Sweet’s Syndrome (Acute Febrile Neutrophilic Dermatosis)

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Disease Entity

Sweet’s syndrome (SS), also known as acute febrile neutrophilic dermatosis, is a primarily dermatologic, auto-inflammatory disorder with accompanying features of systemic inflammation, including inflammation of the eye1,2.


Ocular manifestations of SS include periorbital and orbital inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, choroiditis, retinal vasculitis, and optic nerve involvement although it is most commonly associated with conjunctivitis1,3,4.


Etiology

There are three etiologies associated with SS. The classic/idiopathic type is, per its name, of unclear etiology, although it can be seen in association with upper respiratory tract or gastrointestinal infection, inflammatory bowel disease, or pregnancy1,5.


The malignancy-associated type can precede, follow, or appear concurrently with a patient’s diagnosis of neoplasm6. Approximately 85% of malignancy-associated cases are linked to hematological cancers, most commonly to acute myelogenous leukemia (AML)2,7.


Lastly, a drug-induced type can occur, most commonly seen in those receiving granulocyte colony-stimulating factor7. Case reports have also associated sulfamethoxazole and trimethoprim and several anticancer agents, including all trans-retinoic acid proteasome inhibitors, hypomethylating agents, tyrosine kinase inhibitors, and lenalidomide, with SS7.


Epidemiology

Sweet’s syndrome is more commonly found in women with an estimated female-to-male ratio of 2-3:15. The disease tends to affect women aged 30-50 years and men aged 50-90 years, although all age-groups can be affected1,5.


An estimated 38-53% of SS cases are considered classical/idiopathic8. Recurrence rates are high and can occur in up to one-third of classical SS patients5. The malignancy-associated form occurs with the onset or recurrence of cancer, accounting for 25-44% of cases8. Medication-induced cases are responsible for 4-24% of cases8.


Sweet’s syndrome manifests with extra-cutaneous features in up to 50% of cases5. However, the precise prevalence of ocular involvement amongst SS patients remains uncertain. A review of 138 patients with SS reported eye involvement in only 3% of cases2.  However, a 2008 evaluation of case reports in the literature suggests ocular infiltration occurs in about one-third of patients1. Ocular lesions are reported to be uncommon, although not impossible, in malignancy-associated and drug-induced forms of SS5. Other sites of extra-cutaneous involvement can include the musculoskeletal system, liver, brain, kidneys, lungs, and spleen2,5.


Pathophysiology

The exact pathophysiology of SS has yet to be elucidated, however it is strongly believed that the disease is due to hypersensitivity mediated by cytokines and neutrophils activated by interleukin-17. Circulating autoantibodies, cytokines, dermal dendrocytes, HLA serotypes, immune complexes, leukotactic mechanisms, and type 1 T helper cells have all been suggested as factors contributing to the pathogenesis of SS7. Notably, inflammatory cell markers such as CD3, CD163, myeloperoxidase, metalloproteinases, and vascular endothelial growth factors, are found at higher values in the lesioned skin of SS patients compared to non-SS individuals or those with another neutrophilic dermatoses9.


There is no consistent evidence of a genetic predisposition for SS, however there are documented associations between HLA-B54 typing and SS, particularly amongst Japanese patients3. Analysis of HLA antigens in a Caucasian population, however, showed no association between SS and specific HLA-ABC antigens10.


Currently, as of 2022, there is no available literature specifying a distinct pathophysiology describing ocular involvement in SS, however it can be assumed that auto-inflammatory mechanisms are involved.


Systemic Findings

Clinical Presentation        

Sweet’s syndrome classically presents with an abrupt onset of violaceous or erythematous appearing papules, plaques, or nodules typically spanning several millimeters or centimeters11. Cutaneous lesions are tender to touch but rarely pruritic with an asymmetrical distribution that favors the upper extremities11,12. Headache, myalgias, arthralgias and malaise most commonly accompany the onset of dermatologic disease11. Fever is frequently seen but spares some patients and is not required for diagnosis11. Neutrophilic infiltration of other organ systems is highly variable with ocular and musculoskeletal involvement reported most5,11.


