Eosinophilic Dermatoses 

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Eosinophilic Dermatoses – Introduction

  • many immune or inflammatory dermatologic diseases, including allergic reactions, urticaria, and atopic dermatitis have histologic findings of eosinophilic infiltration
  • some rare eosinophilic dermatoses (sometimes called “classical” eosinophilic dermatoses) with unknown etiology include the conditions covered in this topic:
    • eosinophilic cellulitis (Wells syndrome)
    • eosinophilic fasciitis (Shulman syndrome)
    • granuloma faciale
    • eosinophilic pustular folliculitis
  • eosinophilic cellulitis (Wells syndrome) most commonly presents in adults with large, markedly inflamed, infiltrated plaques associated with a burning sensation and/or pruritus
    • deep lymphocytic and eosinophilic dermal infiltrate is identified on skin biopsy
    • topical or systemic glucocorticosteroids are most commonly advised for treatment
    • eosinophilic cellulitis typically has a benign course responsive to treatment
  • eosinophilic fasciitis (Shulman syndrome) is a rare disorder characterized by erythema, edema, and induration of the fascia of the upper and/or lower extremities
    • may be associated with prior trauma to fascia, infection or medications but cause may be unknow
    • may appear clinically similar to localized scleroderma (morphea), but is distinguished clinically from systemic sclerosis by lack of Raynaud phenomenon, lack of sclerodactyly, and lack of nailfold capillary changes
    • may be associated with hypergammaglobulinemia or monoclonal gammopathy and has been reported as paraneoplastic in up to 10% of patients
    • biopsy shows thickening of the fascia with cellular infiltration of eosinophils and monocytes
    • systemic corticosteroids are considered first-line treatment, with addition of steroid-sparing immunosuppressants if needed
    • complications of joint contracture and functional limitation may occur due to indurated fascia of extremities
  • granuloma faciale is an uncommon, benign cutaneous chronic condition characterized by erythematous plaques or papules on the face in adults
    • may be a localized form of IgG4-related disease
    • histopathology shows inflammatory infiltrate with eosinophils, neutrophils, plasma cells, and lymphocytes in the dermis and a grenz zone of uninvolved dermis, located below normal epidermis
    • initial options for treatment include topical corticosteroids or topical tacrolimus
  • eosinophilic pustular folliculitis (EPF) has several variants, including
    • “classic” EPF, also known as Ofuji disease, characterized by recurrent crops of intensely pruritic, follicular erythematous papules and pustules in seborrheic distribution of head, trunk, and limbs
    • immunosuppression-associated EPF (particularly, HIV-associated EPF), characterized by follicular or nonfollicular papules and large plaques, particularly in patients with a CD4 cell count < 300 cells/mcL
    • infantile EPF, seen most often in the first 14 months of life and characterized by pustules mostly on the scalp, and occasionally on trunk, face, or extremities
    • hematologic malignancy-associated EPF
    • diagnosis is based on typical clinical features, such as sterile follicular papulopustules, with histological evidence of a perifollicular, predominantly eosinophilic infiltrate
    • for classic EPF, initial treatment is generally indomethacin
    • for HIV-EPF, immunosuppression-associated EPF or hematologic malignancy-associated EPF, treatment focused on treating underlying condition
    • infantile EPF typically undergoes spontaneous resolution or may be treated with topical corticosteroids

Introduction

Description

  • eosinophilic dermatoses refer to a broad spectrum of heterogeneous skin diseases characterized by eosinophil infiltration and/or degranulation in skin lesions, with or without blood eosinophilia(1,3)
    • skin lesions may be localized or widespread(2)
    • extracutaneous involvement is common(2)
  • “classic” eosinophilic dermatoses that have tissue eosinophilia as predominant histologic finding are reviewed in this topic and include(1)
    • eosinophilic cellulitis (Wells syndrome)
    • granuloma faciale
    • eosinophilic fasciitis (Shulman syndrome)
    • eosinophilic folliculitis (Ofuji disease)
  • skin lesions of many other dermatologic disorders may show concomitant eosinophilic infiltrate on histology, due to associated or underlying inflammatory or neoplastic processes, such as(1,2)
    •  parasitic infections or infestations
    • arthropod bite reactions
    • allergic contact dermatitis
    • atopic dermatitis
    • urticaria
    • prurigo nodularis
    • bullous pemphigoid
    • dermatitis herpetiformis
    • mycosis fungoides
    • Langerhans cell histiocytosis
    • IgG4-related cutaneous diseases, including
      • angiolymphoid hyperplasia with eosinophilia
      • granuloma faciale
      • Kimura disease
    • eosinophilic dermatoses of hematologic malignancy
      •  may be paraneoplastic cutaneous reactions and are most commonly associated with chronic lymphocytic leukemia and less commonly associated with myelofibrosis, acute leukemias, or lymphomas
  • in addition, blood and tissue eosinophilia may be seen with any of the following conditions(1)
    • eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss vasculitis)
    •  hypereosinophilic syndrome
    •  eosinophilic leukemia
    • drug reaction with eosinophilia and systemic symptoms (DRESS hypersensitivity syndrome)
    • lymphomas (such as Hodgkin lymphoma)
    • mastocytosis

Synonyms

  • cutaneous manifestations of hypereosinophilia
  • eosinophilic skin disease
  • eosinophilic dermatitis

Definitions

  • eosinophils(2)
    • type of white blood cells of granulocytic lineage
      • approximate half-life 8-18 hours in the bloodstream
      • most (> 90%) found in tissues, where they can survive for several weeks
    • typically involved in
      • antigen presentation
      • release of inflammatory mediators
      • clearance of helminth and parasitic infections
      • immune responses
  • eosinophilic spongiosis(4)
    • characterized by edema between epidermal keratinocytes
    • appears sponge-like with variable eosinophil infiltration
    • appears to reflect humoral or T-cell immune-mediated processes

Etiology and Pathogenesis

  • eosinophilic dermatoses are characterized by(1)
    • eosinophilic infiltrate as most prominent histologic finding
    • not associated with parasitic infections/infestations, allergic disorders or other dermatosis with reactive eosinophilia
    • typically associated with idiopathic etiology
    •  blood eosinophilia often reported, but not required for diagnosis
  • production, release, and activity of eosinophils(1,4)
    • regulation of eosinophil maturation and migration
      • maturation of eosinophils occurs in the bone marrow and takes approximately 5 days
      • eosinophil maturation is mediated through interleukin (IL)-5 released by activated T lymphocyte (Th2) cells
      • subsequently, the eosinophils are discharged into the bloodstream where they circulate for roughly 1 day before migrating into tissue
      • secretion of interleukins (IL-4 and IL-13) results in increased expression of VCAM-1 (vascular cell adhesion molecule 1) in the endothelium
      • adhesion to the vessel wall is subsequently mediated by the adhesion molecule very late antigen 4 (VLA-4), expressed by eosinophils
      • chemokines such as eotaxin-3 (CCL11, CC-chemokine ligand-11) stimulate the migration of eosinophils, which bind to eotaxin-3 via their C-C motif chemokine receptor 3 (CCR3)
      • other mediators that play a role and are secreted by various cell types (such as keratinocytes, sebocytes, mast cells, and fibroblasts) include
        • RANTES (regulated on activation, normal T cell expressed and secreted)
        •  complement factor 5 (C5a)
        • lipid mediators such as platelet-activating factor (PAF), leukotrienes (LT) B4 and C4, and prostaglandin (PG) D2
    • direct effects of eosinophilia
      • deposition of eosinophil granule proteins in the affected tissue
      • secretion of reactive oxygen species and eicosanoids
      •  effector cells in inflammatory reactions
    • compounds released by eosinophils include
      • toxic granule proteins, such as major basic protein 1 (MBP1), eosinophilic cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase (EPX or EPO)
      • neurotrophins such as nerve growth factor (NGF)
      • neuropeptides such as substance P and vasoactive intestinal peptide (VIP)
      • interleukins such as IL-4, IL-13, and IL-31
    • indirect effects of eosinophilia mediated by eosinophil-induced recruitment and activation of other inflammatory cells, including
      • lymphocytes
      • fibroblasts
      • mast cells
  • histology of eosinophils(1)
    • eosinophils are readily detectable on hematoxylin-eosin-stained sections
    • intracellular granules and any granules bound to collagen fibers following degranulation will stain bright red
    • extracellular granules also produce thickening of collagen fibers, giving rise to characteristic ‘flame figures’ that represent collagen denaturation due to nonspecific eosinophilic degranulation
  • mast cells and eosinophils, often found together in skin lesions, may trigger each other to stimulate and maintain pruritus(4)

