Coincidence of Systemic Lupus Erythematosus and ANCA-Associated Vasculitis: A Case Report with Perforation of Nasal Septum and Palate

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease with multisystemic involvement, ranging from mild cutaneous involvement to severe organ damage, such as kidney failure, pulmonary hypertension, and cardiac failure.^1,2 The most frequent coexisting autoimmune diseases in SLE patients are autoimmune thyroid disease (18%), antiphospholipid syndrome (APS) (14%), and Sjogren’s Syndrome (SS) (14%),³ but the overlap syndrome between SLE and AAV is rare originally described in 2008.⁴

SLE/AAV overlap syndrome is an inflammatory disease characterized by clinical features of both SLE and AAV.⁵ According to recent literature, any organ may be affected in the SLE/AAV overlap syndrome. It is to be noted that kidney is most commonly involved, with rapidly progressive glomerulonephritis as the most common clinical manifestation.^5,6 Other systemic involvement of the SLE/AAV overlap syndrome include cerebral ischemia, central nervous system vasculitis, subarachnoid hemorrhage, lupus granulomatous pneumonitis, pulmonary hemorrhage, arthritis, serositis, cytopenia, rhinosinusitis, and thrombopenia.^5–7 As we have known so far, few previous cases have reported nasal and palatal perforation in this disorder. Here, we present a SLE/AAV overlap syndrome patient with perforation of the nasal septum and palate.

Case Report

A 16-year-old female patient was admitted to the emergency room with severe epistaxis and increased bleeding for 5 days. The patient was diagnosed with SLE 6 months ago due to facial malar rash, oral ulcer, increased erythrocyte sedimentation rate (ESR), low complement levels and positive anti-Smith antibody. The laboratory test results revealed blood count, urinalysis, immunology and biochemistry (Table 1). SLE disease activity index 2000 (SLEDAI-2K) of the patient was 6.⁸ She had not taken hydralazine, thioridazine or propylthiouracil, known to induce SLE and/or AAV. The patient was initially given intravenous methylprednisolone 80 mg per day for 3 times. After leaving the hospital, she was treated with prednisone 40 mg daily with subsequent dose tapering, hydroxychloroquine (HCQ) 0.2 g twice daily, and intravenous cyclophosphamide (CYC) 0.4 g half a month until remission was achieved and maintained. However, she stopped taking the medicine when prednisone was tapered to 20 mg.

Table 1 Laboratory Results of First Admission

The intraoral examination identified a 1*2 cm ulcer on the hard palate. Laboratory assessments revealed (Table 2) severe pancytopenia, elevated ESR and serum ferritin, decreased serum levels of complement C3 and C4, proteinuria and hepatic insufficiency. Compared to the last hospitalization, anti-Smith antibody turned negative, anti-U1-RNP, anti-SS-A, anti-SS-B and anti-ribosomal P protein (anti-P) antibodies were still positive by line-immunoassay (LIA). Meanwhile, our patient had c-ANCA positivity with a titer of 1:100 (<1:10) by indirect immunofluorescence (IIF). P-ANCA was negative. The titer of anti-PR3-ANCA antibody was >400.00 RU/mL (NR <20 RU/mL) by magnetic particle based chemiluminescent immunoassay (MPCLIA). Anti-MPO-ANCA antibody was <2.00 RU/mL (NR <20 RU/mL). We excluded pancytopenia caused by hematological diseases by performing bone marrow puncture. Cranial computed tomography (CT) scan showed soft tissue densities in paranasal sinuses and nasal cavities, and no bone destruction was found in the maxillary area and oral cavity. Chest CT scan revealed no evidence of numerous pulmonary nodules. SLEDAI-2K was 18.⁸

Table 2 Laboratory Results of Second Admission

Based on the above manifestations and examinations, we considered that the patient had recurrence of lupus. We gave methylprednisolone pulse therapy, intravenous immunoglobulin, together with immunosuppressor. The patient’s rash, blood count, liver enzymes, serum levels of complement C3 and C4, and ESR improved, but the palatal ulcer worsened, resulting in perforation of the hard palate (Figure 1). CT showed the palatal perforation (Figure 2). A nasal endoscopic biopsy was performed and histopathology showed an inflammatory polyp with chronic suppurative inflammation and inflammatory granulomatous hyperplasia (Figure 3). The cells within these lesions consist of fibroblasts, epithelioid cells, giant cells, surrounding scattered infiltrates of lymphocytes, monocytes, macrophages, plasma cells and neutrophils. Palatal perforation, a rare condition, can be seen in infections (eg syphilis, tuberculosis), autoimmune diseases (eg IgG4-RD, GPA), drug abuse (eg cocaine), malignancies (eg oral cavity squamous cell carcinoma, extranodal natural killer/T-cell lymphoma), and trauma.^6,9–11 First, the syphilis antibodies and t-spot detection results for the patient were both negative, we ruled out syphilis and tuberculosis. Second, our patient had no previous history of drug abuse and trauma. Third, pathologists did not detect greater than 50 IgG4-positive plasma cells under high-power microscopy in the nasal histopathology. Furthermore, squamous cell carcinoma was not found in the nasal histopathology. Extranodal natural killer/T-cell lymphoma confirmatory histopathological and immunohistochemical tests with features of CD2+, cytoplasmic CD3+, CD56+, and EBV-encoded small RNA (EBER) positivity in situ.¹⁰ So we performed immunohistochemical tests of CD3, CD56, CD2, CD4, CD5, CD7, CD79a, CD8, CD19, CD20, PAX5, TIA-1, Ki-67, EBER, and Granzyme B were negative (Figure 4). According to Chapel Hill Consensus Conference definitions and 2022 ACR/EULAR classification criteria, the clinical, biological, radiological, and histological findings of our patient substantiated the diagnosis of GPA. At follow-up visits, the patient’s anti-PR3-ANCA antibody turned negative and the palatal perforation did not continue to enlarge. The patient was given low-dose maintenance steroid treatment and then referred to the Department of Otolaryngology for the evaluation of surgical repair of palatal perforation.