Ocular Manifestations

Ocular complaints may affect up to one-third of patients with SS1. Ophthalmologic findings of SS are highly varied and span nearly all aspects of the eye and surrounding structures. Case reports now recognize a spectrum of disease that includes pathology of the orbit, eyelids, anterior and posterior segments1. Other presentations including panuveitis with optic nerve involvement and inflammatory glaucoma have been described3,13. Roughly half of ocular pathology seen in SS presents bilaterally1. Generally, ophthalmologic manifestations present concurrently or within a few days of dermatologic findings1. An extensive list of ophthalmologic presentations is outlined in Table 1.

Orbit Periorbital vesicular eruption
Eyelids Vesicular eyelid lesions, dacryoadenitis
Anterior Segment

Cornea:

Episclera/Sclera:

Iris/Ciliary body

Iritis, Episcleritis, Scleritis, Conjunctivitis, Peripheral ulcerative keratitis, Limbal nodules
Posterior Segment

Retina:

Choroid:

Choroiditis, Retinal vasculitis, Vitritis
Neuro-ophthalmological/Other Inflammatory Glaucoma, Panuveitis with optic nerve involvement

Table 1. Possible ophthalmological manifestations in Sweet’s Syndrome1,3,4.

Periorbital and Eyelid Involvement

An erythematous vesicular eruption of the periorbital skin and eyelids is most common1,14–17. Vesicular eruptions may be associated with painful eyelid swelling, limited ocular movement and an elevated leukocyte count17. Hence, SS of the periorbital space may be confused for orbital cellulitis on presentation17. A single case of dacryoadenitis associated with SS demonstrated orbital fat and lacrimal gland infiltration on computed tomography18. While not routinely indicated, periorbital skin biopsy reveals similar pathologic changes, notably mature neutrophilic infiltrates, to those seen in other dermal lesions16. Periorbital and eyelid eruptions readily respond to systemic corticosteroids1. As such, topical corticosteroids are rarely indicated1.

Anterior Segment

Conjunctivitis is the most common ocular manifestation of SS, yet a spectrum of anterior segment pathologies exist1. Iritis, episcleritis, scleritis, and peripheral ulcerative keratitis are all documented in patients presenting with SS1. Additionally, limbal nodules with similar histopathologic changes to those seen in other SS dermal lesions can arise19. Most commonly, patients with anterior pathology endorse hyperemia with irritation and eye watering1. Blurred vision may also be seen in patients with ocular pathology limited to the anterior segment20. Slit lamp examination should be utilized to evaluate anterior segment inflammation1. A robust  response to systemic corticosteroids is commonly seen with anterior segment pathologies1.  

Posterior Segment

While anterior segment involvement is more common, pathology involving posterior structures is also possible in SS4. Choroiditis, retinal vasculitis, and vitritis have all been described in SS patients4,8,21. Sudden decreased vision is common among those with retinal vasculitis4. Patients may also endorse more mild blurred vision or other visual defects like floaters or scotomas4. Slit lamp exam should be used to reveal vitreous inflammation if it exists4. Retinal examination may uncover exudation along vessels and intraretinal hemorrhages4. Fluorescence angiography may reveal ischemic changes and compensatory corkscrew vessels consistent with retinal vasculitis4. In addition to systemic corticosteroids, more invasive therapeutic measures including intravitreal bevacizumab and retinal photocoagulation may be warranted when vision is threatened4,8.


Neuro-Ophthalmologic & Other Manifestations

Rarely, SS may present with involvement of the optic nerve. A single case of idiopathic panuveitis presenting with decreased vision and optic disc edema demonstrated enhancement of the optic nerve on brain MRI22. Another case of SS associated with microscopic polyangiitis presented similarly yet brain MRI was less revealing23. Panuveitis and papilledema quickly resolved in both patients with the initiation of either steroids or immunomodulators22,23. Interestingly, a single case of inflammatory glaucoma associated with SS has also been documented13.

Diagnosis

Diagnostic Criteria

Diagnostic criteria for SS was originally proposed by Su and Liu in 1986 and revised by Von Den Driesch in 19945,24,25. A summary of these criteria are listed in Table 2.


