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Year : 2020  |  Volume : 63  |  Issue : 2  |  Page : 305-308
Non-bullous neutrophilic lupus erythematosus—Muted bullous disease?

1 Department of Pathology, ABVIMS and Dr. RML Hospital, New Delhi, India
2 Department of Medicine, ABVIMS and Dr. RML Hospital, New Delhi, India

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Date of Web Publication18-Apr-2020


Non-bullous neutrophilic lupus erythematosus is a rare form of cutaneous lupus erythematosus (LE). We hereby present a case of 24-year-old female, known case of discoid LE (DLE) with negative ANA stabilized on hydroxychloroquine for 2 years. She reported new occurrence of erythematous, mildly pruritic, papular lesions and painful mucosal ulceration. The ANA became strongly positive by ELISA and urine showed proteinuria. A provisional diagnosis of Rowell syndrome was made, skin biopsy was taken, and patient started on steroids. Histopathology showed interface vacuolar change and many neutrophils in the dermis with leukocytoclasia without any bulla formation. The skin lesions responded promptly to addition of dapsone following biopsy report. We conclude that the presence of neutrophils associated with interface pathology on biopsy represents a muted form of bullous LE, especially in patients on immunosuppression. This case highlights the importance of histopathologic examination in the evaluation of any new skin lesions in a patient of lupus on therapy.

Keywords: Dapsone, neutrophilic dermatoses, non-bullous neutrophilic lupus erythematosus

How to cite this article:
Malhotra P, Singh P, Kundu BK, Bhardwaj M. Non-bullous neutrophilic lupus erythematosus—Muted bullous disease?. Indian J Pathol Microbiol 2020;63:305-8

How to cite this URL:
Malhotra P, Singh P, Kundu BK, Bhardwaj M. Non-bullous neutrophilic lupus erythematosus—Muted bullous disease?. Indian J Pathol Microbiol [serial online] 2020 [cited 2021 Jun 13];63:305-8. Available from: https://www.ijpmonline.org/text.asp?2020/63/2/305/282712

   Introduction Top

The lupus erythematosus (LE) associated with neutrophilic dermatosis has been reported most commonly in Bullous LE, vasculitis, Sweets/Sweets like syndromes, and pyoderma gangrenosum.[1],[2],[3],[4]

Lesions showing a combination of interface pathology along with the presence of neutrophils have been recently designated as non-bullous neutrophilic LE (NBNLE).[5] It is a rare variant of cutaneous LE. It presents with pruritic, urticarial papules and plaques. We hereby present a rare case of NBNLE treated promptly with dapsone. The present case corroborates the hypothesis that this entity may be considered a muted form of bullous LE in patients on immune-suppressive therapy. Our case underlines the importance of prompt histopathologic evaluation of any new skin lesion occurring in a case of lupus on immunosuppressive therapy.

   Case History Top

Twenty-four-year-old female, known case of DLE with previously negative ANA stabilized on hydroxychloroquine for 2 years, reported the new occurrence of pruritic erythematous papular lesions and plaques on face, chest, arm, and back for the past 2 weeks. She also had multiple painful oral ulcers on soft palate, ventral aspect of tongue, and labial mucosa ranging from 1 to 2 cm with erythematous margins and a shallow central reddish-yellow base [Figure 1] (An informed patient consent was obtained to publish the patient image). There were painful shallow linear ulcers at the introitus. No bullous lesions were identified on skin or mucosa. There was no history of fever, joint pain, Raynaud's phenomenon, or any other clinical manifestations. She had history of cutaneous rash 2 years back for which she required admission. Biopsy showed features compatible with DLE. She was started on hydroquinone and topical steroids and was relieved from the symptoms till the time of presentation.
Figure 1: (a) Erythematous papular lesions on the face and chest. (b) A large erythematous plaque on back. (c) Sublingual ulcers

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Laboratory investigations revealed mild anemia with a raised ESR of 81 mm/h, raised CRP of 14.5 mg/ml and mild proteinuria. Renal and liver functions including serum protein, A:G ratio, and calcium levels were within normal limits. SSA-Ro level was raised, whereas SSB-La, ANA, and Anti-ds DNA were negative and complement levels were normal.

