The neutrophilic dermatoses constitute a heterogeneous but linked spectrum of disease with
- overlapping histopathologic findings (perivascular and diffuse neutrophilic infiltrates without any identifiable infectious agents )
- similar pathogenic mechanisms
- association with underlying internal diseases
- similar therapeutic approaches
Reason for the development of the inflammatory process that leads to Pyoderma gangrenosum (PG) and Sweet syndrome (SS) remains unclear.
In contrast to its name, PG is neither an infectious nor gangrenous condition
Incidence and prevalence: 3 to 10 cases per million people per year
Age: increases with age, with a median age of 59
Sex– commoner in females
Ethnicity: no association of PG with ethnicity
Genetics: mutation in PSTPIP1/ CD2BP1 gene in PAPA syndrome
- 33–50% of cases of PG are associated with classical accepted diseases
- Inflammatory bowel disease (IBD) -pustular form of PG may be associated with similar incidence of Crohn disease and ulcerative colitis, present in 20–30% of cases
- Haematological malignancies- the bullous form of PG is usually associated, approximately in 5% cases (monoclonal gammopathy of undetermined significance, myelodysplastic syndrome, or polycythemia vera)
- Rheumatoid arthritis and other seronegative arthritides- may themselves be IBD related and occur in about 10% of cases
- Visceral malignancies in 5%
- May be associated with anaemia, renal impairment, thyroid disease, obesity, diabetes, depression and peripheral vascular disease
- Vegetative form is usually not associated with underlying disease.
- PASH syndrome- PG, cystic acne and hidradenitis
- PAPA syndrome- pyogenic arthritis, pyoderma and acne
- PAPASH syndrome- pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa
For classical PG, the following criteria must be met:
- Rapid progression of a painful necrolytic cutaneous ulcer with an irregular, violaceous and undermined border
- Exclusion of other causes of cutaneous ulceration
Minor criteria (2 must be present)
- History suggestive of pathergy or the clinical finding of cribriform scarring
- Systemic diseases known to be associated with PG
- Histopathological findings (sterile dermal neutrophilia, with or without mixed inflammation or lymphocytic vasculitis)
- Treatment response (e.g. rapid response to systemic corticosteroid)
Clinical features: Depend on different clinical variants
Classical ulcerative PG
- Commonest and best recognized variant of PG
- Small, tender, red‐blue papules, plaques or pustules that evolve into painful ulcers with characteristic violaceous undermined edges
- There may be granulation tissue, necrosis or purulent exudate at the ulcer base.
- Depth of the ulcer often extends into subcutaneous fat and occasionally reaches the fascia
- Lesions may be solitary or multiple, and occur most commonly on the legs (in 70%), but may affect any body site including the genitals and mucosae.
- Pain is often greater than expected based upon the appearance of the ulcer
- Associated with fever, malaise, myalgia and arthralgia
- Healing usually occurs with an atrophic cribriform or wrinkled paper scar
- may arise as a pathergy response to the trauma of appliances and faecal irritation
- most common with ileostomy for active IBD
- the risk is greater with high BMI, female sex and autoimmune disorders
- often occurs during acute exacerbations of IBD
- Discrete painful pustules, with a surrounding halo of erythema, develop on normal skin.
- Concomitant fever and arthralgias are common
- Pustules commonly arise with a scattered distribution on the extensor aspects of the limbs
- Atypical presentation
- Presents with rapidly arising, superficial, haemorrhagic bullae, often located on the arms and face.
- shares clinical and histopathological findings with Sweet syndrome, but typically ulcerates and heals with scarring.
- Bullous PG is especially associated with myeloproliferative disorders
Granulomatous superficial PG
- Aka Vegetative PG
- Most cases begin as a single superficial ulcer with granulations and an elevated edge
- Granulomatous histology
- most commonly in the lungs, may affect the bones, liver, heart, brain, GIT and muscle
- often with aseptic abscesses
Vascular occlusive or venous disease, vasculitis, cancer, primary infection, drug‐induced or exogenous tissue injury, and other inflammatory disorders, fungi, atypical mycobacteria and opportunistic infections, sporotrichosis, fusariosis, mycosis fungoides, mucormycosis, histoplamosis, blastomycosis and drug‐induced including nicorandil
Disease course and prognosis
- takes many months or years to completely resolve.