Classical SS

Drug-induced SS
Major Criteria 1 Abrupt onset of painful erythematous plaques or nodules An Abrupt onset of painful erythematous plaques or nodules
2 histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis B Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis
Minor Critera 3 Pyrexia >38 C C Pyrexia >38 C
4 Association with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy, OR preceded by an upper respiratory or gastrointestinal infection or vaccination D Temporal relationship between drug ingestion and clinical presentation, OR temporally related recurrence after oral challenge
5 Excellent response to treatment with systemic corticosteroids or potassium iodide E Temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids
6 Abnormal laboratory values at presentation (three of four): erythrocyte sedimentation rate >20 mm/hr; positive C-reactive protein; >8,000 leukocytes; >70% neutrophils

Table 2. A summary of diagnostic criteria used in Sweet’s Syndrome5,24,25.

The presence of both major criteria and two of the four minor criteria is required to establish the diagnosis of classical SS or malignancy-associated SS5,25.


All five criteria (A-E) are required to establish the diagnosis of drug-induced SS5,25.


Malignancy-associated SS initially was considered as a subtype of classical SS, however some may choose to distinguish between classical and malignancy-associated SS5.  


Diagnostic Testing and Supportive Lab Values

Laboratory evaluation should include a complete blood cell count with leukocyte differential and platelet count, acute phase reactants (i.e., erythrocyte sedimentation rate, C-reactive protein), serum chemistries, and a urinalysis. Laboratory values demonstrating peripheral leukocytosis with neutrophilia and an elevated erythrocyte sedimentation rate are the most consistent abnormalities found in SS patients, but are not always observed in confirmed cases5,6,26. Malignancy-associated SS patients may also be found with either anemia, neutropenia, and/or abnormal platelet counts5. Abnormalities in serum chemistries, urinalysis, and acute phase reactants may signal extracutaneous involvement5. Additional viral, bacterial, fungal, mycobacterial, and/or autoimmune workup may be reasonable to rule out other probable causes5,27.


Lesional skin biopsy for routine histopathologic evaluation is a useful procedure to confirm a diagnosis of SS5. Additionally, extracutaneous manifestations of SS may be found on brain single photon emission computed tomography (SPECT), computerized axial tomography (CT), magnetic resonance imaging (MRI), and cerebrospinal fluid analysis5.


Ocular manifestations of SS are highly variable and diagnostic evaluation should be a tailored choice depending on the patient’s presenting symptoms. Slit lamp and fundoscopic examination should be utilized to evaluate possible anterior and posterior pathology in every patient1. Suspected posterior infiltration warrants further examination. Enhanced-depth imaging optical coherence tomography (EDI-OCT) imaging, B-scan ultrasonography, and fluorescein angiography may be helpful in identifying the effusion, choroidal infiltration, diffuse scleritis, retinal vasculitis, and/or inflammation seen in SS4,8. Additionally, brain magnetic resonance imaging may be warranted when involvement of the optic nerve is suspected22.


Differential Diagnosis

The differential diagnosis of SS is extensive but notably includes erythema multiforme (EM), erythema nodosum (EN), and Behcet’s disease5,10,28. Patients with EM may have a history of herpes simplex infection, recurrence of SS symptoms, and drug intolerance with normal-moderately abnormal inflammatory marker levels29. Patients with EN will have similar history and laboratory results to SS patients but may have skin lesions confined to their lower extremities with different histologic features on biopsy5,30. Behcet’s patients present similarly to SS patients, however skin lesions may be more pustular in quality with vasculitis and positive immunofluorescence on histology25,31. Additionally, while SS patients may be HLA-B54 positive, Behcet’s patients are more likely to be HLA-B51 positive31. Ocular manifestations are common among systemic inflammatory disorders and ultimately diagnostic criteria should be utilized to differentiate between overlapping findings4.

Management

Treatment

The management of SS varies according to the etiology of disease – idiopathic, malignancy-associated, or drug-induced12. Malignancy-associated SS has been shown to resolve with control of the underlying cancer32. Similarly, drug-induced SS often improves within weeks of withdrawal of the offending medication33. However, resolution of SS is not guaranteed, and pharmacologic therapy should be initiated to accelerate clinical improvement, regardless of etiology33. Systemic corticosteroid therapy is considered first-line treatment for SS independent of disease presentation33. An individualized approach for recalcitrant and extensive disease may be warranted consisting of intralesional corticosteroid therapy or alternative glucocorticoid-sparing agents33. Ocular manifestations of SS quickly respond to systemic corticosteroid use however intra-ocular steroids may improve outcomes for severe disease1,4,8. Sight threatening retinal vasculitis associated with SS may require more invasive therapeutic measures including intravitreal bevacizumab and retinal photocoagulation4.