A possibility of Rowell syndrome was considered clinically because of acute onset of lesions, association with pain/pruritis, and doubtful targetoid lesions on the anterior chest wall [Figure 1]a. Repeat ANA was advised. Skin biopsy was taken, and the patient was started on steroids. Biopsy showed interface vacuolar change with a focus of neutrophilic microabscess formation at dermoepidermal junction [Figure 2]a, black arrow]. Interspersed necrotic keratinocytes were noted at dermoepidermal junction [Figure 2]a, blue arrow]. Singly scattered neutrophils were noted in papillary dermis in perivascular and interstitial location with leukocytoclasia [Figure 2]b. Basement membrane fragmentation and increased dermal interstitial mucin were highlighted by the Periodic acid-Schiff and alcian blue stain [Figure 2]c. Deep dermis showed periappendageal mucin deposits. There was no evidence of vasculitis or dermoepidermal separation. Conspicuous lymphocytic exocytosis was noted with mild interface change. Histopathologic features in conjunction with serology findings suggested subacute LE. However, the presence of neutrophils was atypical for diagnosis of LE and the same was conveyed to the clinician.
Figure 2: (a) Low magnification showing epidermal atrophy, single neutrophilic microabscess at dermoepidermal junction (DEJ) (black arrow), and necrotic keratinocyte at DEJ (blue arrow) (200×, H and E). (b) High magnification showing vacuolar change at DEJ, papillary dermis shows many neutrophils and lymphocytes (400×, H and E). (c) Basement membrane fragmentation and increased dermal interstitial mucin were noted in Periodic acid-Schiff and alcian blue stain (200×, PAS-AB)

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There was no significant improvement with steroid therapy and the patient came back within a week with raised ANA titers (1:640, homogenous) and proteinuria. On clinicopathological correlation, a possibility of non-bullous neutrophilic lupus erythematosus was considered. The patient was started on dapsone. She responded dramatically in respect of mucosal ulcerations, pain, pruritis, and size of lesions at her next weekly visit. Rowell syndrome was excluded in the absence of classical targetoid lesions, presence of neutrophils, and homogenous ANA pattern.

   Discussion Top

Autoimmune connective tissue diseases like LE, Sjogren syndrome, polymyositis, are classically associated with activation of the adaptive immune system against self-antigens and hence demonstrate lymphocytic infiltrate on histopathologic examination, whereas neutrophilic dermatoses have been categorized as autoinflammatory and are associated with activation of innate immune system (neutrophils).[2] This category includes diseases like Sweet syndrome and pyoderma gangrenosum. NBNLE is a rare entity characterized by a combination of adaptive and innate immune response.

Limited literature is available for this entity. The first clinical cases of NBNLE were reported by Gleason et al.[5] in 2006 who described four patients with Systemic LE (SLE) and urticarial lesions. Brinster et al.[6] reviewed the clinical and pathological findings of four patients with known SLE who developed urticarial papules, plaques, subcutaneous nodules, or a combination of these. Histopathological findings in all patients included an interstitial and perivascular neutrophilic infiltrate with leukocytoclasia, and variable vacuolar alteration along the DE-junction. Direct immunofluorescence study results in two patients were positive for C3, IgG, and IgM along the basement membrane zone. Quatrano et al.[7] reported the case of a 27-year-old woman with SLE-associated neutrophilic dermatosis with palmoplantar involvement [Table 1].
Table 1: Review of Non-Bullous Neutrophilic Lupus Erythematosus cases

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NBNLE presents with pruritic, urticarial papules and plaques. No vesicles, bullae, or pustules are described. There is usually a clinical background of SLE. NBNLE is closely associated with and heralds the onset of systemic disease.[6] This was evident in the present case since the sudden onset of proteinuria and ANA positivity coincided with appearance of neutrophils on biopsy.

The degree of neutrophilic infiltration may range from few interspersed cells to a dense Sweet's-like infiltrate. There is no evidence of vasculitis. Direct immunofluorescence studies may demonstrate complement and/or immunoglobulin deposition along the basement membrane zone in approximately 50% cases. When neutrophilic infiltrate is dense, the absence of papillary dermal edema and the presence of vacuolar alteration or immune-deposits at dermoepidermal junction, help in the distinction from Sweet's syndrome.[8]

Neutrophils in the setting of SLE are most commonly associated with bullous/vasculitic disease.[6] The present case showed no bullous/vasculitic lesions. However, the clinical presentation of our patient showed overlap with bullous LE. Since our patient was a young unmarried female, she was extremely apprehensive regarding the painful ulcerations at the introitus. The location of lesions on sun-protected sites, painful mucosal ulceration, and dramatic response to dapsone therapy are features of bullous lesions. In addition to resolution of symptoms, the therapy had a positive impact on the patient's body image and self-esteem.