- may be recurrent in 16–61% of cases
- consideration should be given to long‐term systemic preventive therapy
- PG has a significant mortality – 16% over 8 years
Investigations should be guided by a thorough clinical evaluation.
- Skin biopsy -not diagnostic in PG but is frequently performed in all but classical cases to exclude other conditions.
Typical findings include
- central necrosis and ulceration of the epidermis and dermis surrounded by an intense inflammatory cell infiltrate, with a more peripheral mixed to chronic inflammatory cell infiltrate
- Ulcerative PG-massive dermal–epidermal neutrophilic infiltrate with suppuration/abscess formation
- Pustular PG- perifollicular neutrophilic infi ltrate with subcorneal pustule formation
- Bullous PG- neutrophilic infiltrate with intraepidermal vesicle formation
- Vegetative PG-granulomatous reaction with peripheral palisading histiocytes and giant cells
- Tissue culture– culture for bacterial, atypical mycobacterial, viral and fungal pathogens to rule out other causes
- Direct immunofluorescence– to exclude autoimmune bullous disease, lupus, or vasculitis as a cause of ulceration
- Complete blood count -to evaluate for underlying hematologic disorders
- Comprehensive metabolic panel -to evaluate for hepatic or renal dysfunction and glucose abnormalities prior to initiation of systemic glucocorticoids or immunosuppressive agents
- Antinuclear antibody titer -to evaluate for the presence of systemic lupus erythematosus or collagen vascular disorders in association with PG
- Antineutrophilic cytoplasmic antibodies -to evaluate for granulomatous vasculitis as a cause of ulceration
- Hypercoagulability studies- antiphospholipid antibody screen to evaluate for antiphospholipid syndrome as a cause of ulceration; based upon clinical suspicion, other tests to evaluate for thrombotic states [eg, cryoglobulins, Factor V Leiden, methylene tetrahydrofolate reductase]
- Hepatitis panel -to evaluate for associated hepatitis B or C, particularly for patients in whom immunomodulatory therapy is considered
- Rheumatoid factor– as a component of the evaluation for cryoglobulinemia and rheumatoid arthritis
- Serum immunofixation electrophoresis -to evaluate for paraproteins
- Chest radiography -to evaluate for presence of extracutaneous involvement and for possible infection prior to the initiation of immunosuppressive therapy
- Colonoscopy -to evaluate for underlying inflammatory bowel disease unless another cause of PG is identified
As PG occurs most frequently on the legs and can be associated with vascular disease and obesity, consideration should be given to provide the most favorable conditions for wound healing
- compression dressing
- Supportive therapy including pain relief and topical agents for cleansing debriding and keeping the wound moist
- For smaller lesions, potent topical corticosteroids, intralesional corticosteroids and topical tacrolimus
- For more severe disease or for PG not responding to simple measures
- systemic prednisolone and ciclosporin
anti‐TNF biologic therapy –
- considered more often as a first line therapy particularly for those with associated IBD
- skin grafting can be very successful if the inflammation has already resolved following systemic therapy such as with corticosteroids
- should be avoided in the inflammatory stage and can frequently induce PG
Sweet syndrome is an uncommon inflammatory disorder characterized by four primary features: a cutaneous eruption consisting of erythematous papules and plaques, fever, peripheral neutrophilia and a dermal nonvasculitic neutrophilic infiltration on biopsy.
• Acute febrile neutrophilic dermatosis
• Gomm–Button disease
Incidence and prevalence: no accurate data on incidence or prevalence of classical Sweet syndrome
Age: may occur at any age but most commonly between 30 and 60 years
Sex: female to male = 4 to 1
Ethnicity: There is no confirmed racial predilection
Streptococcal respiratory tract infections
Gastrointestinal infections by Salmonella and Yersinia
Other reported associations include inflammatory bowel disease, pregnancy, autoimmune thyroid disease, sarcoidosis, rheumatoid arthritis, Behcet disease and erythema nodosum, hematological malignancies (acute myelogenous leukemia, myeloproliferative disorders), solid organ tumors, other neutrophilic dermatoses
Genetic susceptibility – Abnormalities in chromosome 3q and HLA-B54 have been reported in a few patients.