Prognosis

While the initiation of therapy typically provides an early and robust response to SS, the rate of recurrence following tapering, or discontinuation of systemic steroids remains high regardless of etiology33. However, recalcitrant and relapsing disease remains extremely rare for ocular manifestations of SS1,4,8. Significant and lasting visual impairment is unlikely with permanent vision changes limited only to cases of severe retinal vasculitis4. Idiopathic cases of SS require monitoring of underlying hematologic malignancies that may present up to 16 months following dermatologic and ocular manifestations2.


References

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2.         Marcoval J, Martín-Callizo C, Valentí-Medina F, Bonfill-Ortí M, Martínez-Molina L. Sweet syndrome: long-term follow-up of 138 patients. Clinical and Experimental Dermatology. 2016;41(7):741-746. doi:10.1111/ced.12899

3.         Hisanaga K, Iwasaki Y, Itoyama Y, Neuro-Sweet Disease Study Group. Neuro-Sweet disease: clinical manifestations and criteria for diagnosis. Neurology. 2005;64(10):1756-1761. doi:10.1212/01.WNL.0000161848.34159.B5

4.         Baartman B, Kosari P, Warren CC, et al. Sight-threatening ocular manifestations of acute febrile neutrophilic dermatosis (Sweet’s syndrome). Dermatology. 2014;228(3):193-197. doi:10.1159/000357729

5.         Cohen PR. Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. doi:10.1186/1750-1172-2-34

6.         Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet’s syndrome: review of the world literature. J Clin Oncol. 1988;6(12):1887-1897. doi:10.1200/JCO.1988.6.12.1887

7.         Villarreal-Villarreal CD, Ocampo-Candiani J, Villarreal-Martínez A. Sweet Syndrome: A Review and Update. Actas Dermosifiliogr. 2016;107(5):369-378. doi:10.1016/j.ad.2015.12.001

8.         Mishra AV, Fung AT, Pollmann AS, Henderson R, Shields C, Gupta RR. Relentlessly Progressive Sweet Syndrome of the Eye with Scleritis and Choroidal Infiltration. Ocular Immunology and Inflammation. 2022;30(1):90-94. doi:10.1080/09273948.2020.1788611

9.         Marzano AV, Cugno M, Trevisan V, et al. Inflammatory Cells, Cytokines and Matrix Metalloproteinases in Amicrobial Pustulosis of the Folds and other Neutrophilic Dermatoses. Int J Immunopathol Pharmacol. 2011;24(2):451-460. doi:10.1177/039463201102400218

10.       von den Driesch P, Simon M, Djawari D, Wassmuth R. Analysis of HLA antigens in Caucasian patients with acute febrile neutrophilic dermatosis (Sweet’s syndrome). Journal of the American Academy of Dermatology. 1997;37(2, Part 1):276-278. doi:10.1016/S0190-9622(97)80142-9

11.       Alavi A, Sajic D, Cerci FB, Ghazarian D, Rosenbach M, Jorizzo J. Neutrophilic dermatoses: an update. Am J Clin Dermatol. 2014;15(5):413-423. doi:10.1007/s40257-014-0092-6

12.       Rochet NM, Chavan RN, Cappel MA, Wada DA, Gibson LE. Sweet syndrome: clinical presentation, associations, and response to treatment in 77 patients. J Am Acad Dermatol. 2013;69(4):557-564. doi:10.1016/j.jaad.2013.06.023

13.       Fourman S. Inflammatory Glaucoma Associated With Sweet’s Syndrome. American journal of ophthalmology. 1988;105(6):691-692. doi:10.1016/0002-9394(88)90072-4

14.       Bulengo-Ransby SM, Brown MD, Dubin HV, Rasmussen JE, Nickoloff BJ. Sweet’s syndrome presenting as an unusual periorbital eruption. J Am Acad Dermatol. 1991;24(1):140-141. doi:10.1016/s0190-9622(08)80050-3

15.       Anwar S, Hassan S, Fern AI, Douglas WS, Mann B. Bilateral periocular swelling in Sweet’s syndrome. Eye. 2004;18(2):214-216. doi:10.1038/sj.eye.6700588

16.       Morgan KW, Callen JP. Sweet’s syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells. J Am Acad Dermatol. 2001;45(4):590-595. doi:10.1067/mjd.2001.119032

17.       Oshitari K, Hida T, Takahashi M, Okada AA, Shiobara T. [Sweet syndrome presenting as orbital cellulitis]. Nippon Ganka Gakkai Zasshi. 2004;108(3):162-165.

