WELLS’ SYNDROME PROCEEDED BY LEUKOCYTOCLASTIC VASCULITIS: A DISCUSSION WITH NEW INSIGHTS INTO ANALOGOUS PATHOPHYSIOLOGY

AbstractWells’ syndrome, also referred to as eosinophilic cellulitis, is a rare inflammatory dermatosis. Although its etiology is unknown, it is thought to be an abnormal eosinophilic response to one of various causative agents. Its cutaneous manifestations vary in morphology and severity, but the disease often follows a relapsing-remitting course. We report the case of a patient with Wells’ syndrome preceded by leukocytoclastic vasculitis (LCV).

Wells’ Syndrome Proceeded by Leukocytoclastic Vasculitis: A Discussion with New Insights into Analogous PathophysiologyS. Brandon Nickle, DO,* Roxanne Rajaii, MS, DO,** Zachary Hopkins, BS,*** Nelson Charlie, MD****

*Dermatology Resident , 4th year, Broward Health Medical Center, Ft. Lauderdale, FL **Dermatology Resident, 2nd year, Beaumont Hospital, Farmington Hills, MI***Medical Student, 4th year, University of Utah School of Medicine, Salt Lake City, UT****Attending Dermatologist, Lauderdale Academic Dermatology at Broward Medical Center, Ft. Lauderdale, FL

Disclosures: NoneCorrespondence: Brandon Nickle, DO; 4331 SW 78th Dr., Davie, FL 33328; Fax: 801-318-1431; brandonnickle5@gmail.com

IntroductionWells’ syndrome, also referred to as eosinophilic cellulitis, is an uncommon inflammatory dermatosis, with fewer than 200 cases reported worldwide.2 It was first described in 1971 by George Wells, noted as a rare entity with an unknown etiology.1 It often presents with a prodromal burning or pruritic sensation, which is followed by a widespread eruption consisting of urticarial erythematous papules, plaques, and bullae of the trunk and upper and lower extremities. Head and neck involvement has also been reported. Often, the cutaneous manifestations recur.1 Although the exact pathophysiology of the disease is unknown, many associations have been reported. A diagnostic criterion has been developed to aid physicians in this uncommon diagnosis, but many cases of Wells’ syndrome are still misdiagnosed.3

Here, we present a patient with a one-year history of LCV who subsequently developed Wells’ syndrome, an association not yet reported in the literature. Whether this case depicts a causal association or reflects a shared pathophysiology is unknown, but it may spur awareness of and further research into Wells’ syndrome in an effort to better understand the disease’s pathophysiology, diagnosis, and treatment options.

Case ReportA 55-year-old African-American female with a past medical history of hypertension presented to our clinic with a two-month history of a purpuric vesicular eruption of the lower extremities that was clinically and pathologically consistent with leukocytoclastic vasculitis (LCV) (Figures 1, 2). Her LCV was thought to be secondary to hydrochlorothiazide (HCTZ) therapy, which she had recently started for hypertension management. She was switched from HCTZ to lisinopril and attained a partial resolution of her symptoms.

At three-month follow-up, the patient presented with a more widespread eruption consisting of scattered urticarial papules, nodules, and plaques involving the trunk and upper and lower extremities, with occasional vesicles and bullae in a similar distribution (Figures 3, 4). The clinical differential was expanded to include bullous pemphigoid, arthropod assault, bullous Sweet’s syndrome, and Wells’ syndrome with or without coexisting LCV. We performed two 4-0 mm punch biopsies: one lesional biopsy from a

bulla on the left lateral leg, and one perilesional biopsy from skin directly adjacent to the bulla. They were sent for direct immunofluorescence (DIF), which revealed an overwhelming number of eosinophils in the superficial and deep dermis (Figures 5, 6 [p. 46]). The biopsy was read as bullous pemphigoid vs. Wells’ syndrome. The negative DIF together with appropriate clinical and pathologic correlation pointed to Wells’

syndrome. The patient was given a one-month course of prednisone and was free of symptoms at three-month follow-up. She was lost to further follow-up.

