, arthritis, and synovitis, or have a positive pathergy test finding. Racial predisposition has been observed with greater incidence in the Turkish and Japanese populations. This trend is congruent with the observed increased frequency of human leucocyte antigen (HLA) B51 in countries with the higher number of people afflicted with this disease. In addition, this marker imparts a worse prognosis on disease expression. There is a predominance of this disease in men in Middle Eastern populations, whereas women are overrepresented in Japanese and Korean populations. Peak incidence occurs between the ages of 20 and 30 years.51-54 Patients may present with symptoms in virtually any organ. When a symptom or sign presents in isolation, without concomitant aspects of the disease, diagnosis may be delayed. Recurrent apthous stomatitis, which presents as chronic, small, and erythematous macules with subsequent transition to pseudomembranes that ulcerate, is important to note (Fig. 3). These lesions are painful and tend to heal in 10 to 14 days with minimal residual scarring. Symptoms must be present at least 3 times in a 12-month period to meet diagnostic criteria. Cutaneous involvement manifests as pustular disease,55 often in the extremities (Fig. 4). Histologically, neutrophilic aggregates in the dermis and

occasional subcorneal abscesses are observed. These findings are important to distinguish from those seen in pyoderma gangrenosum, bowel-associated arthritis, subcorneal pustulosis, IgA pemphigus, pemphigus vulgaris, cicatricial pemphigoid, Stevens-Johnson syndrome, and herpetic stomatitis. In addition, papular and vesiculobullous eruptions can be noted in facial and acral distributions, which are often pruritic and painful. Erythema nodosum–like lesions are common and occur mostly on the extremities. Recurrent genital ulceration is a second diagnostic criterion. In men, penile and scrotal recurrent ulceration is noted; in women, vulvar ulceration is seen. Perianal disease is observed in men and women. It is critical to rule out infectious etiologies, particularly herpetic ulceration, which is the most common recurrent ulcerative disease of the perineum. Ocular involvement is the most concerning manifestation, which may lead to permanent loss of vision if unrecognized or untreated. Most commonly, posterior uveitis is the presenting complaint, but anterior uveitis, glaucoma, and cataracts are also seen. Less-common manifestations include conjunctivitis, episcleritis, vitreous hemorrhage, and optic neuritis. Finally, a pathergy test may be helpful in diagnosing Behc¸et’s disease. Systemic complications include arthritis, which most commonly presents in the knees and wrists as a nonerosive disease. The incidence of arthropathy is as high as 55%; in one series, arthritis was the third most common finding, following mucocutaneous and ocular symptoms.56 The joint involvement tends to be inflammatory with prominent clinical features of joint pain, stiffness, and swelling. Joint involvement may occur at any time during the course of the disease. When the joint involvement postdates other manifestations, it usually occurs within 2 to 4 years. The knees and ankles are most frequently affected, followed by the wrists, elbows, and shoulders. In most cases, the arthritis is intermittent and self-limited; however, there have been reports of an erosive arthritis similar to rheumatoid arthritis.57-59 Controversy still exists as to whether Behc¸et’s disease should be classified among the spondyloarthropathies.60

Fig. 4

Behc¸et’s disease.