Drug‐induced Sweet syndrome is an established phenomenon.
It can be divided into two main types:
(i) GCSF associated; and (ii) other drugs
Medications with possible associations include antibiotics, antiepileptics, highly active antiretroviral therapy (HAART), antihypertensives, chemotherapeutic agents, colony‐stimulating factors, contraceptives, diuretics, non‐steroidal anti‐inflammatory drugs (NSAIDS) and retinoids
Diagnostic criteria for Sweet syndrome
Both major criteria and two minor criteria are required
- Acute onset of typical lesions
- Histopathological findings consistent with Sweet syndrome
- Fever >38°C
- Association with malignancy, inflammatory disorder or pregnancy, or antecedent respiratory or gastrointestinal infection
- Excellent response to systemic corticosteroids or potassium iodide (KI)
- Abnormal laboratory values at presentation (three of four required: ESR >20 mm; leukocytes >8000; neutrophils>70%; elevated C‐reactive protein)
Three main types of Sweet syndrome are recognized as follows:
Classical– majority of cases, meets the established diagnostic criteria and is not associated with malignancy or drug exposure
Malignancy associated– in association with hematologic malignancies than solid tumor cancers
Drug induced– Granulocyte-colony stimulating factor (G-CSF) is the most widely reported contributory medication, develops about two weeks after drug exposure
may establish the specific subtype of Sweet syndrome
• Any prior history of fever or infectious illness.
• Current or previous malignant disease.
• New drug administration.
The classical appearance:
- tender red papules, nodules and eventually plaques
- plaques are often oedematous and as the process develops they may become studded with pseudovesicles or pseudopustules with subsequent ulceration
- distributed over the head, neck, upper trunk and upper arms
- Fever and feeling of being unwell.
- Arthralgia, ocular involvement in form of conjunctivitis and episcleritis
- Oral and genital involvement is uncommon
- Pathergy-Disruption and stimulation of endothelial cells leading to increased neutrophil activity could contribute to the triggering of Sweet syndrome
- Patients with malignancy‐associated Sweet syndrome differ from idiopathic Sweet syndrome in often having abnormal platelet counts and anaemia and more widespread vesicular, bullous or ulcerative skin lesions
The specific involvement of other organs is known as extracutaneous Sweet syndrome.
- Central nervous system involvement or ‘neuro Sweets’ may involve benign encephalitis, aseptic meningitis, brainstem lesions and psychiatric symptoms amongst others.
- Cardiovascular system – myocarditis, aortitis and aortic stenosis, coronary artery occlusion
- Pulmonary system – neutrophilic alveolitis, pleural effusions, airway obstruction
- Liver – hepatitis, hepatomegaly
- Intestines – neutrophilic inflammation of intestines
- Spleen – splenomegaly
- Kidneys – mesangial glomerulonephritis, hematuria, proteinuria
- Bone – sterile osteomyelitis
Bullous Sweet syndrome
- Uncommon presentation of Sweet syndrome in which vesicles and flaccid bullae overly erythematous to violaceous plaques.
- Most commonly occurs in the setting of hematologic malignancy
Neutrophilic dermatosis of the dorsal hands
- localized disorder that may be on a continuum with Sweet syndrome
- Characterized by bluish or haemorrhagic papules, bullae and nodules on the dorsal hands.
Subcutaneous Sweet syndrome
- This entity presents with erythema nodosum-like tender, subepidermal nodules on the extremities, usually the legs.
- The site of neutrophilic infiltration is in the subcutaneous fat, rather than the dermis.
