Sight-Threatening Ocular Manifestations of Acute Febrile Neutrophilic Dermatosis (Sweet's Syndrome)Baartman B.a · Kosari P.b · Warren C.C.a · Ali S.b, c · Jorizzo J.L.b · Sato M.d · Kurup S.K.a
aDepartment of Ophthalmology, Wake Forest University Eye Center, and Departments of bDermatology and cPathology, Wake Forest University Baptist Medical Center, Winston-Salem, N.C., USA; dDepartment of Ophthalmology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan Corresponding Author
Sweet's syndrome is a primarily dermatologic disorder with many features of systemic inflammation. It is generally characterized by a neutrophilic dermatosis in the setting of fever and an elevated white blood cell count. Inflammation has been described to occur in many organ systems including the lung, bone, liver, spleen, brain and eye. Ocular inflammation is a well-known comorbidity that may occur in the setting of Sweet's syndrome, including conjunctivitis, episcleritis, scleritis, iritis and choroiditis, among other forms. In the current article, we have compiled a series of cases that describe three separate patients who demonstrated a rare form of ocular involvement in Sweet's syndrome, retinal vasculitis. The evidence from these three cases and other reports in recent ophthalmologic literature suggest overlapping of ocular manifestations of Sweet's syndrome and the closely related Behçet's disease. It is important to be aware of the sometimes challenging differential between these two disorders and their sight-threatening complications.
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Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is a multisystem syndrome consisting of cutaneous lesions with potential involvement of nearly any organ system. The most common form of ocular involvement associated with Sweet's syndrome includes conjunctivitis, episcleritis, limbal nodules and iridocyclitis . Limited reports have been published in the literature regarding retinal involvement in this disease; however, emerging evidence suggests that involvement of posterior structures in the eye (vitreous, retina) may be more common than originally thought [2,3]. Furthermore, these particular findings, taken together with other systemic manifestations of the condition including the skin, may overlap with those seen in Behçet's disease . We herein report three cases of potentially blinding retinal vasculitis in patients diagnosed with Sweet's syndrome.
A 31-year-old white female with no significant past medical history was hospitalized for a febrile illness associated with a skin eruption involving the extremities. Laboratory investigation revealed mild leukocytosis with an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Dermatologic examination showed evidence of pustules surrounded by a rim of erythema on the upper extremities. A skin biopsy from the left arm was obtained and histopathologic examination was most consistent with a diagnosis of Sweet's syndrome (fig. 1). She was initiated on colchicine 0.6 mg three times daily and diaphenylsulfone 150 mg daily. A complete work-up including appropriate blood work and age-appropriate cancer screening did not reveal an underlying etiology for the diagnosis of Sweet's syndrome. Her skin condition continued to worsen and she noted decreased vision in the left eye with ocular pain in both eyes. Given the refractory nature of her cutaneous lesions and development of visual complaints, the patient was started on prednisone 20 mg daily. The etiology of her visual complaints was unclear at this point and ophthalmology was consulted.
|Fig. 1. Patient 1. Histopathologic microphotograph of a skin biopsy showing a diffuse neutrophilic infiltrate with karyorrhexis and focal leukocytoclastic vasculitis (×4).|
On ophthalmologic examination, visual acuity was found to be 20/20 in the right eye and only hand motion vision was noted in the left. Pupillary examination found a relatively unreactive pupil in the left eye compared to that of the right, consistent with decreased visual tract input to that side. Slit lamp examination revealed bilateral vitreous inflammation. Retinal examination revealed vascular sheathing (exudation along vessels) with bilateral intraretinal hemorrhages. Fluorescein angiography demonstrated relative ischemia with compensatory corkscrew vessels and bilateral retinal vein occlusions with attenuated retinal vasculature (fig. 2, 3). The findings on retinal examination of vascular sheathing and intraretinal hemorrhage, along with the bilateral retinal vein occlusions on fluorescein angiography, were most consistent with a diagnosis of bilateral retinal vasculitis. A complete review of systems was negative for other inflammatory or infectious etiologies, leading to a likely association of newly-diagnosed Sweet's syndrome.