Neutrophilic dermatoses There have been reports of sacroiliitis and enthesopathy, such as Achilles’ tendonitis. Laboratory studies typically reflect nonspecific systemic inflammation. Serologic data are usually unrevealing with a negative rheumatoid factor and HLA B27. Synovial fluid analysis demonstrates mild inflammation with white blood cell counts ranging from 5000 to 50,000 having a neutrophil predominance. Histologically, there is a nonspecific synovitis and the synovial membrane has been shown to share increased sensitivity to injury similar to findings in the skin.61 Gastrointestinal involvement may be profound and presents as diffuse colic and recurrent intestinal ulceration. Rare cases of spontaneous abdominal perforation at sites of abdominal aphthae have been reported. The cardiovascular system may also be involved, and pulmonary vascular aneurysms, arterial occlusion, venous occlusion, coronary arteritis, myocarditis, and ventricular arrhythmias can be seen. Central nervous system disease may present as sterile meningoencephalitis, isolated cranial nerve palsies, and brainstem and motor deficiencies. Renal manifestations include glomerulonephritis. Because Behc¸et’s disease is a diagnosis of exclusion, one must rule out infectious etiologies. Recurrent herpetic infection must be excluded. In cases of central nervous system involvement, sampling of cerebrospinal fluid is indicated. Coronary disease is also important to exclude, although peak incidence and age at presentation of Behc¸et’s disease usually make its diagnosis less likely. Given multisystem vascular involvement, erythrocyte sedimentation rate and antineutrophil cytoplasmic antibodies should be obtained to rule out primary vasculitis. Positive antineutrophil antibody titers should prompt workup for an alternative diagnosis. Central nervous system disease or vascular involvement of large vessels is a marker for a recalcitrant disease and poor prognosis. Most notably, no diagnostic test exists for this disorder. Pathologic findings include acneiform, vascular, and extravascular types. Acneiform lesions often show folliculitis with occasional granulomatous involvement. Vascular findings are the most common and include vasculitis and vasculopathy with primary neutrophilic cell infiltrates, although scattered lymphocytic and histiocytic cell recruitment may be observed. Aggregates of neutrophils, lymphocytes, and histiocytes may also be observed in a nonvascular distribution, extending down to the panniculus. Treatment includes use of topical and systemic steroids. Ophthalmologic consultation and follow-up are essential in those who present with ocular symptoms, although referral of patients for a baseline examination is indicated even if they are not symptomatic. As with the case in pyoderma gangrenosum and Sweet’s syndrome, treatment with methotrexate, dapsone, thalidomide, and cytotoxic agents has been documented for this disease. Successful treatment of systemic diseases often necessitates combination therapy. Supportive care for apthous stomatitis is paramount because it is recurrent and is the most common presenting sign of the

475 disease. Treatments include topical lidocaine, topical and inhaled corticosteroids, and immunomodulators.55,62,63

Bowel-associated dermatosis-arthritis syndrome This uncommon syndrome is seen as a result of gastroenterological pathology. Whether medical in nature or surgically created, patients present with diarrhea, arthritis, and cutaneous manifestations. The disease occurs most commonly after ileojejunal bypass surgery, the creation of a blind loop of bowel, or pancreatobiliary diversion. It may also be observed in the setting of inflammatory bowel disease, peptic ulcer disease, diverticulitis, or liver disease, highlighting the fact that this is not exclusively a surgical complication. Although occasionally recurrent, it tends to be more acute than other neutrophilic dermatoses, usually evolving in hours or days. Systemic complaints often precede cutaneous manifestations. When related to surgery and blind loops of bowel, this disorder erupts up to 6 years after intervention.10,20,64,65 Systemically, patients exhibit fevers, chills, and arthralgias, resembling the clinical presentation of serum sickness– like disorders. Nondestructive polyarthritis and tenosynovitis are common. Cutaneous involvement may resemble erythema nodosum, showing deep-seated erythematous nodules that only rarely suppurate (Fig. 5). In addition, vesiculopustular eruptions can be observed in addition to pruritic erythematous papules. These last for 2 to 4 weeks if untreated and may recur periodically.66,67 The pathogenesis of this disorder is poorly understood; however, unlike with the entities discussed, a role for

Fig. 5

Bowel-associated arthritis syndrome.

476 infectious agents has been more firmly established for this disease. It is thought that blind loops of bowel and stasis from intestinal disease lead to bacterial overgrowth. Bacterial antigens, most notably peptidoglycans, serve as inciting events that lead to immunocomplex diseases.68-70 In fact, antibodies against bacteria and complement have been isolated from precipitates in patients. Antibiotic therapy at antimicrobial doses rather than at lower antiinflammatory doses has been used successfully and further fortifies the role of infection in the pathogenesis of this disease.21 Nonetheless, as will be discussed, therapy with steroids is still helpful in ameliorating arthritic and cutaneous symptoms. Laboratory evaluation reveals evidence of malabsorption secondary to persistent diarrhea, most commonly in the form of electrolyte imbalance, but other findings include gallstones, nephrolithiasis, and deficiency of fat-soluble vitamins. Laboratory data are not diagnostic. On histologic examination, neutrophilic infiltrates in the dermis, commonly arranged in perivascular and interstitial distribution, are often identified. There are usually nodular infiltrates. Lymphocytes and histiocytes are often admixed, and extension into the panniculus in lobular distribution is not uncommon. The presence of necrosis and fibrotic changes distinguish this entity from erythema nodosum. Leukocytoclasis and pustular vasculitis are less commonly observed. Dermal edema is often present, and stains for microorganisms on skin biopsy specimens are negative.71,72 Treatment incorporates initial antibiotic therapy geared toward enteric flora. Clindamycin, metronidazole, erythromycin, tetracycline, and trimethoprim-sulfamethoxazole have been used most commonly; however, a combination therapy with nonsteroidal antiinflammatory drugs, colchicine, dapsone, and oral steroids is the best approach for systemic symptoms. Topical steroids serve as a valuable adjunct for cutaneous disease, and intralesional steroids are particularly beneficial in treating nodular or panniculitic disease. In the absence of antimicrobial and/or surgical therapy, these symptoms are merely palliated but do not resolve. Surgical correction or revision of blind loops has led to resolution of symptoms and is the only curative intervention.20,21

Synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome Unlike the entities discussed, the synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome has been fully described and studied only in the past 40 years. It is primarily seen in children and young adults and is reportable in patients older than 60 years. It consists of a clinical syndrome of sterile neutrophilic infiltration of skin, articular surfaces, and bone. There is no racial or sexual predilection, but the disease is seen more commonly in Japan and Europe than in the United States. There is an association with inflammatory bowel disease, although it is unclear whether

A.P. Saavedra et al. this is a result of a bystander effect in individuals who are positive for HLA B27.73 This disorder has varied cutaneous expression. More commonly, patients present with palmoplantar pustulosis. Acne may present as vulgaris, conglobate, or fulminant, and the follicular occlusion triad has been reported in this disease, including dissecting cellulitis of the scalp, pilonidal cyst, and hidradenitis suppurativa. Pustular psoriasis, Behc¸ et’s disease, Sneddon-Wilkinson disease, Sweet’s syndrome, pyoderma gangrenosum, and Lyme disease have been reported in association with the synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome.73 Articular lesions are most common in the anterior chest wall, including the manubriosternal, sternoclavicular, and sternocostoclavicular joints, which may present as synovitis, osteitis, and aseptic (sterile) osteomyelitis. Patients present with painful arthritis and fever, not like patients with other neutrophilic dermatoses. It is important to note that rheumatologic manifestations may occur independently of cutaneous findings and that these are often treated separately.74 Laboratory examination may reveal leukocytosis and negative markers for arthritis. In addition, elevated markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate are observed. Although not diagnostic, HLA B27 serotypes are overrepresented in this disease. Radiographic findings using bone scintigraphy and magnetic resonance imaging reveal increased bone uptake at involved sites. Magnetic resonance imaging has been used as a sensitive method to follow disease progression. In addition, it is helpful in evaluating for primary bone malignancies, metastatic disease, and osteomyelitis, which make up the main differential diagnosis. Therapy is geared toward symptomatic control, and nonsteroidal antiinflammatory agents, colchicine, sulfasalazine, and antibiotics such as doxycycline and clindamycin have been used. Escalation to oral steroids, methotrexate, and biologics is often necessary to induce remission. The use of biphosphonates such as alendronate (4 mg), pamidronate (30 mg), and zoledronic acid (4 mg) for bone disease is encouraging.

Pustular psoriasis Acute attacks of generalized pustular psoriasis often present as a syndrome that includes fever and malaise. When present chronically, failure to thrive, weight loss, and myalgias are disclosed in a review of systems. It is uncommon to see other types of psoriasis in the same patient, but occasional pustules can be seen in chronically relapsing plaque psoriasis.75 Generalized pustular psoriasis (von Zumbusch’s type) presents with 2- to 3-mm pustules over an erythematous base (Fig. 6). The trunk, extremities, nail bed, and flexural surfaces may be involved, but the face is usually spared. Annular configuration is rare but can arise from coalescence of pustules into erythematous annular

Neutrophilic dermatoses

477 Methotrexate and cyclosporine are second-line agents followed by cytotoxic agents that are limited by side effects and narrow therapeutic margins in this chronic disease.76 The use of systemic steroids is controversial, and, although used by some in the acute setting, there is an involved high risk of a recurrent and persistent disease.77 Combination therapy with topical adjuncts (steroids, tar preparations, vitamin D3 analogues) and phototherapy is often used. Experience with biologics, which modulate cytokine biology, such as anti– tumor necrosis factor agents, is promising.78-81