Histiocytoid Sweet syndrome
- Clinically, they may resemble classical Sweet syndrome or may present with subcutaneous erythema nodosum type lesions
- Characterized by an infiltrate composed of large histiocytoid mononuclear cells (i.e. they look like histiocytes) but immunohistochemical staining for myeloperoxidase is positive suggesting that they are immature myeloid cells and neutrophil precursors
- Infectious disorders: erysipelas, cellulitis, herpes simplex.
- Inflammatory: panniculitides, pyoderma gangrenosum, syphilis, tuberculosis.
- Neoplastic: metastases.
- Reactive erythemas: erythema nodosum, erythema multiforme, urticarial.
- Systemic disease: Bechet disease, lupus, bowel bypass syndrome.
- Vasculitis: erythema elevatum diutinum, polyarteritis nodosa, granuloma faciale
- Leukaemia cutis.
- Leukocystoclastic vasculitis.
- Neutrophilic eccrine hidradenitis
Complications and co‐morbidities
In the vast majority of cases, Sweet syndrome resolves with no sequelae.
Severe skin lesions with ulceration or with delayed treatment can lead to scarring.
Disease course and prognosis
- Without treatment, the disease will often resolve within 3 months, or a pattern of fluctuating exacerbations may be seen
- Approximately one third of cases will recur.
- Response to corticosteroids is usually rapid
Essential investigations include the following:
- Skin biopsy
The classical and diagnostic histopathological features are:
- dense infiltrate of neutrophils in the dermis
- Other cells involved in the infiltrate can include lymphocytes, eosinophils and histiocytes.
- Cell infiltrate is usually diffuse but perivascular and dermal band patterns are seen
- prominent dermal papillary oedema
- Subepidermal vesicles
- Endothelial swelling and leukocytoclasis without genuine vasculitis
- Routine blood tests- full blood count (peripheral neutrophilia), liver function test, renal function, C‐reactive protein and erythrocyte sedimentation rate.
- Additional tests should be guided by the clinical findings and may include thyroid function test, rheumatoid factor and antistreptolysin O antibody titre.
- Pregnancy test in women of childbearing age
- All suspected malignancies should be investigated according to local guidelines. However the most important components are a full clinical history and medical examination including examination of the lymph nodes and mouth. Examination of the breasts and pelvis in women and that of the prostate and testicles in men should be considered.
- Sigmoidoscopy should be considered in the over fifties.
- Further investigations can be ordered on a case‐by‐case basis depending on the history and clinical findings
- Systemic corticosteroids (Prednisolone 0.5–1 mg/kg for 4–6 weeks)
- Potent topical or intralesional corticosteroids for mild localized disease (triamcinolone acetonide)
- Dapsone (50–100 mg/day)
- Potassium iodide (300 mg three times each day)
- Colchicine (0.5 mg three times each day)
- pulse glucocorticoid therapy
- oral retinoids
Bowel‐associated dermatitis–arthritis Syndrome
Bowel‐associated dermatitis–arthritis syndrome (BADAS) is defined by the presence of pustular vasculitic lesions associated with blind loops of bowel or other causes of stasis of bowel content.
- Blood vessel damage secondary to bowel flora antigen associated circulating immune complexes
- peptidoglycans from gastrointestinal flora may be the antigenic trigger for immune complex mediated vessel damage
BADAS may be related to jejuno‐ileal bypass, gastric resection, blind loops (Bilroth II or Roux‐en‐Y), defunctioning ileo‐anal pouch procedures, and bilio‐pancreatic diversion.
It has also been related to other bowel disease: ulcerative colitis, Crohn disease, diverticulitis of the colon, jejunal diverticula, appendicitis and achalasia of the cardia
In some cases, there are combined causes (e.g. surgery for IBD).
- usually begin as small macular lesions that progress into papules and then pustules on a
- most often on the arms and other areas of the upper body
- The pustules measure 0.5–1.5 cm in diameter and typically occur in crops, with each crop lasting up to 2 weeks, and recurring at intervals of several months
- Larger erythema nodosum like lesions also occur, as do larger pyoderma gangrenosum like pustular lesions.
- cutaneous lesions may be preceded by constitutional signs, fever, flu‐like symptoms, myalgia or gastrointestinal upset.