Eosinophilic Cellulitis (Wells Syndrome)

General Information

  • eosinophilic cellulitis (Wells syndrome) is a rare inflammatory dermatosis with wide variability in presentation but often associated with mild general symptoms and skin lesions resembling urticaria or cellulitis(2)
  • < 200 cases reported in the medical literature by 2012(3)
  • reported to affect all ethnicities and sexes, and is reported in adults and pediatric patients(3)

Etiology and Pathogenesis

  • etiology is unknown (An Bras Dermatol 2019 Jul 29;94(3):370full-text)
  • eosinophilic cellulitis (Wells syndrome) is hypothesized to potentially be a type IV hypersensitivity reaction (An Bras Dermatol 2019 Jul 29;94(3):370full-text)
  • some cases appear idiopathic but others may be associated with triggers/precipitating events or underlying disorders
    • reported possible triggers include
      • insect/arthropod bites or stings such as from mosquitoes, fleas, honeybees, spiders, and centipedes(1)
      • viral infections, such as parvovirus B19, herpes simplex virus 2, varicella zoster, and mumps(1)
      • parasitic infections such as ascariasis or Toxocara canis(3)
      • medications including antibiotics, anticholinergic agents, anesthetics, nonsteroidal anti-inflammatory drugs, thyroid medication, chemotherapy, thiazide diuretics, thiomersal-containing vaccines, and antitumor necrosis factor alpha agents
      • vaccinations(1)
    • underlying disorders reported associated with eosinophilic cellulitis (Wells syndrome) include
      • eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)(3)
      • hematologic malignancies, such as chronic myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphocytic lymphoma(3)
      • nonhematologic malignancies such as renal cell carcinoma, colon carcinoma, and nasopharyngeal carcinoma(3)
      • ulcerative colitis(3)
      • hypereosinophilic syndrome(3)
  • Wells syndrome bullous variant reported in 2 patients with histology showing eosinophilic dermal infiltration, 1 after multiple insect bites and both responding to oral steroids (Int J Dermatol 2021 Apr;60(4):e150)
  • Wells syndrome edematous variant reported in 2 patients presenting with swollen hands and eosinophils in all dermal layers, including 1 precipitated by insect bites, demonstrating hypereosinophilia in the blood and requiring fasciotomy, but both responded well to steroids (Indian Dermatol Online J 2020 Nov;11(6):979full-text)
  • on a pathophysiologic level, variability in clinical features may be readily explained by the varying degree of eosinophilic infiltration and eosinophil degranulation(1)
    • infiltration with only mild degranulation will often result in a plaque-like appearance
    • degranulation with greater release of mediators and toxic granules will result in urticarial, vesicular or even bullous lesions, caused by the resultant vasodilation and additional tissue damage

Clinical Presentation

  • Pustular folliculitis – Eosinophilic pustular folliculitis – pustules on scalp.Copyright© 2014, EBSCO Information Services.
  • Pustular folliculitis – Eosinophilic pustular folliculitis – pustules with surrounding erythema on back.Copyright© 2014, EBSCO Information Services.
  • eosinophilic cellulitis (Wells syndrome) most commonly presents with large, markedly inflamed, infiltrated plaques associated with pain, burning sensation and/or pruritus(1)
  • skin lesions(1)
    • appear as well-defined annular or arcuate areas of edematous erythema; violet halo may be present
    • may be associated with, or preceded by, pruritus or burning sensation
    • atypical presentations may include nodules, infiltrates, vesicles, hemorrhagic blisters, or hives
    • lesions may reoccur in recurrent episodes
    • most commonly affect lower limb, upper limbs, and trunk; but also occur on face and neck
    • clinical presentation and lesions may change over time
  • usually affects adults though occasionally reported in childhood(1)
  • children reported to more frequently have plaque-type and solitary lesions
  • adults more frequently have
    • granuloma annulare-type lesions
    • multifocal manifestations
  • mild general symptoms may occur
    • overall systemic involvement is reported to be rare
    • fever, malaise, and arthralgia has been reported
  • Wells syndrome may be associated with other conditions belonging to the spectrum of eosinophilic dermatoses, such as eosinophilic fasciitis, eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndromes(1)
  • References – (1,2), An Bras Dermatol 2019 Jul 29;94(3):370full-text, J Dtsch Dermatol Ges 2016 Oct;14(10):989, Clin Rev Allergy Immunol 2016 Apr;50(2):189

Evaluation and Diagnosis

  • diagnosis of eosinophilic cellulitis (Wells syndrome) involves clinical features, histopathological findings, and exclusion of other causes
    •  clinical presentation is usually characterized by erythematous or edematous lesions closely resembling urticarial vasculitis(2)
    •  lesions may coalesce forming erythematous pruritic plaques with a granuloma annulare-like appearance(2)
    • plaque-type unilesional presentation mimicking erysipelas is reported more frequently in children than in adults(2)
    • blisters, papulovesicles, and papulonodules are rarely reported(2)
    • fever and arthralgia may accompany cutaneous manifestations in some cases(2)
    • eosinophilia in blood is observed in approximately 50% of the cases, while tissue eosinophilia is more common(2)
    • suspect eosinophilic cellulitis (EC) in patients with recurrent erythematous cellulitis-like cutaneous lesions without clear infection source that are nonresponsive to antibiotics(3)
    • proposed diagnostic criteria
      • ≥ 2 of the following major criteria
        • typical clinical features (any of the following lesion types applicable: plaque type, annular granuloma-like, urticaria-like, papulovesicular, bullous, papulonodular, and fixed drug eruption-like)
        • chronic relapsing course
        • exclusion of systemic disease
        • histology showing eosinophilic infiltrates and no signs of vasculitis
      • ≥ 1 of the following minor criteria
        • flame figures in histology
        • granulomatous changes in histology
        • peripheral eosinophilia up to 1,500 microliters
        • detectable triggering factor
      • Reference –J Dtsch Dermatol Ges 2016 Oct;14(10):989
  • differential diagnoses is broad and includes all of the following
    • urticarial vasculitis(2)
    • Sweet syndrome(2)
    • skin reactions to insect bites(2)
    • bacterial cellulitis(2)
    • erysipelas(2)
    • acute or chronic urticaria(2)
    • contact dermatitis(2)
    • allergic or fixed drug eruption(2)
    • eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (may be co-occurring)(3)
    • hypereosinophilic syndrome (may be co-occurring)(3)
    • other autoimmune disease (such as lupus) (J Dtsch Dermatol Ges 2016 Oct;14(10):989)
  • histopathology
    • initial histologic findings frequently consist of a nonspecific, superficial and deep lymphocytic and eosinophilic dermal infiltrate(1)
    • edema, especially in the papillary dermis, may also be demonstrated(1)
    • typical flame figures develop over the course of 1-3 weeks(1)
    • while they persist, predominantly perivascular histiocytic granulomas with multinucleated giant cells may subsequently occur(1)
    • 3 distinct stages reported for histopathology of eosinophilic cellulitis (EC)
      • initially, dense dermal infiltrate rich in eosinophils extending up to subcutaneous tissue
      • second stage characterized by flame figures, which are typical for EC, but not pathognomonic for EC(3)
        • flame figures are degenerated collagen with eosinophilic grains surrounding collagen(3)
        • may also occur in insect bites, pemphigoid, mastocytoma, dermatophytosis, scabies, scurvy, eczema, herpes gestationis, severe prurigo, drug eruption, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) and follicular mucinoses)(3)
        • flame figures often present in later phases of the disease (corresponding to an area of collagen degeneration secondary to the release of toxic substances by eosinophils)(1,2,3)
      • in last stage, flame figures are surrounded by histiocytes and multinucleated giant cells with foreign body reaction in palisade (An Bras Dermatol 2019 Jul 29;94(3):370full-text)