Acrodermatitis continua and palmoplantar pustulosis

Fig. 6

Pustular psoriasis.

plaques. In addition, exanthematous disease has been reported, although it is short-lived and does not usually cause systemic symptoms. Pustular psoriasis recurs, usually in waves of fever followed by pustulation. When similar lesions are noted during pregnancy, the condition is termed impetigo herpetiformis. During the course of the disease, it is important to rule out superinfection or coincident infection that may have caused the disease to flare. It is not uncommon for patients to have negative blood and wound cultures, although other laboratory findings are generally nonspecific. Elevated erythrocyte sedimentation rate, leukocytosis, hypocalcemia, and hyperuricemia have been observed. Withdrawal of corticosteroids, lithium, antimalarials, and b-blockers, as well as pregnancy, hypocalcemia, and sun exposure, can also cause a pustular flare. Staphylococcus aureus is the most commonly recovered organism when lesions become superinfected, but the disease often flares after systemic viral or streptococcal infection. Unlike pustular psoriasis limited to the palms and soles, generalized pustular psoriasis is overrepresented in HLA B27–positive individuals, who are also at a higher risk of developing spondylitis. Histopathologic examination reveals macropustules with neutrophilic abscess formation. Spongiform Kogoj’s pustules and Munro microabscesses are seen. Psoriasiform hyperplasia may be seen when the disease occurs in the setting of plaque psoriasis, but it may not always be observed when the disease is primarily pustular. There is spongiosis, with some peripheral parakeratosis, as well as dilated capillaries higher up in the papillary dermis. Therapy usually necessitates systemic treatment. Systemic retinoids, such as acitretin, are most commonly used.

Localized pustular psoriasis can occur in the setting of known pustular psoriasis, but it can be divided into 2 main categories—acrodermatitis continua and palmoplantar pustulosis—when recurrent in a specific anatomical distribution. Hallopeau’s acrodermatitis continua suppurativa is a sterile pustular dermatosis that occurs primarily in distal acral distributions and migrates proximally. Digital and nail involvement is common, and destruction of the nail apparatus may be observed. Because pustules cycle or are denuded by trauma, they leave an atrophic shiny surface. This disease is more common in fingers than in toes, although cases of generalized disease have been reported, usually after a prolonged untreated course or complicating systemic corticosteroid therapy. In these cases, the disease may be indistinguishable from generalized pustular psoriasis. Pustulosis palmaris et plantaris (Barber palmoplantar pustular psoriasis) has a worldwide distribution, is most common in men, and is only rarely seen in those younger than 20 years and those older than 60 years. Unlike in acrodermatitis continua, only hands and soles appear to be affected in palmoplantar pustulosis, and these are involved equally. Nail involvement and destruction are not seen. Pustules arise acutely, usually over hours, in symmetrical distribution; these progress to crusts on a dyshidroticlike surface over a few days to weeks (Fig. 7). Scaling and occasional small-plaque psoriasis may be seen. Associations have been made with Sweet’s syndrome and osteomyelitis82 and arthritis. Once joint involvement and osteitis are detected, the synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome may be considered. There is a positive correlation with tobacco use, stress, and infections.83 Cultures are usually performed to rule out bacterial, fungal, and scabietic diseases, especially in the phase of the disease when pustular desquamation may be confused as paronychia or superinfection. Serologies and other laboratory tests are usually unrevealing. X rays of the distal extremities may reveal bone atrophy or resorption in acrodermatitis continua, but this is usually not observed in pustulosis palmaris et plantaris. Histopathology demonstrates a sterile subcorneal or intraepidermal pustule with aggregation of neutrophils. In addition, edema and

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Fig. 7

Pustulosis palmaris et plantaris.

