Treatment of Childhood-Onset Lupus Erythematosus Panniculitis With Rituximab

Key Points

Question

What is known about the clinical and histopathologic features and treatment of childhood-onset lupus erythematosus panniculitis?

Findings

In this case series describing 4 patients with childhood-onset lupus erythematosus panniculitis refractory to many therapies, improvement was noted after treatment with rituximab.

Meaning

Lupus erythematosus panniculitis is a rare and disfiguring cutaneous disease in childhood with no criterion standard therapies; however, the findings from this case series suggest that rituximab may be an effective and well-tolerated treatment.

Abstract

Importance

Childhood-onset lupus erythematosus panniculitis (LEP) is a rare and chronic disfiguring disease. A paucity of literature exists on the clinical manifestations of this disease and how best to treat it.

Objectives

To describe the clinical features of childhood-onset LEP and report on the use of rituximab in treatment-refractory childhood-onset LEP.

Design, Setting, and Participants

A retrospective, observational case series study was conducted of 4 patients with childhood-onset LEP who presented to a single-center, tertiary care clinic with pediatric dermatology and pediatric rheumatology clinics between July 1, 2014, and July 1, 2018, and were treated with rituximab. A literature review was conducted of the clinical features and treatment of childhood-onset LEP.

Exposure

Rituximab therapy for childhood-onset LEP.

Main Outcomes and Measures

Reduction in the number and size of erythematous and tender subcutaneous nodules (both visually and by palpation), reduction of facial atrophy (documented with serial photography), and tolerability of rituximab at 2 to 22 months after initiation of therapy.

Results

Four patients (3 male; mean [SD] age at treatment, 15 [5.9] years) with refractory childhood-onset LEP were successfully treated with rituximab. All patients had a rapid and sustained response to therapy with rituximab. One patient (25%) had minor infusion reactions; otherwise, treatment was well tolerated.

Conclusions and Relevance

This case series suggests that rituximab may hold promise as a treatment for refractory, childhood-onset LEP. Larger, prospective studies are needed to validate these findings; however, given the rarity of disease, large studies may be difficult to conduct.

This case series describes the clinical features of childhood-onset lupus erythematosus panniculitis and reports on the use of rituximab for patients with treatment-refractory, childhood-onset disease.

Introduction

Lupus erythematosus panniculitis (LEP) is a subset of chronic cutaneous lupus erythematosus that presents with indurated nodules primarily located in the head and neck that heal with pronounced lipoatrophy.¹ Lupus erythematosus panniculitis is a rare, progressive, and disfiguring disease, which affects patient quality of life. No well-established, effective treatment protocols exist for LEP. Traditionally, antimalarials have been considered first-line therapy.^1,2,3,4 Systemic corticosteroids, methotrexate, and mycophenolate mofetil have all been used in the treatment of LEP, with variable outcomes.^2,3,5 There are emerging reports on the successful use of rituximab in LEP.^6,7,8,9 Rituximab is well established in the management of systemic lupus erythematosus (SLE)¹⁰ and has been used successfully in the treatment of cutaneous-predominant SLE and refractory subacute chronic cutaneous lupus erythematosus.^11,12 We report 4 cases of childhood-onset LEP resistant to other therapies that were successfully treated with rituximab.

Methods

We conducted a retrospective case series of 4 patients with childhood-onset LEP presenting to our pediatric dermatology and rheumatology clinics between July 1, 2014, and July 1, 2018. The University of Minnesota Institutional Review Board determined that this project was not human participants research and waived the need for institutional review board approval. All patients and/or parents provided written consent to be part of this case series.

Case Series

Patient 1 was an otherwise healthy adolescent who presented with recurrent, tender, disfiguring facial nodules (Figure 1A). He was examined by an otolaryngologist, who suspected a parotid tumor. Magnetic resonance imaging of the head and neck showed multiple T2-hyperintense, enhancing subcutaneous nodules of the face and scalp, with the largest lesion in the left cheek extending to the retromaxillary fat pad. Examination of a subcutaneous tissue biopsy specimen revealed a lobular lymphocytic panniculitis, with a differential diagnosis of T-cell lymphoma. Examination of additional biopsy specimens demonstrated similar features of a lobular panniculitis, which again were unable to exclude subcutaneous panniculitis-like T-cell lymphoma. Results of further oncologic workup were unremarkable. Additional dermatopathology consultation rendered a diagnosis of LEP. The patient was treated with hydroxychloroquine and mycophenolate mofetil and later was switched to treatment with azathioprine but did not improve (Table). Subsequent rituximab therapy led to complete resolution of all skin nodules 6 weeks after treatment (Figure 1B). At the 22-month follow-up, the patient’s skin remained clear and he had no clinical evidence of subcutaneous panniculitis-like T-cell lymphoma.