DiscussionClinical Presentation Wells’ syndrome, first described in 1971 as a “granulomatous dermatitis with eosinophilia,” is commonly referred to as eosinophilic cellulitis and characterized by acute pruritic dermatitis. The clinical appearance can vary depending on the presenting variant. To date, there have been seven clinical variants described in the literature, including plaque, annular granuloma-like, urticaria-like, papulovesicular, bullous, papulonodular, and fixed drug eruption-like.4 Morphologically, one of the most common presentations is a sudden onset of one to several pruritic or painful, edematous, erythematous papules, nodules and/or plaques.1,5,6 Other

Figure 1. Multiple, 2 cm to 3 cm, non-blanchable purpuric vesicular plaques on left lower extremity, clinically and histologically consistent with LCV.

Figure 2. Biopsy of left lateral leg revealing epidermal necrosis with neutrophils and neutrophilic debris in the epidermis. In underlying dermis, neutrophils and eosinophils are present along with significant leukocytoclastic debris, vessel fibrin, and thrombi (H&E, 20x).

Figure 3. Multiple erythematous urticarial plaques on the chest.

Figure 4. Multiple erythematous urticarial plaques on the back.

NICKLE, RAJAII, HOPKINS, CHARLIE

presentations include a sudden eruption of cellulitic lesions with blistering, and annular or circinate, erythematous plaques with infiltrated borders.1 Lesions evolve over two to three days, with complete resolution in about two to eight weeks. The disease recurs in many patients.1,7,8 In a comprehensive review, Sinno et al. calculated a recurrence probability of approximately 56%.2

Etiology The etiology of Wells’ syndrome is uncertain; however, some important associations have been documented in the literature. Multiple medications have been cited as causal agents, including antibiotics, anticholinergic agents, anesthetics, non-steroidal anti-inflammatory agents, thyroid medications, chemotherapeutic agents, thiomersal-containing vaccinations, and anti-TNF agents.1 Tugnet et al. reported a case of Wells’ syndrome secondary to infliximab therapy.9 Of note, the thiazide group of drugs is known to cause a variety of cutaneous reactions, including LCV.1 However, an association between thiazides and Wells’ syndrome has not been reported.

Wells’ syndrome has been linked to colonic adenocarcinoma and several hematologic diseases, including chronic lymphoid leukemia, malignant lymphoma, and polycythemia vera. Nakazato et al. reported a case of Wells’ syndrome in a patient with CML.10 Due to the association between Wells’ syndrome and underlying malignancy, investigation for underlying disorders is warranted in patients diagnosed with Wells’ syndrome.16 Reports also associate Wells’ syndrome with ascariasis, colon carcinoma, Churg-Strauss, Sweet’s syndrome, SLE, HSV type 2, autoimmune disorders, arthropod bites, and viral or bacterial infections.1,6,7,11-16 To our knowledge, this is the first published report of a possible association between Wells’ syndrome and leukocytoclastic vasculitis (LCV).10

It has been speculated that a hypersensitivity reaction may play a role in the disease process, lending support for arthropod bites as a possible etiology of Wells’ syndrome.1,6 Furthermore, there is some

evidence that abnormal “homing” of eosinophils to target tissue via abnormal levels of IL-5 is involved in the underlying pathophysiology.17,18

Pathophysiology While the unique presentation of LCV and Wells’ syndrome in this case may not represent associated processes, it may offer insight into the underlying pathophysiology of both diseases. Like Churg-Strauss and Sweet’s syndrome, LCV is a form of vasculitis characterized by inappropriate infiltration of vessels by inflammatory cells such as neutrophils.8 This process is thought to be due to a dysregulation in the complex process of inflammatory-cell recruitment and homing to specific tissues. In the case of LCV, one of the most common findings is that of immune complex deposition leading to the inappropriate recruitment of neutrophils to a tissue. Some studies also note dysregulation of key integrins and selectins involved in leukocyte rolling and homing.19

In the case of Wells’ syndrome, one case study suggests that altered levels of IL-5 are involved in inappropriate recruitment and homing of eosinophils to tissues.17 Furthermore, an animal study in mice noted the importance of IL-5 and other cytokines in eosinophilia and tissue homing, demonstrating how dysregulation of IL-5 could plausibly lead to eosinophilia and inappropriate recruitment of eosinophils into specific tissues.18 Thus, while the exact underlying mechanisms of both LCV and Wells’ syndrome are not well understood, it is plausible that the processes underlying the dysregulation involved in neutrophil recruitment in LCV could also trigger alterations in IL-5 or other homing signals, leading to inappropriate recruitment of eosinophils to the skin.

