Rituximab in the Treatment of Subarachnoid Hemorrhage and Widespread Bleeding in Microscopic Polyangiitis : A Case Report
Article information
Abstract
Microscopic polyangiitis (MPA) is a rare autoimmune disorder characterized by small-vessel vasculitis and the presence of anti-neutrophil cytoplasmic antibody (ANCA). Typically, MPA primarily affects the respiratory system, kidneys, and skin, with infrequent involvement of the nervous system, resulting in neuropathy. However, the occurrence of subarachnoid hemorrhage (SAH) in MPA is exceedingly rare, especially when it is accompanied by hemorrhagic events in multiple organs. This case report details the clinical presentation of a 61-yearold male patient diagnosed with MPA who experienced an exceptionally uncommon occurrence of SAH, coupled with extensive bleeding manifestations including epistaxis, skin purpura, and gastrointestinal bleeding. Notably, the patient's symptoms exhibited potential improvement following a treatment regimen consisting of rituximab and glucocorticoids. This case emphasizes the critical importance of promptly recognizing and comprehensively managing rare complications in MPA patients to optimize clinical outcomes.
INTRODUCTION
Microscopic polyangiitis (MPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterized by autoimmune-mediated inflammation and damage to small blood vessels, with an incidence of 0.5 to 24.0 cases per million person-years [16]. This rare disease affects various organs, including the upper and lower respiratory tract, kidneys, and skin. Less commonly, MPA can involve the gastrointestinal tract, heart, thyroid, liver, or breast. Neurological involvement in MPA can manifest as multiple mononeuropathy, sensory neuropathy, cranial nerve abnormalities, and central nervous system mass lesions. While subarachnoid hemorrhage (SAH) is a rare complication of MPA, there are limited reported cases in the literature [24]. MPA-induced SAH accompanied by multiple systemic hemorrhages is even more exceptional.
In this article, we present a case of a 61-year-old male patient diagnosed with MPA who experienced the extremely rare occurrence of SAH along with simultaneous widespread bleeding, including gastrointestinal bleeding, nasal bleeding, and skin purpura. The treatment regimen of rituximab and glucocorticoids (GC) was helpful for the patient’s remission.
CASE REPORT
A 61-year-old male patient was admitted to the local hospital on January 28th 2023, with a one-month history of lower extremity swelling. Physical examination revealed bilateral lower extremity edema and a blood pressure of 165/85 mmHg. Laboratory tests (Table 1) showed a white blood cell count (WBC) of 4.68×109/L, platelet count (PLT) of 311×109/L, hemoglobin (HB) of 68 g/L, urea nitrogen (BUN) of 22.39 mmol/L, serum creatinine concentration (SCR) of 370.5 μmol/L, albumin concentration (ALB) of 34.8 g/L, complement 3 level of 0.88 g/L, and urine protein content of 2.11 g/24 hours. Serological tests for anti-nuclear antibody (ANA), anti-double stranded DNA antibody (anti-dsDNA), and anti-phospholipase A2 receptor antibody (anti-PLA2R) were negative. However, the patient tested positive for perinuclear ANCA (P-ANCA) using indirect immunofluorescence method (IIF) and myeloperoxidase ANCA (MPO-ANCA) using enzyme-linked immunosorbent assay (ELISA), with a quantified MPO-ANCA immunoglobulin G antibody level of 2095.99 RU/mL. Chest computed tomography (CT) scan revealed multiple small pulmonary nodules, and gastrointestinal endoscopy showed chronic atrophic gastritis and a sigmoid polyp. The patient was diagnosed with MPA and received intravenous cyclophosphamide (CTX) (0.4 g, once) and methylprednisolone (40 mg, q.d.) therapy during hospitalization, followed by oral prednisone tablets (50 mg, q.d.) after discharge on February 7th, 2023. Half a month later, the patient received another CTX infusion (0.4 g, once).
Relevant Laboratory testing
On March 3rd 2023, the patient presented to the emergency department due to chest tightness and palpitations. Laboratory tests upon admission showed a WBC of 7.04×109/L, PLT of 161×109/L, HB of 68 g/L, BUN of 56.46 mmol/L, SCR of 1010.6 μmol/L, ALB of 26.7 g/L, serum potassium (K+) of 7.55 mmol/L, buffer excess (BE) of -16.88 mmol/L, lactic acid (LAC) of 4 mmol/L, procalcitonin (PCT) of 40.68 ng/mL, C-reactive protein (CRP) of 16.47 mg/L, interleukin-6 (IL-6) of 521.5 pg/mL, brain natriuretic peptide (BNP) of 14605.6 pg/mL, and urine protein content of 2.71 g/24 hours. Occult blood in the stool was negative. Chest CT revealed pulmonary inflammatory infiltrates and bilateral pleural effusion, while cranial magnetic resonance imaging showed no significant abnormalities. The patient was treated with meropenem (1 g, q12h) for infection, hemodialysis, methylprednisolone (40 mg, q.d.), and plasma exchange.