Management

  • evidence for management is limited and based on case reports and series(2)
  • if a trigger or underlying condition identified, treat the trigger or condition per usual management(2)
  • topical and systemic corticosteroids are first-line treatment, while cyclosporine A (3-5 mg/kg/day) and dapsone (of 0.5-1.5 mg/kg/day, which is an immunomodulator that may theoretically inhibit eosinophil recruitment and activation) are alternative therapies(2)
  • approach to treatment with initial corticosteroids(1)
    • although there is no dosing regimen that is clearly better than any other, optimal results reportedly achieved with an initial dose of 2 mg/kg/day over a period of 1-2 weeks, followed by a taper over 2-3 weeks
    • if corticosteroids are not sufficiently effective or long-term treatment is required, alternative therapies may include dapsone and cyclosporine A as well as antihistamines
  • for skin lesions
    • consider systemic corticosteroids
      • prednisone orally 20-30 mg/day reported to usually clear lesions within several weeks
      • if persistent and recurring lesions, consider maintenance with prednisone orally 5 mg every other day
    • if resistant or intolerance to steroids, options include
      • dapsone, tacrolimus, or cyclosporine
      • adalimumab in recent case report
      • other therapies used individual case reports (including azathioprine, hydroxychloroquine, and colchicine)
    • antihistamines may be considered as symptomatic treatment for associated pruritus
    • other monoclonal antibodies that have been used with success anecdotally include omalizumab (anti-IgE) and mepolizumab (anti-IL-5)
    • follow-up – consider comprehensive evaluation for potential underlying diseases such as
      • hematologic malignancies
      • eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
      • hypereosinophilic syndrome
    • Reference – Clin Rev Allergy Immunol 2016 Apr;50(2):189
  • evidence
    • no randomized trials identified evaluating treatments for eosinophilic cellulitis (Wells syndrome) in systematic review (J Eur Acad Dermatol Venereol 2016 Sep;30(9):1465)
    • topical or systemic glucocorticosteroids reported to be most common treatment for patients with eosinophilic cellulitis (Wells syndrome) (level 3 [lacking direct] evidence)
      •  based on systematic review of observational studies with limited descriptive data
      • systematic review of 94 case series or case reports on treatments for eosinophilic cellulitis in 149 patients
      •  largest case series included 19 patients; 7 case series included 3-7 patients; 86 case reports included ≤ 2 patients
      • topical or systemic glucocorticosteroids reported to be most common treatment and have reported efficacy; options include
        • topical steroids, particularly in children (typical presentation is classic plaque rather than granuloma-variant form more common in adults)
        • oral prednisolone initiated at 1-2 mg/kg/day, continued at 5 mg/day
        • oral prednisolone 2 mg/kg/day for 5-7 days then tapered over 2-3 weeks
        • prednisolone 1 mg/kg/day
      • medications reported to yield remission in single case reports included cyclosporine 1.25 or 2.5 mg/kg/day for 3-4 weeks, dapsone 100 mg/day, adalimumab 40 mg once weekly for 1 month, interferon alpha, sulfasalazine, psoralen ultraviolet A (PUVA) phototherapy, hydroxychloroquine, azathioprine, minocycline 100 mg orally/day plus niacinamide 500 mg orally/day for 2 weeks, griseofulvin
      • Reference – J Eur Acad Dermatol Venereol 2016 Sep;30(9):1465
    • colchicine 1.5 mg/day reported to resolve eosinophilic cellulitis refractory to systemic prednisolone at 3 weeks in 18-year-old woman with no recurrence reported at 6-month follow-up in case report (Indian Dermatol Online J 2019 Jul;10(4):467full-text);

Prognosis

  • disease course is chronic and/or relapsing with a high rate of spontaneous resolution(2)
  • recurrences are not uncommonly reported(1)
  • eosinophilic cellulitis (Wells syndrome) usually has benign course is responsive to treatment
    • lesions may spontaneously resolve within 4-8 weeks
    • with treatment, lesions typically resolve in weeks to months
    • resolved lesions may appear as morphea-like residual skin atrophy and hyperpigmentation without scarring
    • lesions may recur intermittently for years
    • consider follow-up with patients to evaluate for underlying diseases
    • Reference – Clin Rev Allergy Immunol 2016 Apr;50(2):189
  • mean duration of recurring symptoms of 5 years for adults and 3 years for children in case series of 19 patients with eosinophilic cellulitis (Wells syndrome) (Arch Dermatol 2006 Sep;142(9):1157)

Eosinophilic Fasciitis

General Information

  • eosinophilic fasciitis is a rare disorder characterized by erythema, edema, and induration of the fascia of the upper and/or lower extremities(1,2)
    • also known as Shulman syndrome
    • may appear clinically similar to localized scleroderma (morphea), but can be distinguished from systemic sclerosis by lack of involvement of the hands and fingers

Epidemiology

  • very rare(7)
    • generally occurs in adults aged 20-60 years
    • has been reported in children and older adults
    • may be underreported overall
  • about 300 cases reported worldwide(3)

Etiology and Pathogenesis

  • etiopathogenesis of eosinophilic fasciitis (EF) is not completely clear
    • autoimmune mechanism is thought to be a primary pathophysiologic component(1,2,7)
      • similarities to autoimmune conditions include occasional associated hypergammaglobulinemia, positive rheumatoid factor, antinuclear antibodies, and immune complexes, as well as beneficial response to corticosteroids
      • onset with strenuous exercise suggests that damaged fascia may trigger autoimmune mechanism
      • role of eosinophils
        • eosinophil degranulation may induce tissue damage and fibrosis due to accumulation of collagen and other extracellular matrix proteins
        • high levels of eosinophilic cationic protein and serum interleukin-5 (IL-5) are present
        • eosinophils may interact with fibroblasts and produce fibrogenic cytokines (such as transforming growth factor [TGF-beta] and interleukins [IL-1 and IL-6])
        • other reports of increased production of IL-2, interferon-gamma (IFN-g), and leukemia inhibitory factor (LIF) by peripheral mononuclear cells in the blood; overexpression of CD40 ligands, and elevated superoxide dismutase (SOD) levels
      • involvement of mast cells has also been reported, with an increase in plasma histamine levels
      • fascial damage and resultant thickening is characterized by infiltration of lymphocytes, macrophages, and eosinophils
      • unlike morphea, the pathogenesis seems to be associated with predominance of CD8+ and CD4+ cells as well as Th17 cells
  • specific cause may be unknown, but certain triggers and precipitating disorders associated with eosinophilic fasciitis, according to Japanese Dermatological Association, may include(5)
    • trauma or injury to affected fascia
      • reported in 30%-46%
      • extensive exertion of limbs and/or history of bruising prior to symptoms may be noted
      • strenuous exercise, labor, or trauma reported few days to 1-2 weeks before the onset of illness
    • trauma and resulting nonspecific inflammation of injured fascia may be a trigger for an autoimmune process
    • other purported triggers include
      • infections, such as
        • Borrelia burgdorferi (similar to localized scleroderma, some cases are positive for Borrelia burgdorferi antibodies)
        • Mycoplasma infection (which may also trigger onset of the disease)
      • use of certain drugs may be associated, including
        • statins
        • phenytoin
        • ramipril
        • heparin
      • contact with organic solvents such as trichloroethylene and trichloroethane (similar clinical presentation reported)
      • procedural interventions including hemodialysis or radiotherapy
      • graft-versus-host disease (GVHD)
  • paraneoplastic eosinophilic fasciitis has been reported
  • immune checkpoint inhibitors and statins appear to be among most common drugs reported to be associated with drug-induced eosinophilic fasciitis
    •  based on cohort study
    • individual case safety reports (ICSR) from World Health Organization (WHO) global database (Vigibase3) and a French Pharmacovigilance Database were evaluated for eosinophilic fasciitis
      • among 876,617 ICSRs in the French Pharmacovigilance Database, 13 EF cases were reported, including 16 distinct suspected drugs
      • among 21,719,823 ICSRs in VigiBase, 101 distinct EF cases were reported including 85 different suspected drugs
    • drugs associated with EF in ICSRS
      • immune checkpoint inhibitors reported in 22 different ICSRs (reporting odds ratio [OR] 75.3, 95% CI, 46.9-120.8)
      • statins reported in 12 different ICSRs (reporting OR 10.8, 95% CI, 5.9-19.8)
      • tumor necrosis factor (TNF) inhibitors reported in 9 ICSRs but nonsignificant association (reporting OR 1.7, 95% CI, 0.8-3.3)
      • other drugs implicated included proton pump inhibitors, vaccines (human papillomavirus [HPV] and influenza), bisphosphonates, and antiparkinsonian agents (such as dopamine agonists, carbidopa/levodopa, ropinirole, and pramipexole)
    • Reference – J Am Acad Dermatol 2021 May 27;doi: 10.1016
  • case reports of other associations