Diagnosis Clinically, diagnosis of Wells’ Syndrome requires certain criteria be met. Caputo et al. describe them as: “(1) protean cutaneous manifestations that showed spontaneous resolution or response to nonaggressive treatments; (2) a recurrent course; (3) benign clinical behavior; (4) no evidence of

systemic illness; (5) lack of evidence of triggering factors, including insect bites, bacterial, viral, and parasitic infections or infestations, as well as any kind of drug intake; (6) histopathologic changes of eosinophilic dermatosis, with or without granulomatous features, with possible presence of typical flame-shaped figures; (7) negative direct immunofluorescence findings; and (8) inconsistent blood eosinophilia.”3

Histologically, dermal eosinophilic infiltration and, in the acute phase, peripheral eosinophilia differentiate Wells’ syndrome from infectious cellulitis.5 During the early phase of disease, dermal edema and diffuse dermal infiltration of eosinophils is seen. In the subacute phase, a characteristic infiltrate of phagocytic histiocytes and flame figures is seen on histopathology. In later phases of disease, fewer eosinophils, histiocytes, giant cells, and flame figures are present. Although important in the histologic diagnosis of Wells’ syndrome, flame figures are not pathognomonic.1 Flame figures may be present in various other dermatologic conditions including pemphigoid, severe prurigo, eczema, arthropod bites, Churg-Strauss and other inflammatory conditions characterized by eosinophilia.4 Thus, clinical correlation with histologic findings is essential.

Based on the infiltrate pattern seen on histopathology, a differential diagnosis for Wells’ syndrome may include granuloma annulare, granuloma faciale, urticaria, and, as in this case, leukocytoclastic vasculitis.6 Histopathologically, both LCV and Wells’ syndrome show eosinophils. LCV can be differentiated by its angiocentric infiltrate, representing fibrin around inflamed vasculature, and the presence of neutrophilic debris (leukocytoclasis), which differs from the diffuse dermal infiltration of eosinophils seen in Wells’ syndrome.7,20,21

Treatment A variety of treatments has been cited in the literature as possible therapies for Wells’ syndrome, including low-dose oral corticosteroid therapy.5 Studies report success rates of up to 92% with steroid therapy alone.2 Other case reports document varying degrees of success with griseofulvin, dapsone, antihistamines (cetirizine), sulphones, interferon-α, cyclosporine, and antimicrobial agents.1,22

Conclusion Wells’ syndrome is a cutaneous inflammatory syndrome that runs a benign but often relapsing course. A patient with an atypical presentation of cellulitis unresponsive to antibiotic therapy should prompt suspicion of Wells’ syndrome. While Wells’ syndrome has been associated with several diseases, this case report is novel in that it is the first of its kind to present a patient with Wells’ syndrome in the setting of LCV.10 We hope that this possible association between Wells’ syndrome and LCV leads to further study and insight into this syndrome’s etiology, pathophysiology, and ideal management strategies.

Figures 5 (4x), 6 (20x). H&E: Superficial and deep infiltrate comprised predominantly of lymphocytes and abundant eosinophils.

Figure 5 Figure 6

WELLS’ SYNDROME PROCEEDED BY LEUKOCYTOCLASTIC VASCULITIS: A DISCUSSION WITH NEW INSIGHTS INTO ANALOGOUS PATHOPHYSIOLOGY

References1. Heelan K, Ryan JF, Shear NH, Egan CA. Wells syndrome (eosinophilic cellulitis): Proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013 Dec 30;7(4).

2. Sinno H, Lacroix J-P, Lee J, Izadpanah A, Borsuk R, Watters K, et al. Diagnosis and management of eosinophilic cellulitis (Wells’ syndrome): A case series and literature review. Can J Plast Surg. 2012;20(2):91-7.