histiolymphocytic infiltrates may be observed in the dermis. Spongiform dermatitis may be observed in pustulosis palmaris et plantaris, but it is usually not observed in acrodermatitis continua. Therapy for these localized pustular disorders is similar to that used in generalized pustular psoriasis. Successful treatment with superpotent topical steroids, dapsone, calcipotriene, psoralen ultraviolet A, and acitretin has been reported.84 In addition, combined treatment with etanercept has been used in recalcitrant cases.85 The best evidence points to the use of systemic retinoids and psoralen ultraviolet A.86 It is however important to note that these diseases often follow a chronically remitting course, requiring treatment during flares and tapered therapy during quiescence. Curative therapy is not available, but avoidance of trauma and infection, which are considered potential culprits in pathogenesis, should be noted, particularly in acrodermatitis continua. On the other hand, palmoplantar pustulosis may be harder to treat and systemic therapy with methotrexate and acitretin is often necessary to induce remissions. There is a role for cyclosporine in recalcitrant diseases, and colchicine has also been attempted with variable success. Combination therapy with topical regimens is usually necessary to prevent relapse.

immunofluorescence on histopathologic sections. This disorder is more common in women and in those older than 40 years but can occur at any age. Although it is most common in White patients, reports in those with darker skin types are available.87 The disease often arises in normal or slightly erythematous skin in the form of vesicles that quickly develop into flaccid pustules that can coalesce into serpiginous, arcuate, polycyclic, or annular configurations. As the pustules evolve, they crust, often appearing as areas of impetigo. When completely healed, postinflammatory hyperpigmentation is seen. The periphery of the eruption may evolve, whereas the center of the lesion may clear. Distribution is most often truncal and flexural, with only rare extension to acral sites. Sites of predilection include the axilla, groin, submammary region, and trunk. Lack of involvement of the hands and feet may help differentiate subcorneal pustulosis from acrodermatitis continua. Mucosal surfaces are not usually involved. The Sneddon-Wilkinson disease is associated with IgA and IgG paraproteinemia, pyoderma gangrenosum, rheumatoid arthritis, and multiple myeloma.88,89 Although this condition was first described in 1956,90 its association with arthritis was not recognized until the 1970s. The first case documented in the literature described a young woman who developed classic subcorneal pustular dermatosis with a crippling arthritis, similar to rheumatoid arthritis.91 Since then, there have been limited reports of patients having an associated arthritis and several cases of those with documented seropositive rheumatoid arthritis.92-95 Most cases were associated with polyclonal elevation of IgA, and one case was associated with a raised IgM band.96 Subcorneal pustular dermatosis is usually clinically indistinguishable from IgA pemphigus. Flaccid bullae with pus levels can be seen in both entities but are most common in subcorneal pustular dermatosis (Fig. 8). As a result, biopsy evaluation with immunofluorescence is required. Both entities will show sterile subcorneal aggregation of polymorphonuclear lymphocytes, with occasional eosinophils. Perivascular dermal neutrophilic

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) The unifying characteristics of this disorder are a diffuse pustular eruption, which is sterile and shows mostly polymorphonuclear leukocytes with negative

Fig. 8

Subcorneal pustular dermatosis.

Neutrophilic dermatoses infiltrates may be observed. There is occasional acantholysis, keratinocyte atypia, or spongiosis. In IgA pemphigus, intercellular accumulation of IgA is always noted and indirect immunofluorescence identifies IgA autoantibodies in a subset of patients. Subcorneal pustular dermatosis is a chronic disorder marked by acute exacerbations and remissions. Sulfones such as dapsone (50-150 mg daily) and sulfapyridine provide the best therapeutic benefit. These features further differentiate this disorder from pustular psoriasis, which is not usually responsive to these agents. The role of systemic corticosteroid is reserved for control in acute flares. Retinoids and phototherapy have been used alone or in combination with sulfones with variable efficacy.97

Conclusions The neutrophilic dermatoses comprise a number of disorders characterized by infiltration of polymorphonuclear leukocytes into various layers of the cutis and subcutis. Diagnosis relies on characteristic features of the physical examination, laboratory testing, and histopathologic evaluation. Treatment is directed at inhibiting neutrophilic migration and function, usually with sulfa drugs and immunosuppressant medications. As a result, it is important to exclude (or treat) infection before initiating therapy. Finally, complete medical evaluation for associated disorders, particularly malignancy, is important to consider because therapy aimed at these associated diseases often leads to the resolution of these dermatoses. In addition, failure to diagnose associated disorders may impart a worse prognosis for the patient or lead to a recurrent cutaneous disease.

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