Clinical Presentation

  • clinical presentation(1,2,7)
    • course of illness
      • acute onset of erythematous, edematous plaques and pitting edema of lower and/or upper limbs
        • involvement of extremities is typically symmetrical (although unifocal involvement has been reported)
        • Shulman originally described diffuse fasciitis affecting all 4 limbs
        • face and fingers rarely affected, but spread to trunk has been reported
      • sudden onset reported in 50% of the cases, with gradual onset demonstrated in other cases
      • patients may have associated myalgia, arthralgia, fever or fatigue
      • history of overexertion of limbs or trauma may be present
      • joints of the limbs may develop restricted range of motion
  • physical exam
    • skin and joints of affected extremity are characterized by swelling, induration and thickening, resulting in limited joint mobility(5)
    • orange peel-like appearance (peau d’orange) and “groove sign” are useful clinical findings to suggest diagnosis (5)
    • peau d’orange appearance
      • edema may progress to deep sclerosis with a peau d’orange appearance(2)
      •  reported in about 50%(5)
    • “groove” sign
      • characterized by visible depression of skin along superficial veins, particularly on elevation of affected limb (occurs due to fixation of veins to connective tissue underneath mobile epidermal and dermal layers)(1,2)
      •  reported in 50% (5)
    • hardness of the forearms can lead to flexion contracture of the wrists and fingers, leading to “prayer sign”(3)
  • Raynaud phenomenon, digital sclerodactyly and nailfold changes are NOT typical for eosinophilic fasciitis, but are more commonly seen with systemic sclerosis (scleroderma)(1,2)

Evaluation and Diagnosis

  • diagnosis of eosinophilic fasciitis is based on (1,2,3,4)
    • clinical symptoms of edema and induration of extremities
    • imaging findings of fascial involvement
    • histology showing inflammatory infiltrates with lymphocytes and/or eosinophils of fascia
    • exclusion of other causes, particularly systemic sclerosis
  • diagnostic criteria for diffuse eosinophilic fasciitis (EF) was established by Japanese Dermatological Association guidelines with requirement for 4 limbs involved, although published reports of EF often note that either upper or lower extremities are affected(3)
  • according to Japanese Dermatological Association guidelines, definitive diagnosis of eosinophilic fasciitis is fulfilled with presence of a major criterion plus at least 1 of the minor criteria(5)
    • major criterion requires symmetrical plate-like sclerotic lesions present on 4 limbs, but lacking Raynaud phenomenon, and excluding systemic sclerosis
    • minor criteria 1 requires skin biopsy with the following histologic findings
      • fascia shows fibrosis of the subcutaneous connective tissue
      • thickening of the fascia
      • cellular infiltration of eosinophils and monocytes
    • minor criteria 2 requires the imaging findings (such as magnetic resonance imaging [MRI]) showing thickening of the fascia
  • differential diagnosis
    • localized scleroderma (morphea) should be included in differential diagnosis but may also coexist with eosinophilic fasciitis in some patients(2)
    • systemic sclerosis is in differential, but eosinophilic fasciitis lacks the digital and facial skin sclerosis, nail fold capillary abnormalities and/or disease-specific autoantibodies (antitopoisomerase I antibodies, anticentromere antibodies and anti-RNA polymerase antibodies)(5)
    • additional differential diagnoses include
      • eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome) (will have organ involvement)
      • other scleroderma-like syndromes including eosinophilia-myalgia syndrome (EMS) caused by l-tryptophan ingestion, and toxic oil syndrome
      • miscellaneous diseases characterized by signs of inflammation and peripheral increases in eosinophil count
      • hypereosinophilic syndrome (HES) (will have organ involvement)
      • nephrogenic systemic fibrosis in patients with advanced renal failure, or a history of gadolinium administration
      • Reference – Am J Clin Dermatol 2017 Aug;18(4):491 full-text
  • testing(1)
    • due to an association with (predominantly hematologic) malignancies, consider blood tests
    • diagnosis of eosinophilic fasciitis should be confirmed by a deep biopsy that includes subcutis, fascia and muscle
    • imaging including ultrasound, magnetic resonance imaging (MRI) or PET/CT may be useful, not only to establish the diagnosis of fasciitis but also to determine the best site for biopsy
  • blood tests(5)
    • peripheral eosinophil count
      • elevated peripheral eosinophils reported in 63%-86%
      •  eosinophilia typically transient and may be demonstrated during acute phase only
      •  reportedly correlates with disease activity, since levels decrease with treatment
      • eosinophilia may help distinguish eosinophilic fasciitis from systemic sclerosis because peripheral eosinophilia is rare in systemic sclerosis
    • elevated inflammatory markers (erythrocyte sedimentation rate [ESR] and/or C-reactive protein [CRP]) may be identified
      • high erythrocyte sedimentation rate reported in approximately 29%-80%
      • may correlate with disease activity
    • antinuclear antibodies
      • consider testing for antinuclear antibodies (ANA) to help rule out systemic sclerosis
      • ANA typically not elevated with eosinophilic fasciitis, but may be seen with systemic sclerosis
      • ANA may be seen with localized scleroderma (morphea)
    • serum aldolase levels may be elevated
      • serum creatine kinase levels usually normal, but elevated serum aldolase reported in about 60%
      • levels may fluctuate with disease activity (decreasing with treatment and rising again with relapse of skin symptoms)
      • aldolase levels may take longer to normalize than other blood test abnormalities
    • hypergammaglobulinemia or monoclonal gammopathy may be present
      •  serum immunoglobulin G (IgG) levels elevated in approximately 3%-72% of cases
      • levels may correlate with disease activity
    • serum soluble interleukin-2 receptor levels, serum type III procollagen amino peptide levels, serum immune complexes and serum tissue inhibitor of matrix metalloproteinase-1 (TIMP) levels are other reported markers that may monitor disease activity
  • imaging studies
    • Japanese Dermatological Association recommendations for imaging studies(5)
      • use magnetic resonance imaging (MRI) for diagnosis of eosinophilic fasciitis if biopsy not available (JDA Grade 1, Level D)
      • consider MRI to help determine biopsy sites and assess disease activity or therapeutic effect (JDA Grade 2, Level D)
      • consider ultrasound as alternative for diagnosis (JDA Grade 2, Level D)
      • computed tomography (CT) scans may be an alternative option if MRI is not possible, but is supported by limited to no evidence
    • magnetic resonance imaging (MRI)
      • IV gadolinium-based contrast may improve visualization of perifascial inflammation(2)
      • findings characterized by hyperintense fascia on T2-weighted imaging(2)
      • MRI prior to, and during, treatment may be useful for monitoring disease course(2)
    • ultrasound(5)
      • subcutaneous thinning may be identified on ultrasound in eosinophilic fasciitis
      •  eosinophilic fasciitis may be associated with reduced subcutaneous tissue compressibility (upon skin compression with probe) than other fibrotic diseases such as systemic sclerosis
  • biopsy
    • Japanese Dermatological Association recommendations for biopsy(5)
      • use en bloc biopsy spanning skin to fascia for diagnosis of eosinophilic fasciitis (JDA Grade 1, Level D)
      • punch biopsy not considered adequate for diagnosis
    • histologic findings
      • edema in the fascia and deep subcutaneous tissue seen initially
      • infiltration with lymphocytes, plasma cells, histiocytes and eosinophils
      •  plasma cells and macrophages may also be present
      •  lymphoplasmacytic inflammation may involve subcutaneous fat septa, fascia, and sometimes muscle
      • thickened fascia surrounded by lymphocytes and eosinophils
      • epidermal atrophy and thickened collagen bundles in the subcutaneous tissue and lower layers of the dermis may be seen with disease progression
      • epidermal atrophy is reported in 16% of cases, increase of thickened collagen bundles in 40%-70% of cases, eosinophil infiltration in 65-80% of cases, thickening of fat septum in > 50% of cases, and fascia thickening in almost all cases
      • with long-term disease or following treatment initiation, eosinophils may also be absent and thickening of dermal collagen fiber may occur
      • concomitant myositis is a common finding
      • Reference – J Dtsch Dermatol Ges 2019 Oct;17(10):1039 and J Dermatol 2018 Aug;45(8):881
  • severity classification by Japanese Dermatological Association guidelines(5)
    • total of ≥ 2 points is classified as severe
    • 1 point is assigned for each of the following
      • joint contracture (upper limbs)
      • joint contracture (lower limbs)
      • limited movement (upper limbs)
      • limited movement (lower limbs)
      • expansion and worsening of skin rash (progression of symptoms)
  • screening for malignancy
    • eosinophilic fasciitis has been reported as associated with development of malignancies, more often hematologic malignancies than solid cancers(3)
    • consider screening for malignancy, based on individual clinical signs(5)
    • screening modalities may include lab tests, x-rays, CT or PET scan, ultrasound or endoscopy as determined by clinical signs and symptoms (Am J Clin Dermatol 2017 Aug;18(4):491full-text)