Figure 1. Patient 1 Before and After Treatment With Rituximab.

A, Patient 1 at presentation, with large, erythematous subcutaneous nodule on the right cheek. B, Five months after treatment with rituximab.

Table. Clinical and Histologic Description of Cases of Childhood-Onset LEP.

Patient No./Sex/Age, y	Lesion Location	Duration Prior to Diagnosis	ANA, ENA, dsDNA Positivity	Features of SLE	Key Histopathologic Findings	Treatments Before Rituximab	Rituximab Dosage
1/M/18	Face	4 y	No	No	Lymphocytic lobular panniculitis with admixed plasma cells, deep dermal mucin, and perieccrine lymphocytes	(1) HCQ and MMF for 6 mo; (2) AZA for 3 mo	2 Doses, 1 g, 8 wk apart
2/M/22	Scalp, neck, and upper back	>5 y	No	No	Dense lymphocytic lobular panniculitis; no features suggestive of SPTCL	HCQ and AZA for 6 mo	2 Doses, 1 g, 8 wk apart
3/M/7	Face	4 mo	ANA, 1.6 AI; RNP, 1.9 AI	No	Normal-appearing epidermis, increased mucin in the lower reticular dermis, and a predominantly lobular panniculitis with dense lymphocytic infiltrates seen around fat lobule peripheries, with hyaline fat necrosis and rare admixed plasma cells	(1) Oral prednisone, 60 mg daily (tapering dose), and MTX for 3 mo; (2) HCQ for 3 mo	2 Doses, 1 g, 2 wk apart
4/F/8	Face	1 y	No	No	Normal-appearing epidermis and dermis above a predominantly lobular panniculitis of mostly lymphocytes, with admixed plasma cells and occasional histiocytes as well as zones of hyaline fat necrosis; no lymphocytic cytologic atypia	(1) HCQ for 4 mo; (2) HCQ and MMF for 3 mo	2 Doses, 750 mg, 2 wk apart; patient received approximately 50% (approximately 375 mg) of the full first dose; stopped early owing to 2 minor infusion reactions; patient received the full second dose without issue

Abbreviations: AI, antibody index; ANA, antinuclear antibody; AZA, azathioprine; dsDNA, double-stranded DNA; ENA, extractable nuclear antibodies; HCQ, hydroxychloroquine; LEP, lupus erythematosus panniculitis; MMF, mycophenolate mofetil; MTX, methotrexate; RNP, ribonucleoprotein antibody; SLE, systemic lupus erythematosus; SPTCL, subcutaneous panniculitis-like T-cell lymphoma.

Patient 2 was the brother of patient 1. He presented with a 5-year history of tender subcutaneous nodules on the scalp, neck, and upper back. Histopathologic examination of a scalp nodule demonstrated a dense lymphocytic lobular panniculitis consistent with LEP (Figure 2). The patient was treated with hydroxychloroquine and azathioprine, but the patient’s condition did not improve. He was subsequently treated with rituximab and had complete resolution of all nodules at 8 weeks after treatment. No recurrence was observed in 14 months of follow-up.

Figure 2. Histologic Findings in Patient 2.

A, Subcutaneous fat lobules infiltrated by lymphocytic aggregates, with increased deep dermal mucin (hematoxylin-eosin, original magnification ×20). B, Lymphocyte clusters confined to lobular zones (hematoxylin-eosin, original magnification ×40). C, Predominantly small lymphocytes without significant atypia or pleomorphism, with admixed hyaline fat necrosis (hematoxylin-eosin, original magnification ×100).

Patient 3 was an adolescent male with a complex medical history that included recurrent Kikuchi disease and severe atopy. Results of an extensive work-up for SLE, immunodeficiency, and other autoimmune conditions were negative. He presented with a 1-month history of facial lipoatrophy and extensive erythematous, tender subcutaneous nodules involving the face and neck. He was initially diagnosed as having parotitis and lymphadenitis. Results of sialography were normal, and examination of a cervical lymph node biopsy specimen revealed a reactive node without signs of Kikuchi disease. He was initially treated with prednisone and methotrexate without improvement. Later, a diagnosis of LEP was considered and the patient’s treatment was switched to hydroxychloroquine. Examination of a skin biopsy specimen from a mandibular nodule confirmed the diagnosis of LEP (Table). The patient was then treated with rituximab, with complete resolution of facial nodules and marked improvement in lipoatrophy at the 1-month follow-up. At 6 months, no signs of recurrence were noted.