Following treatment, the patient’s infection gradually improved. However, the patient developed a complex multi-systemic bleeding process. The initial manifestation was nasal bleeding, which was managed with symptomatic compression hemostasis. Five days later, the patient presented with abdominal pain and melena, accompanied by positive fecal occult blood test results and a significant drop in HB, suggesting gastrointestinal bleeding. The patient received fasting, blood transfusion, fluid infusion, and nutritional support. Vasculitis activity was assessed using the Birmingham vasculitis activity score (BVAS). Intravenous rituximab (0.5 g, q1w) was administered on March 17th and 24th. On March 31st, the patient experienced sudden headaches, vomiting with red vomit, drowsiness, urinary and fecal incontinence, and generalized skin purpura (Fig. 1). Emergency head CT scan revealed multiple patchy high-density shadows around the right brainstem, under the cerebellar tentorium, and in the bilateral frontal sulci, accompanied by hydrocephalus, indicating SAH (Fig. 2). The patient then underwent magnetic resonance angiography (MRA), but there was insufficient evidence of aneurysm on the MRA scan (Supplementary Video 1). Laboratory findings showed an HB level of 84 g/L, PLT of 161×109/L, SCR level of 156.2 μmol/L, Ddimer of 2.31 μg/mL, plasma fibrinogen of 4.8 g/L, and activated partial thromboplastin time (APTT) of 48.3 seconds. MPO-ANCA antibody was quantified at 284.99 RU/mL. The total lymphocyte count was 75/μL, and the count of CD19(+) B cells was 2/μL. The patient’s family declined surgical treatment, and supportive symptomatic measures were implemented, including mannitol to lower intracranial pressure, blood pressure control, and maintenance of normal blood volume. Dialysis was suspended, and the dynamic creatinine and urine output monitoring was relatively stable. The patient was given the third dose of rituximab (0.5 g) on April 1st. On April 3rd, the patient had regained consciousness and demonstrated voluntary urination, reduction of skin purpura, and reversal of fecal occult blood. The patient received his fourth rituximab treatment (0.5 g) on April 8th and was discharged on April 12th. A follow-up head CT scan showed mild high density shadows in the bilateral posterior horns of the lateral ventricles, with significant absorption observed in other areas compared to previous scans (Fig. 3). The timeline of the patient’s clinical course is presented in Fig. 4.
The patient presented with generalized skin purpura.
The head computed tomography imaging revealed subarachnoid hemorrhage in different locations. A and B : Bilateral frontal sulci. C : Prepontine cistern. D : Quadrigeminal cistern.
A follow-up head computed tomography scan showed significant absorption observed in other areas compared to previous scan. A and B : Bilateral frontal sulci. C : Prepontine cistern. D : Quadrigeminal cistern.
The timeline of the patient's clinical course and changes in serum creatinine and hemoglobin. HB : hemoglobin, GC : glucocorticoids, CTX : cyclophosphamide, SCR : serum creatinine concentration.
DISCUSSION
In this study, we present a 61-year-old male patient diagnosed with MPA who developed the infrequent occurrence of SAH along with simultaneous widespread bleeding, including gastrointestinal bleeding, nasal bleeding, and skin purpura. After receiving rituximab combined with glucocorticoid, the patient showed potential improvement in symptoms and was discharged smoothly.
MPA is an autoimmune vasculitis characterized by the activation of immune cells, dysregulation of cytokines and chemokines, endothelial cell injury, and involvement of the complement system [4]. The presence of ANCAs triggers the activation of immune cells, leading to the release of inflammatory mediators and the recruitment of immune cells. Dysregulated cytokines and chemokines further contribute to immune response and tissue damage. Endothelial cells undergo phenotypic changes and express adhesion molecules, facilitating immune cell adhesion and migration [12]. The complement system is dysregulated, leading to complement deposition and amplification of inflammation [10]. The kidneys and lungs are the most commonly affected organs in MPA. Renal involvement is a hallmark feature, characterized by rapidly progressive glomerulonephritis, which can lead to renal failure if untreated. Pulmonary manifestations include alveolar hemorrhage and interstitial lung disease. We conducted a literature review of relevant articles published until July 2023, using PubMed and Web of Science as the primary databases. After careful screening, we identified six reported cases of SAH caused by MPA [1,8,17,21,23,24]. In these cases, the concomitant organ damage primarily involved arterial aneurysm rupture or cardiac diseases. Currently, there is no literature reporting MPA-induced SAH with widespread multifocal hemorrhage. In this article, we present an exceptionally rare and intriguing case study.