3. Caputo R, Marzano AV, Vezzoli P, Lunardon L. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006 Sep;142(9):1157–61.

4. Tan CZ, Novoa R, Chen JK. Erythematous Plaques on the Buttock. JAMA. 2016;315(1):79–80.

5. Falagas ME, Vergidis PI. Narrative review: diseases that masquerade as infectious cellulitis. Ann Intern Med. 2005;142(1):47–55.

6. Haddad F, Helm TN. Wells syndrome. Cutis. 2014 Jan;93(1):17, 38–9.

7. Tsuda S, Tanaka K, Miyasato M, Nakama T, Sasai Y. Eosinophilic cellulitis (Wells’ syndrome) associated with ascariasis. Acta Derm Venereol. 1994 Jul;74(4):292–4.

8. Consigny S, Courville P, Young P, Richard C, Gauthier V, Maillard V, et al. [Histological and clinical forms of the eosinophilic cellulitis]. Ann Dermatol Venereol. 2001 Mar;128(3 Pt 1):213–6.

9. Tugnet N, Youssef A, Whallett AJ. Wells’ syndrome (eosinophilic cellulitis) secondary to infliximab. Rheumatology. 2012 Jan 1;51(1):195–6.

10. Nakazato S, Fujita Y, Hamade Y, Nemoto-Hasebe I, Sugita J, Nishie W, et al. Wells’ Syndrome Associated with Chronic Myeloid Leukaemia. Acta Derm Venereol. 2013;93(3):375–6.

11. Ratzinger G, Zankl J, Eisendle K, Zelger B. Eosinophilic leukocytoclastic vasculitis – a spectrum ranging from Wells’ syndrome to Churg-Strauss syndrome? Eur J Dermatol. 20149-10;(5):603–10.

12. Ludwig RJ, Grundmann-Kollmann M, Holtmeier W, Wolter M, Glas J, Podda M, et al. Herpes simplex virus type 2-associated eosinophilic cellulitis (Wells’ syndrome). J Am Acad Dermatol. 2003 May;48(5):S60–1.

13. Schuttelaar ML, Jonkman MF. Bullous eosinophilic cellulitis (Wells’ syndrome) associated with Churg–Strauss syndrome. J Eur Acad Dermatol Venereol. 2003;17(1):91–3.

14. Yin G, Xie Q. Systemic lupus erythematosus associated with Wells’ syndrome. Rheumatol Int. 2012 Apr;32(4):1087–9.

15. Fujimoto N, Wakabayashi M, Kato T, Nishio C, Tanaka T. Wells syndrome associated with Churg-Strauss syndrome: Wells syndrome associated with Churg-Strauss syndrome. Clin Exp Dermatol. 2011 Jan;36(1):46–8.

16. Hirsch K, Ludwig RJ, Wolter M, Zollner TM, Hardt K, Kaufmann R, et al. Eosinophilic cellulitis (Wells’ syndrome) associated with colon carcinoma. JDDG J Dtsch Dermatol Ges. 2005;3(7):530–1.

17. España A, Sanz ML, Sola J, Gil P. Wells’ syndrome (eosinophilic cellulitis): correlation between clinical activity, eosinophil levels, eosinophil cation protein and interleukin-5. Br J Dermatol. 1999;140:127–30.

18. Mould AW, Matthaei KI, Young IG, Foster PS. Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J Clin Invest. 1997;99(5):1064.

19. Kevil CG, Bullard DC. Roles of leukocyte/endothelial cell adhesion molecules in the pathogenesis of vasculitis. Am J Med. 1999 Jun;106(6):677–87.

20. Moossavi M, Mehregan DR. Wells’ syndrome: a clinical and histopathologic review of seven cases. Int J Dermatol. 2003;42(1):62–7.

21. Aberer W, Konrad K, Wolff K. Wells’ syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol. 1988 Jan;18(1 Pt 1):105–14.

22. Bokotas C, Kouris A, Stefanaki C, Sgotzou T, Christofidou E, Kontochristopoulos G. Wells Syndrome: Response to Dapsone Therapy. Ann Dermatol. 2014;26(4):541.