Management

  • general principles of management
    • early treatment may prevent irreversible fibrotic changes; however, data is limited to support most treatment options(2)
    • systemic corticosteroids are considered first-line treatment(2)
    • for steroid-sparing and/or refractory symptoms, immunosuppressant and adjuvant medications are frequently used to treat eosinophilic fasciitis, with reported options potentially including
    • consider interdisciplinary consultation and shared decision-making with dermatologist, rheumatologist and patient
  • no randomized trials exist to support any treatment option over another(5)
  • corticosteroids
    • systemic corticosteroids are considered first-line treatment
      • typical initial dosing is prednisone 0.5-1 mg/kg/day(2)
      • pulse therapy with methylprednisolone (125-500 mg/day orally for 3-5 consecutive days) is another option(2)
    • use of moderate-to high-dose corticosteroids (for example, prednisone > 10-15 mg/day) should be avoided in patients with systemic sclerosis at risk for scleroderma renal crisis
    • Japanese Dermatological Association guidelines for corticosteroid therapy(5)
      • oral corticosteroids (JDA Grade 1, Level D) and steroid pulse therapy (JDA Grade 1, Level C) recommended as effective for treating eosinophilic fasciitis
      • steroid pulse therapy associated with higher rate of complete remission than no steroid treatment (87% vs. 53%, p = 0.06) and lower rate of concomitant immunosuppressant use (20% vs. 65%, p = 0.02) in retrospective cohort study of 32 patients (Rheumatology (Oxford) 2012 Mar;51(3):557)
      • topical therapies (corticosteroids or tacrolimus) are not likely to be sufficient to treat eosinophilic fasciitis, and if considered, should be combined with appropriate systemic therapies (JDA Grade 2, Level D)
  • Japanese Dermatological Association guidelines on adjuvant and immunosuppressive therapy(5)
    • immunosuppressive therapy (such as methotrexate, mycophenolate mofetil, cyclosporine, azathioprine and cyclophosphamide) are also options for treating eosinophilic fasciitis, particularly in cases of refractory disease (JDA Grade 2, Level D)
    • although limited evidence supports any specific immunosuppressive therapy, use of methotrexate is more common than other agents
    • other therapies that have reportedly been used as adjuvant therapy with some success include dapsone, ketotifen, cimetidine, infliximab, chloroquine and hydroxychloroquine (JDA Grade 2, Level D)
    • further investigation required for rituximab, IV immunoglobulin (IVIG), antithymocyte globulin, and fasciectomy before they can be recommended
  • methotrexate
    • oral or subcutaneous methotrexate (10-25 mg weekly) may be added to corticosteroids, or may be used as maintenance therapy(2)
    • high-dose pulse IV methotrexate given monthly reported as beneficial in 1 series of 12 patients
    • addition of methotrexate to corticosteroid therapy associated with higher rates of complete response (resolution of erythema and/or edema) in patients with eosinophilic fasciitis compared to other treatment combinations or corticosteroids alone (level 2 [mid-level] evidence)
      •  based on retrospective cohort study
      • 63 patients with eosinophilic fasciitis (EF) were evaluated for complications and treatment responses
      • mean time from onset of EF to diagnosis was 11 months (79% of patients initially misdiagnosed with systemic sclerosis, deep vein thrombosis, hypereosinophilic syndrome or cellulitis)
      • 50% of patients had joint contractures, 37% of whom were referred for physical therapy
      •  trauma or intense exercise preceding the onset of EF in 8 patients (28%)
      • complete response defined as resolution of erythema and/or edema with no or minimal persistent induration; partial response defined as incomplete improvement of erythema, edema, and/or induration; and no response defined as lack of improvement
      • mean follow-up was 39 months
      • complete response in
        • 21 of 33 patients (64%) with combination of corticosteroids and methotrexate
        • 10 of 33 (30%) with corticosteroid monotherapy (p = 0.007 compared to corticosteroids plus methotrexate)
        • 9 of 31 (29%) with other treatment combinations (p = 0.006 compared to corticosteroids plus methotrexate)
        • 1 of 6 (17%) with treatment without corticosteroids (p = 0.03 compared to corticosteroids plus methotrexate)
      • complete response in 67% treated ≤ 6 months from diagnosis vs. in 55% treated >6 months from diagnosis (not significant)
      • Reference – JAMA Dermatol 2016 Jan;152(1):97
    • methotrexate plus prednisone reported to induce remission in some adults with eosinophilic fasciitis (level 3 [lacking direct] evidence)
      •  based on case series
      • 16 adults (mean age 52 years, range 30-75 years) with biopsy-proven eosinophilic fasciitis diagnosed between January 1998 and December 2012 were reviewed
      • treatments included
        • 13 patients started on prednisone then had methotrexate added as steroid-sparing treatment
        • 2 patients started on combination prednisone and methotrexate
        • 1 patient with diabetes started on methotrexate
      • dosing of methotrexate not reported
      • clinical response reported at about 6 months of treatment
      • complete remission in 9 patients at mean 31.4 months (range 12-84 months)
        • 3 patients had sustained remission off methotrexate at 12-36 months follow-up
        • relapse at mean 27.1 months (range 7-36 months) in 6 patients after stopping methotrexate (restart of methotrexate induced response)
      • Reference – Am J Clin Dermatol 2017 Aug;18(4):491
    • high-dose pulse IV methotrexate given monthly reported to improve skin scores and range of motion scores for most joints in patients with eosinophilic fasciitis (level 3 [lacking direct] evidence)
      •  based on uncontrolled trial
      •  12 patients (90% women) diagnosed with biopsy specimen-proven eosinophilic fasciitis were treated with IV methotrexate (4 mg/kg) monthly for 5 months with folic acid rescue 24 hours after MTX administration
      • joint contractures were monitored by measuring passive range of motion (ROM) of affected joints; visual analog scale (VAS) scores for disease activity were scored by the physician and patient
      • median modified skin score (according to Zachariae skin score) improved from 17.5 (range 8.0-24) at baseline to 8.5 (range 1-20) at month 5 (p = 0.001)
      • secondary outcome measures that significantly improved included VAS scores (p = 0.001), range of motion scores (for wrists, knees, and ankles; p ≤ 0.01 for each); durometer scores and range of motion of the elbows did not significantly improve
      • adverse events included gastrointestinal symptoms (in 9 patients), mild stomatitis (in 5 patients), and alopecia (in 4 patients)
      • Reference – JAMA Dermatol 2016 Nov 1;152(11):1262
  • mycophenolate
    • mycophenolate (typically in combination with corticosteroids) reported to induce complete or partial response in ≥ 90% of patients with eosinophilic fasciitis (level 3 [lacking direct] evidence)
      •  based on systematic review of case series
      • 29 patients with eosinophilic fasciitis that were treated with mycophenolate mofetil or mycophenolic acid were assessed
      • all but 2 patients also received systemic corticosteroids; mycophenolate (MMF/MPA) was given as a steroid-sparing agent in 27 patients (93.1%), in 1 patient (3.4%) as adjunctive therapy with other immunosuppressants, and as monotherapy in 1 patient (3.4%)
      • response with MMF/MPA
        • complete response in 19 (66%)
        • partial response in 6 (21%)
        • unresponsive (to diverse immunomodulators) in 2 (7%)
        • no outcome data for 2 patients
      • Reference – J Dermatolog Treat 2021 Feb 21;:1
  • biologic agents
    • IL-6 inhibitors, TNF inhibitors, and IV immunoglobulin (IVIG) therapy each associated with complete response in about 25% of cases and partial response in 30%-75% in patients with refractory eosinophilic folliculitis (level 3 [lacking direct] evidence)
      •  based on systematic review of case reports and series
      • systematic review of 21 studies evaluating biologic treatments in 34 patients (mean age 49.4 years, 56.7% male) with refractory eosinophilic fasciitis
      • EF was located on the lower portion of the extremities (79.4%), upper portion of the extremities (76.5%), and trunk (47.1%)
      • biologic treatments were given with corticosteroids (in 28.9%), immunosuppressants (in 26.3%), and corticosteroid and immunosuppressant combinations (in 26.3%)
      • biologic therapies given
        • tumor necrosis factor (TNF) inhibitor (infliximab, etanercept or golimumab) in 13 (34.2%)
        • immunoglobulins (IVIG or antithymocyte globulin) in 12 (31.6%)
        •  anti-CD20 monoclonal antibody (rituximab) in 6 (15.8%)
        •  IL-6 inhibitor (tocilizumab) in 4 (10.5%)
        • tyrosine kinase inhibitor (imatinib) in 2 (5.3%)
        • combination therapy (thrombopoietin mimetic agent [romiplostim] and IVIG) in 1 (2.6%)
      • complete resolution and partial resolution in
        •  25% and 75% with IL-6 inhibitor
        • 23.1% and 53.8% with TNF inhibitor
        • 33.3% and 33.3% with immunoglobulins
        • 33.3% and 33.3% with anti-CD20 monoclonal antibody
      • Reference – J Am Acad Dermatol 2021 Apr 2;doi: 10.1016
    • case reports
      • rituximab reported to improve symptoms in case series of 8 patients with eosinophilic fasciitis refractory to other immunosuppressants (Rheumatol Int 2021 Oct;41(10):1833)
      • baricitinib reported to improve symptoms and allow for reduced corticosteroids in patient aged 37 years with refractory eosinophilic fasciitis (J Rheumatol 2021 Jun;48(6):948full-text)
      • infliximab reported to improve symptoms in patient aged 43 years with eosinophilic fasciitis that started during pregnancy (infliximab administered after delivery) (Rheumatol Int 2021 Aug;41(8):1531)
      • tofacitinib 5 mg orally twice daily for 5 months reported to reduce skin sclerosis and fascial lesions in 68-year-old male with refractory eosinophilic fasciitis Clin Exp Rheumatol 2020 May;38(3):567
  • phototherapy
    • Japanese Dermatological Association recommendations for phototherapy(5)
      • phototherapy may be an effective option for treating the skin lesions of eosinophilic fasciitis (JDA Grade 2, Level D)
      • psoralen plus ultraviolet A (PUVA) therapy reported to be effective within 6 months for 1 patient who was unresponsive to steroids and chloroquine
  • rehabilitation services
    • Japanese Dermatological Association recommendations for rehabilitation(5)
      • rehabilitation may improve limb contractures in patients with eosinophilic fasciitis (JDA Grade 2, Level D)
      • specific rehabilitation program not identified, but commonly advised protocols include
        • joint range of motion exercises with active assistance using a pulley for shoulder joint, passive range of motion exercises for major joints, and leg muscle strength training using wall bars after warming the joints with a hot pack
        • occupational therapy (muscle strength training for intrinsic hand muscles)
        • physical therapy with paraffin baths, active/passive movement, and walking in a pool