Patient 4 was a school-age girl who presented with a 1-year history of tender, indurated nodules on the cheeks and temples. An otolaryngologist had diagnosed parotitis. On examination, the cheeks showed areas of induration and numerous subcutaneous nodules, significant facial asymmetry with lipoatrophy, and patchy alopecia of the scalp consistent with alopecia areata. Concern for LEP prompted a skin biopsy; examination of the specimen confirmed the diagnosis of LEP (Table). The patient was treated with hydroxychloroquine and mycophenolate mofetil but continued to worsen. We then treated her with rituximab. She had 2 minor reactions during the first administration that necessitated early discontinuation of treatment. The patient tolerated the second infusion well. At 6 months after treatment, we noted resolution of erythema, nodules, and alopecia; however, lipoatrophy remained marked.

Discussion

This case series documents the efficacy of rituximab in the treatment of childhood-onset LEP in a small cohort. Rituximab is used to treat SLE; however, similar to previous reports on childhood LEP, none of our patients had systemic disease.^1,2,3 All patients had failed other systemic therapies, and all had marked softening and resolution of palpable facial nodules without recurrence after several months of posttreatment follow-up. In all but patient 4, lipoatrophy improved. We considered the possibility that the lack of improvement in patient 4 was owing to delayed treatment; however, patients 1 and 2 exhibited improved lipoatrophy despite having nodules for several years prior to rituximab therapy. Disease duration thus may not be associated with treatment response. The female sex, younger age, and concurrent alopecia areata (previously reported to coexist with LEP⁵) of patient 4 were unique in this series; therefore, the natural history of her disease may be different. However, her histopathologic findings were effectively identical to those of the other 3 patients.

The pathogenesis of LEP remains incompletely understood. Patients 1 and 2 were siblings, suggesting a familial predisposition; however, familial LEP has not been previously reported, to our knowledge. As suggested in studies of other forms of chronic cutaneous lupus erythematosus, immunopathogenesis likely involves a complex interplay between innate and adaptive arms of the immune system. Resolution of LEP after treatment with rituximab, a monoclonal antibody therapy targeting CD20 expressed on B cells, implies an antibody-mediated role in this disease. However, the role of autoantibodies in LEP is unclear, as results of serologic studies are often negative. Approximately half of previously described patients with childhood LEP have positive antinuclear antibody results; however, antinuclear antibody positivity is not clearly associated with prognosis or treatment response.^1,2,3 Histopathologic characteristics of LEP indicate a T-cell–predominant lymphocytic infiltrate, with only minor B cell infiltrates in some cases. Admixed plasma cells are common, although their role in the pathophysiology of LEP is unclear. Similar to SLE, regulatory T cells and interferon-producing cells (including plasmacytoid dendritic cells) are believed to play a more significant role than B cells.^1,13

Childhood-onset LEP is rare, and skin biopsy is required for confirmation. Diagnosis may be delayed for patients presenting to nondermatologists. Given the distribution of nodules overlying the cheeks, our patients were initially diagnosed with parotitis or parotid tumor, although none underwent parotid gland biopsies. We propose that LEP be included in the clinical differential diagnosis for parotid pathologic findings. Histopathologic diagnosis of LEP is straightforward in most cases; however, biopsy specimen findings may overlap with subcutaneous panniculitis-like T-cell lymphoma; in fact, some consider these entities to be on a single disease spectrum, with reported cases of LEP progressing to lymphoma.^14,15 Careful histopathologic and ongoing clinical evaluation to monitor for atypical features is important to exclude evolving subcutaneous panniculitis-like T-cell lymphoma in these patients.

Limitations

This study has some limitations. It was a small, retrospective case series at a single institution, and there are no validated tools to measure treatment response in LEP.

Conclusions

Childhood-onset LEP is a disfiguring cutaneous disease that affects the head and neck and can be mistaken for parotid gland pathologic conditions. We present 4 young patients with LEP who were successfully treated with rituximab after other therapies failed. All patients had resolution of erythematous nodules (visually and by palpation), and most had marked improvement of lipoatrophy. Larger studies are needed to better understand the immunopathogenesis of LEP and to more fully assess the safety and efficacy of rituximab for patients with childhood LEP.