|Fig. 2. Patient 1. Fundus photography demonstrating bilateral intraretinal hemorrhage as manifestation of retinal vasculitis associated with Sweet's syndrome. a Right eye. b Left eye.|
|Fig. 3. Patient 1. Fluorescein angiogram showing venous occlusions, likely due to occlusive vasculitis. a Right eye venous occlusion is supported by hyperfluorescence in a branch of the inferior vascular arcade. The white arrow corresponds to an area of hemorrhage. b Left eye fluorescein angiogram shows more hypofluorescence surrounding the inferior vascular arcade.|
Treatment for the retinal vasculitis consisted of intravitreal bevacizumab 1.25 mg and panretinal photocoagulation in the left eye, followed by a sector (partial) panretinal photocoagulation in the right eye, and oral methotrexate 10 mg/week. Visual acuity gradually improved over 10 months and methotrexate was tapered after 2 years. The patient's visual acuity stabilized at 20/15 in the right eye and 20/25 in the left eye. At her 3-year follow up visit, ophthalmologic examination revealed no signs of inflammation and a stable appearance of both her retina and skin (fig. 4).
|Fig. 4. Patient 1. Fundus photography following laser photocoagulation and methotrexate therapy, showing clinically inactive vasculitis in the posterior segment of the right (a) and left eye (b). Both eyes show a posterior segment free of intraretinal hemorrhage and vascular sheathing (compared to fig. 2a and b). Laser photocoagulation scars are noted in the left eye (b, white arrow).|
Initially reported by Sato et al. , this 36-year-old Japanese woman with no previous medical or surgical history presented with a 3-day history of fever, painful skin lesions on the face and new-onset vision loss bilaterally. Dermatologic examination revealed erythematous facial plaques with irregular borders (fig. 5a) and oral aphthae. Her laboratory evaluation revealed neutrophilia with an elevated ESR and CRP. Serology studies were negative for presence of rheumatoid factor, rapid plasma reagin as well as anti-nuclear and anti-double-stranded DNA antibodies. Additionally, antibodies to herpes simplex virus, varicella zoster virus, cytomegalovirus, human immunodeficiency virus and human T-lymphotropic virus-1 were all negative. Skin biopsy was obtained from a facial lesion which demonstrated significant edema in the superficial papillary dermis with a dense inflammatory cell infiltrate, predominantly composed of neutrophils. These findings were most consistent with a diagnosis of Sweet's syndrome. Age-appropriate cancer screening and a complete history did not reveal an underlying cause for her Sweet's syndrome.
|Fig. 5. Patient 2. a Cutaneous pustular lesions in a woman with Sweet's syndrome. b, c Fluorescein angiography showing bilateral retinal vasculitis (the vessels are very fluorescent) in association with Sweet's syndrome. b Right eye. c Left eye.|
On ophthalmologic examination, visual acuity was found to be 20/60 in the right eye and 20/100 in the left eye. She had no obvious anterior inflammation (conjunctivitis or iritis) and had mild vitreous inflammation. There were no other obvious abnormalities on retinal examination. However, fluorescein angiography revealed bilateral retinal vasculitis (fig. 5b, c).
The patient was initiated on a treatment regimen of oral diaphenylsulfone 50 mg daily, colchicine 1.2 mg daily and prednisolone 60 mg daily for 10 days, tapered over the following 8 weeks. Her visual acuity returned to 20/20 in both eyes after 2 weeks of treatment, with cutaneous lesions resolving after 3 weeks. Over the course of a 3-year follow-up period, there were no ocular or dermatologic recurrences.
A 58-year-old Caucasian female with type II diabetes mellitus, hypertension and congestive heart failure presented with complaints of blurred vision, floaters and redness in her left eye. She also had a known diagnosis of retinal vasculitis and, per her report, had been managed by an outside provider with methotrexate, azathioprine and prednisone. Unfortunately, her medication regimen had only modestly controlled her ocular disease and 3 months prior to presentation she had undergone surgical removal of her right eye.