Complications and Prognosis

  • complications
    • joint contractures and functional limitation are most common complications (JAMA Dermatol 2016 Jan;152(1):97)
    • other complications may include
      • carpal tunnel syndrome, due to pressure on the median nerve(7)
      • muscle pain and weakness, may develop due to perimyositis, but not typically reported(5)
    • hematologic abnormalities have been associated with eosinophilic fasciitis, including(5)
      • aplastic anemia
      • autoimmune hemolytic anemia
      •  idiopathic thrombocytopenic purpura
      •  leukemia or lymphoma
      • myelodysplastic syndrome
    • autoimmune conditions have been associated with eosinophilic fasciitis, including(7)
      • systemic lupus erythematosus
      • rheumatoid arthritis
      • Sjögren syndrome
      •  autoimmune thyroiditis
    • other reported complications or associations include peripheral neuropathy and visceral malignant neoplasias including prostate cancer and breast cancer(5)
  • prognosis

Granuloma Faciale

General Information

  • granuloma faciale (GF) is an uncommon, benign cutaneous chronic condition of unknown etiology(2,3)
    • lesions typically appear as erythematous plaques or papules on the face
    • histopathology shows inflammatory infiltrate with eosinophils, neutrophils, plasma cells, and lymphocytes in the dermis and a Grenz zone of uninvolved dermis, located below normal epidermis
    • GF is not a granulomatous disease
  • most commonly reported in middle aged adults, with slight predominance in women (Acta Derm Venereol 2018 Jan 12;98(1):14, An Bras Dermatol 2016 Nov;91(6):803full-text)

Etiology and Pathogenesis

  • reported risk factors for granuloma faciale (GF) may include sun exposure and history of local trauma (including surgery to remove skin cancer) (An Bras Dermatol 2016 Nov;91(6):803)
  • pathogenesis of GF remains unclear, but some authors suggest GF may be a localized and chronic form of cutaneous vasculitis
    • leukocytoclastic vasculitis has been described in GF, some even reporting vessel wall necrosis
    • immunofluorescence studies have shown the presence of immune complex in the walls of dermal vessels, although immunoglobulin deposits have also been reported in the basement membrane zone
    • extravasated red blood cells and hemosiderin deposits also can be reported; vascular changes were frequently observed, mostly in the form of perivascular infiltrates with neutrophils and leukocytoclastic vessel wall necrosis very rare
    • Reference – J Am Acad Dermatol 2005 Dec;53(6):1002
  • association with IgG4-related diseases
    • detection of an increased content of immunoglobulin G (IgG4+) plasma cells associated with obliterative vascular inflammation and storiform sclerosis is reported in some GF specimens
    • though controversial, GF may represent a localized form of IgG4-related disease
    • Reference – An Bras Dermatol 2016 Nov;91(6):803full-text
  • association with eosinophilic angiocentric fibrosis
    • granuloma faciale reported to be associated with eosinophilic angiocentric fibrosis (an IgG4-related diseases disease)(4)
    • eosinophilic angiocentric fibrosis considered a variant of granuloma faciale that affects orbits and upper respiratory tract, particularly sinonasal tract(4)
    • case of concomitant orbital granuloma faciale and eosinophilic angiocentric fibrosis can be found in Ophthalmic Plast Reconstr Surg 2017 Mar/Apr;33(2):e47
  • granuloma faciale is not associated with systemic diseases(4)

Clinical Presentation

  • granuloma faciale typically presents with reddish-brown to violaceous plaques or nodules(1,2,3)
    • typically found on the face, particularly on the forehead, nose, cheeks, or preauricular region
    • lesions may be markedly raised and measure 1-2 cm in diameter
    • superficial telangiectasias may cover lesions
    • generally asymptomatic, but may be associated with itching
    • lesions tend to be chronic
    • in most cases, cutaneous lesions are isolated, but multiple lesions may affect approximately 30% of the cases
  • extrafacial lesions may less commonly occur; most typically on the trunk, extremities, or genitalia(2)
  • physical exam
    • single (or less commonly multiple) well-demarcated, reddish papule, nodule, or plaque on face(3)
    • may have a smooth appearance, or may show prominent follicular orifices with a peau d’orange appearance(3)
    • superficial telangiectasia may overlie lesion(3)
  • dermoscopy of granuloma faciale may identify any of following
    • translucent whitish-grayish background with orthogonal whitish streaks
    • linear, slightly arborizing vessels in parallel pattern
    • dilated follicular openings and brown dots and/or globules
    • Reference – Dermatol Ther 2016 Sep;29(5):325

Evaluation and Diagnosis

  • diagnosis of granuloma faciale (GF) is based on clinical features and histopathological findings on skin biopsy(3)
  • diagnosis should be confirmed by histology to rule out broad differential diagnosis which includes(1)
    • rosacea
    • basal cell carcinoma
    • sarcoidosis
    • cutaneous lupus, including lupus erythematosus tumidus or discoid lupus erythematosus
    • persistent arthropod bite reaction
    • leishmaniasis
    •  B-cell lymphomas or cutaneous lymphomas
    • deep trichophytosis
    • erythema elevatum diutinum
      • characterized by violaceous, red-brown, or yellowish papules, nodules, or plaques on extensor surfaces of the upper and lower extremities
      • histopathology shows cutaneous small-vessel vasculitis
  • biopsy and histopathology findings of granuloma faciale
    • histopathology findings may include leukocytoclastic vasculitis associated with a dermal dense mixed cell (neutrophilic and lymphocytic) inflammatory infiltrate as well as a grenz zone (a narrow zone that contains no inflammatory cells)(1,2)
    • grenz zone is reported in 74% to 100% of cases of granuloma faciale (An Bras Dermatol 2016 Nov;91(6):803)
    • composition of the inflammatory infiltrate varies between cases
      • lymphocytes are nearly always present, along with neutrophils (93% of cases), plasma cells (70%), eosinophils (57.5%), and other mononucleated cells
      • inflammatory infiltrates often involve the papillary, middermis, and perivascular area in most cases, but may also be diffuse
      • vascular changes are frequently demonstrated, although necrotizing vasculitis appears to be rare
      • Reference – J Am Acad Dermatol 2005 Dec;53(6):1002
    • dilated follicular ostia and/or follicular plugs at the ostium of hair follicles reported in ≥ 60% of specimens (J Am Acad Dermatol 2005 Dec;53(6):1002)