- Arthralgia or non‐erosive polyarthritis affecting the hands, wrists and other peripheral joints are common
- ocular involvement such as episcleritis, and haematuria or proteinuria may also occur
- Rarely, severe skin lesions and marked systemic manifestations may occur.
It is important to distinguish between BADAS and Behcet disease as both may include oral aphthae and lesions of pustular vasculitis.
- Clinicopathological evaluation of skin lesions is required but does not exclude lesions of Behcet disease or early lesions of either
- Histopathology- The changes noted in the dermal blood vessels from early lesions of pustular vasculitis in patients with BADAS are similar to those in biopsies from patients with Sweet syndrome and Behcet disease
- Pustules should be swabbed for microbiological assessment.
- Urinalysis-haematuria or proteinuria, possibly representing an immune complex initiated glomerulonephritis
- For patients with BADAS following bowel bypass surgery, surgical correction of bowel anatomy often eliminates the signs and symptoms.
- In other cases, such as patients with blind loops, surgical correction may be difficult and resolution of symptoms is therefore less likely.
- systemic tetracycline, metronidazole, ciprofloxacin or erythromycin
- Systemic corticosteroids are typically unnecessary but may be justified depending on the degree of skin, joint or systemic symptoms, or to concurrently treat IBD.
- Other treatments include oral colchicine, dapsone and mycophenolate
- systemic immunosuppressants may need to be combined with an appropriate antibiotic.
Subcorneal pustular dermatosis
Definition and nomenclature
Subcorneal pustular dermatosis is a rare neutrophilic dermatosis, with sterile subcorneal pustules typically affecting the flexural areas of the trunk and proximal extremities.
• Sneddon–Wilkinson disease
Incidence and prevalence: This is a rare condition with about 200 cases described.
Age: occurs most frequently in adults aged 40–60 years.
Sex: female to male ratio of about 4: 1.
Benign monoclonal gammopathy, more commonly immunoglobulin A (IgA) (occasionally IgG), IBD, multiple myeloma, lymphomas, PG, rheumatoid arthritis and connective tissue disease, including systemic lupus erythematosus.
- Pathogenesis is obscure and is similar to other neutrophilic dermatoses.
- However, it has also been considered to overlap with pemphigus although in most cases immunofluorescence is negative
- The eruption occurs with acute flares lasting for several days or weeks
- Distribution is mainly in the flexures of the trunk and proximal limbs, sparing the face and mucous membranes
- Lesions are oval, pea‐sized flaccid pustules on a normal or erythematous base. Pustules may be isolated or grouped and coalescent to form annular or serpiginous patterns
- Characteristic fluid level with pus in the lower half and clear fluid in the upper half may be seen.
Impetigo, pustular psoriasis, pemphigus foliaceus, dermatitis herpetiformis, intercellular IgA pemphigus and acute generalized exanthematous pustulosis (AGEP).
Disease course and prognosis
The condition is benign but chronic with an average duration of 5.8 years, although serious associated disease may have a worse prognosis.
- Skin biopsy
- subcorneal vesicles or pustules composed of predominantly neutrophils with occasional eosinophils
- spongiosis and spongiotic pustules are absent and acantholysis is only seen in old lesions.
- Immunofluorescence- negative in the classical form but may be positive to IgA in a subgroup.
- Bacterial culture of skin swabs – to exclude impetigo
- laboratory investigation for underlying associated pathologies should be guided by clinical signs
- Dapsone 50–150 mg daily is the treatment of
- Potent topical or oral corticosteroids: Some cases respond but overall these are not particularly effective
- Acitretin and tacalcitol have been used effectively.
- Narrow‐band UVB phototherapy, psoralen and UVA (PUVA) and retinoids plus PUVA (RePUVA).
- Ciclosporin in combination with prednisolone
- Ketoconazole has been reported to be of benefit.
- Anti‐TNF therapy alone or in combination, including etanercept
- Adalimumab combined with mycophenolate mofetil
Characterized by oral mucosal thickening with multiple pustules and ‘snail track’ superficial ulceration on an erythematous base (at any site, although the tongue is less affected).