Thorough physical examination also demonstrated presence of erythematous and edematous, tender papules on her back and arms. Skin biopsy from one of these lesions showed superficial papillary edema with a dense infiltration of neutrophils consistent with Sweet's syndrome (fig. 6). Laboratory evaluation, including anti-nuclear and anti-double-stranded DNA antibodies, revealed no evidence of systemic immune-mediated disease or malignancy.
|Fig. 6. Patient 3. Histopathologic microphotograph of a skin biopsy showing a diffuse neutrophilic infiltrate with karyorrhexis and focal leukocytoclastic vasculitis (×4).|
On ophthalmologic examination, visual acuity was 20/25 in the left eye with a prosthetic in place on the right side. Slit lamp examination revealed no evidence of anterior inflammation. On retinal examination, moderate tortuosity of the retinal vascular arcades was evident. She was diagnosed with acute panuveitis (diffuse ocular inflammation) with an element of retinal vasculitis. Cyclosporine 75 mg twice daily was initiated in addition to the methotrexate, azathioprine and prednisone. At 6-month follow-up, she complained of worsening vision in her left eye, now seeing 20/40. Repeat slit lamp examination revealed moderate vitreous inflammation. Fluorescein angiography showed mild retinal vascular leakage, suggesting active retinal vasculitis. Her dose of azathioprine was increased from 50 mg twice daily to 75 mg twice daily.
At 3-year follow up, she had improvement in her skin lesions and was tolerating her medications well and had no active flare of ocular symptoms. Her drug regimen is being simplified and efforts are ongoing to taper the drugs serially.
In 1964, Robert Sweet  reported on middle-aged women who presented with erythematous plaques in the setting of an acute onset of fever and either an upper respiratory tract or gastrointestinal infection. Further histopathologic evaluation revealed and categorized Sweet's syndrome as a neutrophilic dermatosis. Sweet's syndrome is an uncommon disorder with a female predominance of 4:1. Most commonly, patients between 30 and 60 years of age are affected. The exact etiology of Sweet's syndrome is unknown; however, there are many reported associations including infections, autoimmune diseases, inflammatory bowel disease and malignancies [5,6]. Clinically, patients present with a fever and an associated rash characterized as tender, non-pruritic, erythematous papules which can coalesce to form plaques. Secondary to the extensive edema, lesions can have a vesicular, pseudovesicular or pustular appearance. The head, neck and upper extremities are favored in an often asymmetric distribution, but lesions can occur anywhere on the body. Histologically, extensive papillary dermal edema with a diffuse nodular and perivascular neutrophilic infiltrate is evident . A peripheral leukocytosis with neutrophilia and elevated ESR and CRP can help narrow the diagnosis. Frequently, a preceding upper respiratory tract or gastrointestinal tract infection is reported [6,8]. Successful treatment has been achieved with systemic corticosteroid therapy, however recurrences are common. Alternative and adjunct therapy has been reported with potassium iodide, dapsone, colchicine, non-steroidal anti-inflammatory drugs, clofazimine, cyclosporine, thalidomide, interferon-α and methotrexate .
The cases presented above represent three patients whose clinical, laboratory and histopathologic findings led the clinicians to the diagnosis of Sweet's syndrome. Sweet's syndrome falls within a broader category of diagnoses associated with a neutrophilic dermatosis, which also includes Behçet's disease, pyoderma gangrenosum and neutrophilic urticaria, among others. All of these disorders share the common feature of neutrophilic stimulation and proliferation in the skin . Within the category of neutrophilic dermatoses, distinguishing between different clinical entities can sometimes be difficult due to shared clinical findings, especially in Sweet's syndrome and Behçet's disease. Behçet's disease may also present with skin lesions, described as papular or pustular pseudofolliculitis or as erythema nodosum of the lower extremities, in the setting of genital and oral ulcerations, arthritis, vascular and cardiac abnormalities such as thrombotic events and cardiomyopathy. Skin findings are predominant in Sweet's syndrome, while oral and genital ulcers are rare . Both conditions are said to have good response to glucocorticoid therapy.
Common to all three patients presented here are the abrupt onset of skin findings consistent with Sweet's syndrome and the histopathologic finding of dense dermal neutrophilic infiltrate and absence of vasculitis, both of which are considered the major criteria in the diagnosis of Sweet's syndrome . However, each patient possesses one or multiple characteristics that lend consideration to a diagnosis of Behçet's disease. Certainly, the pustular appearance of the rash in patient 1 is atypical, though not an entirely novel finding [6,9]. This finding could be said to overlap in appearance with the pseudofolliculitis commonly ascribed to Behçet's disease. Patient 2, as previously addressed by Sato et al. , was found to have oral ulceration at presentation, which is a rare finding in Sweet's syndrome and much more commonly found in Behçet's disease. All three patients presented with an ocular finding not commonly seen in Sweet's syndrome, and that is retinal vasculitis.