Management

  • management of granuloma faciale (GF)(1,2)
    •  topical corticosteroids and tacrolimus ointment are most commonly advised
    • there is limited evidence to support treatment options
    • no randomized trials of treatment identified in systematic review
    • Reference – Acta Derm Venereol 2018 Jan 12;98(1):14
  • corticosteroids
    • topical corticosteroids (clobetasol) or intralesional corticosteroid (triamcinolone acetonide) have been used with limited benefit (Int J Dermatol 1997 Jul;36(7):548)
    • corticosteroids may be associated with adverse effects such as skin atrophy or telangiectasias
  • tacrolimus 0.1% ointment
    • applied twice daily
    •  reported as effective (successful or some effect) in 100% of 28 patients in pooled analysis of systematic review of case reports and case series of granuloma faciale
    •  > 60% reported excellent results
    • Reference – Acta Derm Venereol 2018 Jan 12;98(1):14
  • dapsone
  • other medications, typically for refractory cases, that have demonstrated success in case reports and series include
  • tacrolimus reported as most effective option to treat granuloma faciale, but evidence for any therapy for this condition is limited; topical and intralesional corticosteroids reported as ineffective in up to 42% of cases (level 3 [lacking direct] evidence)
    •  based on systematic review of observational studies with limited evidence
    • systematic review of 67 studies(case reports, case series, and cohort studies; all retrospective) evaluating interventions for granuloma faciale
    • topical corticosteroids (either locally applied or administered as intralesional injections), were reported to be ineffective in 42% of cases (and were associated with deleterious effects such as skin atrophy)
      • topical corticosteroid reported as effective (successful or some effect) in 52% of 31 patients in pooled analysis
      • intralesional corticosteroid reported as effective (successful or some effect) in 65% of 26 patients in pooled analysis
    • tacrolimus (0.1% ointment) applied twice daily reported to be effective in 100% of 28 cases, with > 60% reporting excellent results
    • topical dapsone 5% gel for treatment of GF has been demonstrated to be effective in other case reports
    • limited evidence for systemic treatments
      • variable results reported with oral dapsone (at dose of 50-150 mg daily), and additionally associated with adverse effects such as nausea, loss of appetite, and blood dyscrasias (hemolysis and methemoglobinemia)
      • systemic corticosteroids have not been sufficiently studied
      • clofazimine (an antileprosy drug with anti-inflammatory effects and antiproliferative activity for lymphocytes and carcinoma cells) was reported to be successful at a dose of 300 mg/day in case reports
    • procedural therapies such as cryotherapy, laser therapy, or surgical excision, may cause scarring or postinflammatory pigmentation and results are conflicting for initial and continued efficacy
    • Reference – Acta Derm Venereol 2018 Jan 12;98(1):14
  • cryotherapy
    • inconsistent reports of effectiveness for granuloma faciale in case reports and small case series
    • may cause scarring or postinflammatory pigmentation
    • Reference – Acta Derm Venereol 2018 Jan 12;98(1):14
  • laser
    • limited evidence regarding laser treatment for granuloma faciale
    • various lasers, such as pulsed dye laser (PDL), potassium-titanyl-phosphate (KTP) laser and carbon dioxide (CO2) laser, reported as effective in 17 (74%) of 23 case reports in systematic review
      • lasers generally advised for lesions unresponsive to other treatment options, but results may be variable
      • PDL can target oxyhemoglobin in vessels and may be helpful for flat lesions, but likely less effective for exophytic granuloma faciale
      • pulse stacking with PDL suggested to improve effectiveness
      • KTP 532-nm laser typically used with vascular lesions and reported to resolve granuloma faciale in 2 reports
      • CO2 lasers target tissue water and may be associated with higher risk of scarring
      • Reference – Acta Derm Venereol 2018 Jan 12;98(1):14
    •  CO2 emulated Er:YAG laser treatment for 3 ablations (initial, then again after 9 months, and again after 6 months) reported to markedly improve granuloma faciale in 50-year-old patient with lesion unresponsive to 2 intralesional steroid injections in case report (Plast Reconstr Surg Glob Open 2021 Oct;9(10):e3847full-text)

Complications and Prognosis

  • granuloma faciale is generally chronic and progressive
    • may have remissions and exacerbations
    • although inconsistently reported, duration of the lesion is not considered to be correlated with any of the histopathologic parameters
    • Reference – J Am Acad Dermatol 2005 Dec;53(6):1002

Eosinophilic Folliculitis

General Information

  • eosinophilic pustular folliculitis is a rare, chronic, relapsing, inflammatory dermatosis of unknown etiology and is a variant of a superficial pustular dermatosis(2)
  • eosinophilic pustular folliculitis (EPF) has 3 primary types
    • “classic” EPF, also known as Ofuji disease
      •  characterized by recurrent crops of intensely pruritic, follicular erythematous papules and pustules in seborrheic distribution of head, trunk, and limbs(2)
      •  folliculocentric sterile papulopustules may coalesce into annular plaques(2)
    • immunosuppression-associated EPF (particularly, HIV-associated EPF), which is associated with HIV infection or other clinical immunosuppression(2)
      • characterized by follicular or nonfollicular papules and large plaques in patients with a CD4 cell count < 300 cells/mcL
      • most often develops on face
      • immunosuppression-associated variant is often associated with intense and persistent pruritus, and also may affect the scalp
    • infantile EPF
      • seen most frequently in the first 14 months of life and typically resolves by age 3 years, but reported to occur up to age 10 years(6)
      • characterized by pustules mostly on the scalp, and occasionally on trunk, face, or extremities(2)
      • benign and self-limiting condition characterized by recurrent crops of pruritic follicular or nonfollicular papulopustules, which lack the typical annular distribution of the classic variant (J Am Acad Dermatol 2013 Jan;68(1):150)
    • hematologic malignancy-associated EPF(2)
      • rare, condition characterized by extremely pruritic folliculitis
      • reported with hematologic malignancies and/or bone marrow or peripheral blood stem cell transplantation for malignancy
  • pathogenesis unclear
    • in classical EPF, mechanism appears to involve increased expression of prostaglandin D synthase leading to prostaglandin D2 induced upregulation of eotaxin-3 via peroxisome proliferator-activated receptor (PPAR) gamma in sebocytes(2)
    • peripheral eosinophilia may be seen with any variant of EPF

Clinical Presentation

  • eosinophilic pustular folliculitis (EPF) typically presents with follicular pustules or papules(4)
  • classical EPF (Ofuji disease)
    •  reported in Japanese female patients(4)
    • chronic recurrent pustules surrounding hair follicles on face, extremities and/or trunk(4)
    • pustules tend to coalesce into erythematous, circinate plaques(4)
  • infantile EPF
  • immunosuppression-associated or HIV-associated EPF
    •  presents with pruritic follicular papules on face and/or upper trunk(2)
    • HIV-associated EPF seen in patients with CD4 cell count < 300 cells/mcL(2)
  • ask patients about
    • medications, particularly carbamazepine, minocycline, allopurinol, foscarnet, or indeloxazine hydrochloride, which can produce drug-induced folliculitis(6)
    • resistance of pruritic erythematous papulopustules to topical corticosteroids, which may suggest eosinophilic pustular folliculitis(6)
    • hematologic malignancy or bone marrow or peripheral blood stem cell transplant(2)
  • physical exam
    • may present with follicular papulopustules on normal skin or on erythematous plaques