Little is known about the pathogenesis
Synonyms and inclusions
• Mycosis‐like pyoderma
• Pyoderma vegetans
The pathogenesis is as yet unknown although immunological and microbial factors have been suggested as possible aetiological factors
The strongest association, particularly for oral lesions, is with IBD, particularly ulcerative colitis. Leukaemias, lymphoma, diabetes, acne conglobata, hidradenitis suppurativa and dissecting cellulitis, immunosuppression and malnourishment are also associated.
- The skin lesions, if present, are often flexural and clinically suggestive of pemphigus vegetans with verrucous plaques studded with pustules
- There may be associated dorsal hand lesions that are morphologically very similar to neutrophilic dermatosis, and a rash resembling Sweet syndrome.
- Lesions may display pathergy.
- Possible diagnostic clues include raised IgE in some cases, and peripheral eosinophilia which is present in 50–90%.
- Intraepithelial and/or subepithelial abscesses containing large numbers of eosinophils
- pseudoepitheliomatous hyperplasia and neutrophilic microabscesses on histology with negative immunofluorescence
- Antimicrobials, rather than corticosteroids or antineutrophil therapies
- Oral disease may respond to topical corticosteroids or tacrolimus
- Systemic prednisolone is often effective where topical therapies fail
- Prednisolone and ciclosporin have been used successfully where dapsone was ineffective
- Azathioprine in combination with oral steroids
- monotherapy with adalimumab
- Crohn disease associated cases have been treated with combination methotrexate and infliximab
Amicrobial pustulosis of the skin folds
Most cases occur in patients with systemic lupus erythematosus but can occur with coeliac disease and other autoimmune conditions including autoimmune thyroid disease and autoimmune hepatic disease
Recurrent eruptions of follicular and nonfollicular sterile pustules that exhibit a predilection for intertriginous skin, scalp, and periorificial areas on the head (mouth, nostrils, ear canals)
- Essential criteria include pustulosis involving one or more major skin fold, one or more minor folds in the ano‐genital area, a histological pattern of intraepidermal spongiform pustules and a mainly neutrophilic dermal infi ltrate, negative culture from an unopened pustule.
- Minor criteria include an association with one or more autoimmune disorders, positive antinuclear antibodies 1 : 160 or higher and the presence of autoantibodies (anti‐extractable nuclear antigens (ENA), anti‐dsDNA, antismooth muscle, antimitochondrial or antiendomesial
Subcorneal pustular dermatosis, pustular forms of psoriasis, erosive pustular dermatosis of scalp
- Oral corticosteroids – effective in most cases
- Dapsone, Ciclosporin, Oral zinc, Topical corticosteroids, Colchicine, Cimetedine, Ascorbic acid, Anakinra
Aseptic abscess syndrome
- As with many of the neutrophilic dermatoses, systemic aseptic abscess may occur and may precede the onset of the cutaneous manifestations.
- Joints, pulmonary and intra‐abdominal neutrophilic infiltrates or abscesses may occur
- Often occurs in association with IBD
- Associated with Crohn disease or neutrophilic dermatoses in some cases
- Mutations in the promoter of the PSTPIP1 gene similar to PAPA syndrome
Systemic corticosteroids are usually an effective therapy; they have been used in combination with infliximab followed by etanercept.
- Rook’s Textbook of Dermatology, 2016
- Fundamentals of Pathology, Husain A. Sattar
- Ruocco E, Sangiuliano S, Gravina AG, et al. Pyoderma gangrenosum: an updated review. J Eur Acad Dermatol Venereol 2009; 23:1008.
- Allen CP, Hull J, Wilkison N, Burge SM. Pediatric pyoderma gangrenosum with splenic and pulmonary involvement. Pediatr Dermatol 2013; 30:497.
- Bhat RM, Shetty SS, Kamath GH. Pyoderma Gangrenosum in childhood. Int J Dermatol 2004; 43:205.
- Dickson EL, Bakhru A, Chan MP. Topotecan-induced Sweet’s syndrome: A case report. Gynecol Oncol Case Rep 2013; 4:50.