Retinal vasculitis, as other forms of vasculitis, occurs when there is inflammation of the vessels of the retina. Although it can occur as an isolated finding, retinal vasculitis is commonly associated with a systemic pathology such as infectious, inflammatory or collagen-vascular diseases. Clinically, patients present with blurred vision, scotoma or floaters, though patients with underlying retinal vasculitis may have minimal or no symptoms secondary to involvement of the peripheral retina. Diagnosis of retinal vasculitis is typically made on high clinical suspicion, fundoscopic examination showing perivascular inflammation and sheathing, most commonly of the retinal veins, and fluorescein angiography demonstrating perivascular staining, a product of increased vascular permeability. Ocular tissue biopsies, while not practical for these cases, may reflect similar changes as seen in cutaneous lesions of vasculitis [11,12].
Several known systemic inflammatory disorders and infections may have an ocular component consistent with retinal vasculitis. Sarcoidosis, systemic lupus erythematosus, and most relevant to this discussion Behçet's disease are examples of common inflammatory causes, while toxoplasmosis, tuberculosis, syphilis and Lyme disease comprise the more common infectious causes . Ocular findings in Behçet's disease are very common, present in up to 70-85% of patients, with manifestations ranging from iritis to vision-threatening vitreous opacification and retinal vasculitis [3,9].
Sweet's syndrome is well known in the ophthalmologic community to have ocular complications, most commonly in the anterior structures of the eye, presenting as conjunctivitis, episcleritis, keratitis and iritis [1,2,3]. Recent case reports published on the subject, however, have brought about evidence of newly recognized, posterior ocular involvement in Sweet's syndrome [2,3]. Matsumiya et al.  recently published a small case series of two Japanese patients presenting with fever and cutaneous findings consistent with Sweet's syndrome. Much like the three patients we present here, these patients also reported decreased visual acuity and were found to have posterior inflammation (vitritis and retinal vasculitis). The authors reported a diagnosis of Sweet's syndrome in these two patients based on their clinical findings of fever and characteristic cutaneous findings, confirmed on histopathologic examination. Taken together, these cases bring to light the difficulty in distinguishing Sweet's syndrome from Behçet's disease based on the previously reported ‘characteristic' ocular findings in the respective conditions.
Given the overlap of many clinical characteristics of Sweet's syndrome and Behçet's disease, some have recently called into question their distinct relationship from one another. In fact, Sweet's syndrome and Behçet's disease have been reported to coexist in the same patient , leading the authors to consider whether Behçet's disease may be an additional, underlying clinical entity in which Sweet's syndrome may arise. The emerging literature among the ophthalmologic community of the seemingly continuous spectrum of ocular presentation in these two conditions, as presented here, may lend evidence to this consideration.
Management of patients presenting with any form of retinal vasculitis is of urgent concern, as it may lead to irreversible vision impairment due to retinal ischemia if not treated. Systemic or intraocular steroids should be employed, depending on the severity [12,13]. The most important clinical clue is a decrease in visual acuity, and it is important to realize that inflammation of anterior structures may also cause patients to complain of blurry vision; any visual impairment in Sweet's syndrome or Behçet's disease should prompt referral to an ophthalmologist. Good visual outcomes in patients with even severe retinal vasculitis may be realized with urgent intervention, as in the patients presented here. All three of our patients remained in remission at 3-year follow-up and none experienced permanent vision loss.
We are indebted to Wake Forest Baptist Hospital and the patients who graciously allowed us to report their medical histories for the betterment of medical care.
There is no conflict of interest. The authors have no proprietary interests in material presented in this study.
Shree K. Kurup, MD
Department of Ophthalmology, Wake Forest University Eye Center
Medical Center Boulevard
Winston-Salem, NC 27157 (USA)
Received: March 4, 2013
Accepted after revision: December 2, 2013
Published online: March 1, 2014
Number of Print Pages : 5
Number of Figures : 6, Number of Tables : 0, Number of References : 13
Vol. 228, No. 3, Year 2014 (Cover Date: June 2014)
Journal Editor: Saurat J.-H. (Geneva)
ISSN: 1018-8665 (Print), eISSN: 1421-9832 (Online)
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