18.       Maalouf T, Angioi K, Ssi-Yan-Kai I, Vernerey F, Witz B, George J. Dacryoadenitis associated with subcutaneous Sweet’s syndrome in a patient with acute myeloid leukemia. Orbit. 2005;24(1):55-57. doi:10.1080/01676830590903562

19.       Davies R. Limbal nodules in Sweet’s syndrome. Aust N Z J Ophthalmol. 1992;20(3):263-265. doi:10.1111/j.1442-9071.1992.tb00951.x

20.       Wang W, Wang X, Zhao H, Cui Y. A Case Report of Sweet’s Syndrome with Panuveitis and Rhegmatogenous Retinal Detachment. Ocul Immunol Inflamm. 2021;29(7-8):1345-1347. doi:10.1080/09273948.2020.1746357

21.       Salvador-Osuna C, Fernandez-Mosteirin N, Mayayo P, Delgado P, Giralt M. Choroiditis as systemic manifestation of a Sweet’s syndrome associated to myelodysplasia: a case report. Haematologica (Roma). 2002;87(1):ECR07-.

22.       Lobo AM, Stacy R, Cestari D, Stone JH, Jakobiec FA, Sobrin L. Optic nerve involvement with panuveitis in Sweet syndrome. Ocul Immunol Inflamm. 2011;19(3):167-170. doi:10.3109/09273948.2011.560411

23.       Sudhakar P, Tobin S, O Connor W, Kedar S. Neuro-Ophthalmic Presentation of Neuro-Sweet Disease. Neuroophthalmology. 2017;41(4):202-206. doi:10.1080/01658107.2017.1291687

24.       Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis. 1986;37(3):167-174.

25.       von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol. 1994;31(4):535-556; quiz 557-560. doi:10.1016/s0190-9622(94)70215-2

26.       Cohen PR, Kurzrock R. Sweet’s syndrome: a neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol. 2000;18(3):265-282. doi:10.1016/s0738-081x(99)00129-7

27.       Cohen PR, Kurzrock R. Sweet’s syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42(10):761-778. doi:10.1046/j.1365-4362.2003.01891.x

28.       Cohen PR, Kurzrock R. Sweet’s syndrome and cancer. Clin Dermatol. 1993;11(1):149-157. doi:10.1016/0738-081x(93)90112-p

29.       Trayes KP, Love G, Studdiford JS. Erythema Multiforme: Recognition and Management. Am Fam Physician. 2019;100(2):82-88.

30.       Suzuki Y, Kuroda K, Kojima T, Fujita M, Iseki T, Shinkai H. Unusual cutaneous manifestations of myelodysplastic syndrome. Br J Dermatol. 1995;133(3):483-486. doi:10.1111/j.1365-2133.1995.tb02684.x

31.       Karadoğan SK, Başkan EB, Alkan G, Saricaoğlu H, Tunali S. Generalized Sweet syndrome lesions associated with Behçet disease: a true association or simply co-morbidity? Am J Clin Dermatol. 2009;10(5):331-335. doi:10.2165/11310790-000000000-00000

32.       O’Connor Reina C, Garcia Iriarte MT, Rodriguez Diaz A, Gomez Angel D, Garcia Monge E, Sanchez Conejo-Mir J. Tonsil cancer and Sweet’s syndrome. Otolaryngol Head Neck Surg. 1998;119(6):709-710. doi:10.1016/S0194-5998(98)70042-7

33.       Cohen PR, Kurzrock R. Sweet’s syndrome: a review of current treatment options. Am J Clin Dermatol. 2002;3(2):117-131. doi:10.2165/00128071-200203020-00005

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