Ackerman[9] has suggested that NBNLE may represent an early form of bullous LE, as in patients already on immunosuppressants, the ability to form bullae may be inhibited. Three of four patients in Brinster's report were also on immunosuppressive therapy at the time of diagnosis. The clinical course in the present case corroborates Ackermans' hypothesis.

In the absence of a distinctive clinical presentation, patients of NBNLE are misdiagnosed as acute LE flare and unsuccessfully treated by increasing immunosuppression. However, as noted in our case, dapsone produces prompt and significant symptomatic relief to these patients. Dapsone was tried in one patient in Brinster's series and produced a rapid resolution of symptoms. These findings corroborate with the dramatic therapeutic response to dapsone that is known in patients of bullous LE.

Dapsone is a known neutrophil migration inhibitor with a known therapeutic effect in Bullous LE. It acts by inhibiting myeloperoxidase enzyme which prevents accumulation of hypochlorous acid and thus reduces tissue damage.[10]

NBNLE is an underrecognized neutrophilic dermatosis in patients with LE. It must be included in the differential diagnosis of neutrophil-rich eruptions. Increased awareness of the clinical spectrum of neutrophilic dermatoses in the setting of SLE is essential. Neutrophils on biopsy may be the harbinger of systemic disease in a patient of DLE. Pathologists must note and convey the presence of neutrophils in acute exacerbations of LE so that patients can benefit from prompt addition of dapsone to their therapeutic regimen.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Masatlioglu SP, Goktay F, Mansur AT, Akkaya AD, Guneş P. Systemic lupus erythematosus presenting as pyodermagangrenosum in two cases. Rheumatol Int 2009;29:837-40.  Back to cited text no. 1
Vassileva S. Bullous systemic lupus erythematosus. Clin Dermatol 2004;22:129-38.  Back to cited text no. 2
Tsuji H, Yoshifuji H, Nakashima R, Imura Y, Yukawa N, Ohmura K, et al. Sweet's syndrome associated with systemic lupus erythematosus: A case report and review of the literature. J Dermatol 2013;40:641-8.  Back to cited text no. 3
Kieffer C, Cribier B, Lipsker D. Neutrophilic urticarial dermatosis is a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature. Medicine 2009;88:23-31.  Back to cited text no. 4
Gleason BC, Zembowicz A, Granter SR. Non-bullous neutrophilic dermatosis: An uncommon dermatologic manifestation in patients with lupus erythematosus. J Cutan Pathol 2006;33:721-5.  Back to cited text no. 5
Brinster NK, Nunley J, Pariser R, Horvath B. Nonbullous neutrophilic lupus erythematosus: A newly recognized variant of cutaneous lupus erythematosus. J Am Acad Dermatol 2012;66:92-7.  Back to cited text no. 6
Quatrano NA, Criscito MC, Femia AN, Brinster NK. Systemic lupus erythematosus-associated neutrophilic dermatosis with palmo-plantar involvement. JAAD Case Rep 2016;2:329-33.  Back to cited text no. 7
von den Driesch P. Sweet's syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol 1994;31:535-56.  Back to cited text no. 8
Ackerman AB. Histologic Diagnosis of Inflammatory Skin Diseases: Analgorithmic Method Based on Pattern Analysis. 2nd ed. Baltimore: Williams and Wilkins; 1997. p. 542.  Back to cited text no. 9
Kettle AJ, Gedye CA, Winterbourn CC. Superoxide is an antagonist of anti-inflammatory drugs that inhibit hypochlorous acid production by myeloperoxidase. Biochem Pharmacol 1993;45:2003-10.  Back to cited text no. 10

Correspondence Address:
Purnima Malhotra
Room Number-323, OPD Building, Dr. Ram Manohar Lohia Hospital, New Delhi - 110 001
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_704_19

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