Evaluation and Diagnosis

  • diagnosis is based on typical clinical features, such as sterile follicular papulopustules, with histological evidence of a perifollicular, predominantly eosinophilic infiltrate(2)
  • consider testing for complete blood counts and antibody to HIV, if eosinophilic pustular folliculitis suspected and patient has risk factors(6)
  • peripheral eosinophilia may be present in any subtype of EPF(2)
  • differential diagnosis includes(6)
    •  acne vulgaris
    • steroid-related acne
    • other types of folliculitis
    • rosacea
    • seborrheic dermatitis
    • infections and infestations including
      • scabies, toxocariasis, cutaneous larva migrans, strongyloidiasis
      • bacterial folliculitis (typically caused by Pseudomonas and Staphylococcus, which respond well to antibiotics)
      • dermatomycosis (with presence of fungi, which usually responds well to antifungal agents)
    • drug-induced (allopurinol, timepidium bromide, carbamazepine, indeloxazine hydrochloride, minocycline, paroxetine, etizolam, maprotiline) or L tryptophan-induced (eosinophilic-myalgia syndrome involving the torso and palms) eruptions
    • cutaneous T-cell lymphoma/mycosis fungoides
    • reactions to silicone injections used to augment nose and chin
    • follicular mucinosis; absence of eosinophilic infiltrate in the upper outer sheath of the hair follicle (follicular mucinosis can be associated with EPF)
  • biopsy needed for confirmation of diagnosis(2)
  • histologic findings include
    • eosinophil-dominated infiltrate within and around the pilosebaceous units(2)
    • eosinophilic spongiosis(2,6)
    • histopathologic findings of infancy-associated EPF are reportedly indistinguishable from those of classic EPF(6)

Management

Classical Eosinophilic Pustular Folliculitis

  • indomethacin generally advised for first-line treatment for classic EPF(2)
    • both systemic indomethacin (25-75 mg orally daily) and topical formulations may be considered (topical not available in the United States)(6)
    • avoid use of nonsteroidal anti-inflammatory drugs (NSAIDs) in children < 14 years old, during pregnancy or lactation and with concomitant nephrotoxic drugs(6)
  • reported options for second-line therapy include
    • topical tacrolimus (may be used as monotherapy or in combination with indomethacin)(1,6)
    • Saireito (traditional Japanese herbal medicine) 6-9 g/day(6)
    • ultraviolet (UV) phototherapy(1,6)
      • dosing not well established for this indication(6)
      • in general, narrowband ultraviolet B (NB-UVB, preferred) or broadband UVB applied 2-3 times a week with an initial dose of 40 millijoules (mJ)/cm2 or one-half of minimal erythema dose (MED), followed by a 50% increase in dose(6)
      • ultraviolet A (UVA) therapy applied (without psoralen) twice a week with initial dose of one-half minimal phototoxic dose (MPD) until the lesion subsides or resolves, or psoralen UVA (PUVA) protocol for psoriasis(6)
      • avoid combination of tacrolimus and phototherapy(6)
    • oral dapsone 50-100 mg/day; consider combination indomethacin and dapsone(6)
    • oral cyclosporine 100-150 mg/day or 3-5 mg/kg/day(6)
    • oral doxycycline 100 mg/day or minocycline 100-200 mg/day(6)
    • transdermal nicotine patches(6)
  • although other second-line agents can be combined with each other, cyclosporine should not be combined with systemic indomethacin to avoid synergistic nephrotoxicity(6)
  • alternative options reported in case reports include(6)
    • naproxen (300-1,000 mg/day) and loxoprofen (60-120 mg/day) (loxoprofen not available in the United States)
    • tranilast (300 mg/day)
    • metronidazole (500 mg/day)
    • prednisolone (5-10 mg/day) plus topical tacrolimus
    • injection of triamcinolone (5 mg/mL)
    • nicotinamide (900 mg/day) (nicotinamide is a water-soluble form of niacin or vitamin B3)
    • eicosapentaenoic acid (EPA) (1,800 mg/day)
    • etretinate (25-50 mg/day)
    •  acitretin (0.5 mg/kg per day)
    • suplatast tosilate (300 mg/day) (not available in the United States)
    • biologics (including interferon [alpha and gamma] therapy and infliximab)
  • if maintenance therapy is required, consider screening for underlying immunosuppression(6)
  • be aware that long-term use of corticosteroids or tetracycline antibiotics can cause rosacea-like dermatitis(6)

HIV-associated Eosinophilic Folliculitis or Immunosuppression-associated Eosinophilic Folliculitis

  • for patients with HIV and CD4 cell counts < 300/mcL(6)
    • ensure adequate antiretroviral treatment
    •  folliculitis may improve spontaneously with increase in CD4 counts
    • options for treatment of lesions include
      • topical tacrolimus
      • oral indomethacin 25-75 mg/day orally
      •  UVB-based phototherapy
  • reported second-line options include(6)
    • indomethacin
    • tetracyclines (minocycline or doxycycline)
    • dapsone (50-100 mg/day)
    • metronidazole
    • isotretinoin (0.3-1.2 mg/kg/day)
    • itraconazole or other topical antifungals
  • immunosuppression-associated EPF (non-HIV)(6)
    • goal is to reduce symptoms until lesions resolve
    • rule out graft-versus-host disease (GVHD) if applicable
    • first-line options include topical corticosteroids and UVB-based phototherapy
    • second-line options include
      • topical tacrolimus
      • oral indomethacin 25-75 mg/day
      • systemic prednisolone (0.1-1 mg/kg/day)
      • oral dapsone (50-100 mg/day)
      • oral tetracyclines (minocycline 100-200 mg/day or doxycycline 100 mg orally daily)

Infantile Eosinophilic Pustular Folliculitis

  • for eosinophilic pustular folliculitis of infancy
    • conservative management may be appropriate to wait for spontaneous resolution(6)
    •  consider topical corticosteroids, which have been reported effective in 90% of cases in infancy (J Am Acad Dermatol 2013 Jan;68(1):150)
  • other reported options for infancy-associated EPF include(6)
    • oral erythromycin (25-50 mg/kg/day)
    • other systemic antibiotic (such as dicloxacillin, penicillin, cephalexin, or cefaclor)
    • topical tacrolimus (0.03%, for children > 2 years old)
    • UVA phototherapy
  • NSAIDs are contraindicated in children < 14 years old(6)

Complications and Prognosis

  • classical form of eosinophilic pustular folliculitis (EPF) often spontaneously resolves but with persistent hyperpigmentation(1)

Guidelines and Resources

Guidelines

European Guidelines

  • ​European League Against Rheumatism (EULAR) recommendations on vaccination in adult patients with autoimmune inflammatory rheumatic diseases can be found in Ann Rheum Dis 2020 Jan;79(1):39.
  • European Dermatology Forum (EDF) S1-guideline on diagnosis and treatment of sclerosing diseases of the skin (part 1: localized scleroderma, systemic sclerosis, and overlap syndromes) can be found in J Eur Acad Dermatol Venereol 2017 Sep;31(9):1401.
  • Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (Association of the Scientific Medical Societies in Germany) (AWMF) guideline on diagnosis and management of localized scleroderma can be found in J Dtsch Dermatol Ges 2016 Feb;14(2):199 [German].

Asian Guidelines

  • Japanese Dermatological Association (JDA):

Review Articles

  • To search MEDLINE for (Eosinophilic Dermatoses) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis.

Patient Information

References

General References Used

  1. Peckruhn M, Elsner P, Tittelbach J. Eosinophilic dermatoses. J Dtsch Dermatol Ges. 2019 Oct;17(10):1039-1051.
  2. Marzano AV, Genovese G. Eosinophilic Dermatoses: Recognition and Management. Am J Clin Dermatol. 2020 Aug;21(4):525-539.
  3. Long H, Zhang G, Wang L, Lu Q. Eosinophilic Skin Diseases: A Comprehensive Review. Clin Rev Allergy Immunol. 2016 Apr;50(2):189-213.
  4. Leiferman KM, Peters MS. Eosinophil-Related Disease and the Skin. J Allergy Clin Immunol Pract. 2018 Sep ;6(5):1462-1482.e6.
  5. Jinnin M, Yamamoto T, Asano Y, Ishikawa O, et al. Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis. J Dermatol. 2018 Aug;45(8):881-890.
  6. Nomura T, Katoh M, Yamamoto Y, Miyachi Y, et al. Eosinophilic pustular folliculitis: A proposal of diagnostic and therapeutic algorithms. J Dermatol. 2016 Nov;43(11):1301-1306.
  7. Ihn H. Eosinophilic fasciitis: From pathophysiology to treatment. Allergol Int. 2019 Oct;68(4):437-439full-text.

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