Figure 1 Perforation of the hard palate, and the nasal cavity could be peered through the perforation.

Figure 2 CT showed the palatal perforation (red arrow).

Figure 3 The nasal endoscopic biopsy section indicates inflammatory polyp with chronic suppurative inflammation and inflammatory granulomatous hyperplasia. (Hematoxylin-eosin stain).

Figure 4 Immunohistochemical tests of nasal biopsy were negative. (A) EBER. (B) Ki-67. (C) CD19. (D) CD20. (E) TIA-1. (F) CD8. (G) CD3. (H) CD2. (I) CD56. (J) CD79a. (K) CD7. (L) CD4. (M) Granzyme B. (N) Pax-5.

Discussion

In conclusion, SLE patients with positive ANCAs can be characterized into two categories. One group of patients only present with positive ANCAs (in which more than 96% present with positive MPO),⁹ but with no clinical manifestations and pathological features of AAV. Another group of patients fulfill the classification criteria of both SLE and AAV, which can be defined as an overlap between SLE and AAV. The coexistence of SLE and AAV as an overlapping syndrome is not common, the patient that we discussed here had specific clinical manifestations and pathological features of GPA. Therefore, SLE/AAV overlap syndrome was established as the final diagnosis. This case suggests that there are several causes for nasal septal perforation, such as syphilis, tuberculosis, drug abuse, GPA, IgG4-RD and malignancies.

We searched and summarized the characteristics of SLE/AAV overlap syndrome in previous literature (Table 3). Of all cases, 18 patients were female, and the average age of diagnosis was 42. The patients mainly presented with multisystem involvement, of which nondestructive polyarthritis was the most common clinical presentation, and all patients were MPO positive. The case we reported was a young female with epistaxis onset, and then gradually developed nasal septal and palatal perforation, accompanied with hematological involvement and positive PR3-ANCAs, negative MPO-ANCAs. Positive PR3-ANCAs was also consistent with the clinical features of the patient, who presented with epistaxis, nasal septal perforation, and palatal perforation.

Table 3 Summary of Patients with the SLE/AAV Syndrome from Previous Reports in the Literature

The concept of Shared Autoimmunity posits that overlap syndromes may be explained by a combination of common environmental factors and predisposing genes.¹² During analysis of AAV genetic risk factors, it was found that SLE is associated with susceptibility genes for AAV (eg CD40, HLA-DRB1, IL-10, IL2RA, PTPN22, FCGR3B).¹³ The association indicates that is possible the presence of a common mechanism shared by SLE and AAV. No specific genetic studies were tested in this patient, but given these relations there is likely a common underlying genetic susceptibility.

SLE/AAV overlap syndrome is less common compared to SLE overlapping with SS or APS. The analysis of gene expression has revealed a robust neutrophil signature in SLE, while the activation of neutrophils is recognized as a characteristic feature of AAV.¹⁴ It indicates that the mechanism of SLE/AAV overlap is perhaps associated with neutrophils. Recently, it has been proposed that neutrophil extracellular traps (NETs) play a significant role in a variety of autoimmune diseases, such as SLE and AAV.¹⁵ NETs are extracellular networks of DNA scaffolds decorated with granular components, histones and cytoplasmic proteins which protrude from the membrane of activated neutrophils.^16,17 Impaired degradation of NETs was observed in the serum of SLE patients, which was due to the presence of DNase-1 inhibitors and anti-NET antibodies that prevented access of DNase-1 to NETs.¹⁸ Meanwhile, SLE immune complexes can drive NETs formation.¹⁹ In AAV, ANCAs stimulate polymorphonuclear leukocytes (PMNs), monocytes, and endothelial cells to produce IL-8, which in turn cause NETs formation. Following that, NETs formation activates autoreactive B cells to produce more ANCAs.¹⁶ Impaired NETs clearance generates the accumulation of active-NETs at inflammatory sites, resulting in greater inflammation and the persistence of NETs autoantigens for a longer period of time. Reduced serum DNase1 activity was observed in both AAV and SLE.^18,20 The imbalance between the creation and destruction of NETs during the NETosis process may be linked to the etiology of autoimmune diseases.¹⁶ NETs can interrupt self-tolerance by being a source of autoantigens for autoantibodies, such as anti-citrullinated protein antibodies (ACPAs) in RA, anti-dsDNA in SLE, and MPO-ANCA and PR3-ANCA in AAV.²¹ In the light of the above, we propose a hypothesis for the SLE/AAV overlap syndrome: regardless of whether the patient was first diagnosed with SLE or AAV, the excessive production and impaired degradation of NETs may cause the production of the autoimmune antibodies for another autoimmune disease, which in turn leads to overlap syndrome.

Conclusion

Not all SLE could be associated with AAV, it’s a small probability event. Since similar clinical features exist in both SLE and AAV, the symptoms should be first identified as caused by which disease before considering the diagnosis of SLE/AAV overlap syndrome. When a patient develops new symptoms that cannot be explained by the original disease, consideration should be given to whether the patient has overlapping syndrome, especially autoimmune diseases that are more likely to overlap with other autoimmune diseases. Characteristic histopathologic manifestations play an important role in the diagnosis of SLE/AAV overlap syndrome. More researches are needed to study the mechanisms of SLE/AAV overlap syndrome in order to better guide future treatments.