The diagnosis of multiple hemorrhages associated with MPA requires a comprehensive assessment that includes clinical manifestations, laboratory findings, and imaging studies [2]. Key diagnostic tools include ANCA assessment, imaging modalities such as CT angiography (CTA) and magnetic resonance imaging, and histopathological examination of affected tissues. Thorough exclusion of alternative causes of hemorrhage is imperative for accurate diagnosis. The management of multiple hemorrhages secondary to MPA involves a multidisciplinary approach that integrates pharmacotherapy, supportive care, and immunosuppressive therapy [3]. Immunotherapy to control the activity of vasculitis is the cornerstone of treatment [14,19,20]. Additionally, the treatment strategy should incorporate measures to address complications and provide supportive care. Multiple hemorrhage secondary to MPA carries a high mortality rate, primarily due to the severity of the underlying vasculitis and associated complications [5]. Prognosis is influenced by factors such as the extent of organ involvement, response to treatment, and the presence of comorbidities. Early diagnosis and aggressive immunosuppressive therapy significantly improve prognosis, highlighting the importance of timely intervention.
The diagnostic process and assessment of disease activity in this patient can be guided by tangible evidence. Given the complexity of the patient’s clinical presentation, we suspected the possibility of microangiopathic hemolytic anemia (MAHA) and thrombocytopenic purpura (TTP), but the laboratory results showed normal PLTs at the time of the attack and over the next few days, and there was no erythrocyte fragmentation in the peripheral blood smears. Also, the patient’s coagulation results and recovery from the infection did not support the diagnosis of disseminated intravascular coagulation due to severe infection. Although rare, the patient’s nasal bleeding, gastrointestinal bleeding, SAH, and skin purpura indicate disease activity. Gastrointestinal endoscopy ruled out common causes of gastrointestinal bleeding, such as ulcers and tumors, suggesting vasculitis as a potential cause. The simultaneous presentation of SAH and skin purpura further supports the hypothesis of active vasculitis as the underlying etiology. According to literature reports, SAH in patients with AAV can occasionally manifest as aneurysm rupture or intracranial artery dissection [6,13,18,22]. The MRA results in this patient do not show a definite aneurysm. However, MRA test does not appear to completely exclude the possibility of aneurysm. Transfemoral cerebral angiography (TFCA) and CTA could provide more accurate imaging evidence, but they were not performed in this case because of concerns about contrast-induced renal injury[11].
According to current guidelines, the recommended treatment approach for MPA involves a comprehensive strategy to achieve disease remission, prevent relapse, and minimize longterm complications [4]. Induction therapy consists of high-dose GC in combination with immunosuppressive agents such as CTX or rituximab to control inflammation and induce remission [9,15]. Maintenance therapy follows with lower-dose GC, methotrexate, azathioprine, or mycophenolate mofetil to sustain disease control and reduce relapse risk [7,15]. In this case, the patient initially received the standard treatment regimen of GC and CTX. However, the treatment plan was interrupted due to an infection, resulting in inadequate adherence to the prescribed CTX dosage and duration. This may have contributed to inadequate disease control and the occurrence of systemic multiple bleeding. Subsequently, after receiving antimicrobial therapy, GC and rituximab treatment were initiated promptly. However, the efficacy and time to respond to rituximab may vary among individuals. The favorable prognosis observed in this patient may be attributed, in part, to the administration of rituximab. Several factors support this speculation. Firstly, gastrointestinal bleeding improved within a week after the initial rituximab infusion. Additionally, SAH showed noticeable alleviation within a relatively short period. Furthermore, the patient successfully discontinued dialysis, and their SCR levels remained relatively stable.
CONCLUSION
This case study presents a patient diagnosed with MPA who experienced a rare and life-threatening complication characterized by the combination of SAH and widespread bleeding, including gastrointestinal bleeding, nasal bleeding, and skin purpura. The treatment regimen of rituximab and glucocorticoid was helpful for the patient’s remission. Timely recognition and prompt initiation of appropriate immunosuppressive therapy are crucial for managing this exceptionally rare and potentially life-threatening complication.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Informed consent
Informed consent was obtained from the patient.
Author contributions
Conceptualization : TT, HY, LZ; Data curation : LL, AT; Formal analysis : LW, JC; Funding acquisition : TT, JC, LZ; Methodology : ML, SL; Project administration : LZ; Visualization : LL; Writing - original draft : TT; Writing - review & editing : LZ
Data sharing
None
Preprint
None
Acknowledgements
This study was supported by the Chengdu University of Traditional Chinese Medicine Apricot Grove Scholars Program (MPRC2024009), Sichuan Province Traditional Chinese Medicine Research Special Project (2021MS414), the Chengdu Science and Technology Program (2022-YF05-01896-SN), the Chengdu University of Traditional Chinese Medicine Science and Technology Development Funding (Y2024064). The funding agencies had no role in this case report; we received no support from any pharmaceutical company or other industry.
The authors are grateful to the patient for allowing the publication of this case details.
Supplementary materials
The online-only data supplement is available with this article at https://doi.org/10.3340/jkns.2023.0232.
It showing the computed tomography imaging of subarachnoid hemorrhage in the reported patient.