IgG4-related disease characterized by recurrent episodes of transient ischemic attacks: A case report and literature review

doi:10.21203/rs.3.rs-5230464/v1

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IgG4-related disease characterized by recurrent episodes of transient ischemic attacks: A case report and literature review

https://doi.org/10.21203/rs.3.rs-5230464/v1

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IgG4-related disease (IgG4-RD) is a rare fibroinflammatory condition that involves multiple organs in the body. The most commonly affected tissues or organs include lymph nodes, submandibular glands, lacrimal glands and the pancreas. However, a minority of cases can involve the central nervous system (CNS), manifesting as hypertrophic pachymeningitis, cerebral vasculitis, cerebellar infarction and other related conditions. The present case report documents a patient with IgG4-RD with recurrent transient ischemic attacks (TIA), aiming to explore the pathogenesis, clinical features, treatment and prognosis of IgG4-RD complicated with TIAs. By analyzing the present case, the aim was to raise clinician awareness of the potential neurological implications caused by IgG4-RD and to explore its possible pathological mechanisms.

IgG4-related disease

transient ischemic attack

recurrent episodes

glucocorticoids

biologics

IgG4-related disease (IgG4-RD) is a chronic autoimmune-mediated inflammatory and fibrotic disease of unknown origin, which can affect multiple organs and systems throughout the body. In IgG4-RD, the lesions are frequently infiltrated by large numbers of lymphocytes and plasma cells, where the clinical manifestations are complex and varied.¹ When it involves blood vessels (vasculitis), it frequently manifests as thickening of the vessel wall or narrowing of the vessel lumen.² This disease tends to be more common in the middle-aged and elderly population, occur more in men compared with women, but its etiology is unknown. The incidence rate of IgG4-RD is ~0.6 per 100,000 people. Due to its rarity, poor recognition and easy formation of a mass, it is frequently mistaken for a malignant tumor.³ In this disease, there are few cases of combined neurological disorders. The most common of these is IgG4 hypertrophic dural meningitis, with three cases diagnosed as IgG4-associated cerebral vasculitis. In addition, there has been one previous case of IgG4-RD combined with cerebellar infarction ⁴ and one case of IgG4-RD combined with carotid artery dissection accompanying pseudoaneurysm.⁵ The present case reports a patient with IgG4-RD combined with recurrent transient ischemic attacks (TIA).

The patient, a 43-year-old male, was admitted the Affiliated Hospital of Jining Medical College, Shandong Province, in December 2023, with a chief complaint of ‘episodes of immobility of the left side of the limbs for >1 month’. The patient presented with episodic weakness of the left side of the limbs without an apparent inciting cause >1 month ago, accompanied by the blurring of consciousness and gaze with both eyes to the right. Each episode lasted for several minutes with complete symptom resolution, without nausea, vomiting, visual blurring, limb convulsions or incontinence of bowel and bladder. No specific diagnosis or treatment was administered at the time, but these symptoms recurred every 2-3 days. Since the onset of the illness, the patient has been conscious during inter-episode periods, although with poor spirit. The patient's appetite and sleep have been relatively stable and there have been no significant changes in bowel and bladder habits or body weight. In March 2023, the patient was diagnosed with ‘acute anterior wall myocardial infarction’ in Jining Second People 's Hospital due to ‘sudden chest pain’. Coronary angiography was performed on March, 2023, which revealed mid-segment occlusion of the left anterior descending (LAD) artery, 60% stenosis in the mid-segment of the first diagonal branch, 80% stenosis in the proximal segment of the first septal branch and antegrade blood flow was rated as TIMI 0. There were plaques at the ostium and mid-segment of the right coronary artery. The patient then underwent percutaneous transluminal coronary angioplasty (PTCA), thrombus aspiration and intracoronary thrombolysis. The patient was treated medically and showed improvement leading to discharge. After discharge, the patients regularly consumed aspirin enteric-coated tablets, ticagrelor tablets, rosuvastatin calcium tablets, metoprolol succinate extended-release tablets, sacubitril valsartan sodium tablets and lansoprazole enteric-coated tablets. After being discharged from the hospital, the patient continued to suffer from recurrent chest pain and discomfort before being subsequently presented to Affiliated Hospital of Jining Medical College's cardiology department. On April 2023, the patient underwent coronary angiography + PTCA+ coronary stent implantation + coronary Optical Coherence Tomography examination (Fig. 1). Intraoperative findings revealed diffuse stenosis of 80-85% in the mid-proximal segment of the LAD artery after the first diagonal branch, 30-40% stenosis in the mid-segment, 50-60% stenosis in the proximal segment of the first diagonal branch and 80-90% stenosis in the proximal segment of the septal branch. No significant stenosis or obstruction was observed in the left circumflex artery. The mid-segment of the right coronary artery (RCA) showed diffuse stenosis of 30-50%. The patient was discharged from the hospital when his condition improved, before being instructed to regularly take medications, such as Aspirin, Ticagrelor, Rosuvastatin and Metoprolol, with his symptoms under control. On October 2023, the patient presented with recurrent chest pain and consulted the cardiology department of Affiliated Hospital of Jining Medical College again, during which he underwent cardiac ultrasound, which showed the following: i) Ejection fraction, 64%; ii) segmental ventricular wall motion abnormality (anterior wall); iii) left ventricular diastolic dysfunction; and iv) pericardial effusion (small amount). Thyroid stimulating hormone levels were 6.00 mIU/l. Chest CT showed the following (Fig. 2): i) Irregular pleural thickening of the right parietal pleura of the thoracic 7-9 vertebrae; and ii) multiple enlarged lymph nodes in the mediastinum, right axilla and hepatogastric hiatus and retroperitoneum. It was subsequently recommended that the patient undergo lymph node biopsy and enhanced CT scans of the chest and abdomen. However, the patient refused and requested to be discharged. After discharge, the patient was instructed to take medications such as Aspirin, Ticagrelor, Rosuvastatin and Metoprolol regularly, which kept his symptoms were under control. The patient denied history of other chronic diseases, infectious diseases, surgery, trauma and blood transfusions, in addition to denying a history of allergy. The patient has a history of smoking and alcohol consumption, both of which he had been abstained from for 3 years. The patient's father has a history of ‘cerebral infarction and hypertension’. On admission, the physical examination revealed a blood pressure of 128/84 mmHg and a heart rate of 75 beats per min. The internal examination showed no abnormalities. Neurological examination results were unremarkable. Subsequent to admission, on December 2023, C-reactive protein (CRP) levels measured 7.78 mg/l. For liver function, total protein measured 73.6 g/l and albumin measured 37.9 g/l. On January 2024, for hepatic function, total protein measured 63.7 g/l and albumin measured 34.9 g/l. Renal function: Urea, 2.60 mmol/l; and uric acid 195 µmol/l; blood sedimentation, 16.00 mm/h; IL-6, 5.24 pg/ml. Total lymphocyte subpopulation: B-lymphocyte ratio (CD19+), 4.34%; T-helper lymphocytes (CD3+CD4+)/total lymphocytes, 55.00%; T-helper lymphocytes/T-suppressor lymphocytes, 2.91; and immunoglobulin subclass quantitative determination of IgG4 (scattering turbidimetric method), 14 g/l. The rest of the indicators were not abnormal. On January 2024, the patient underwent a video electroencephalogram (EEG) which showed mild abnormalities (Fig. 3). There was normal background activity, with a small number of slow waves and a small number of fast waves interspersed with a full-conductance medium- and long-range α rhythm 9-10 Hz. Multiple episodes were monitored during the seizure period, all of which occurred during wakefulness and were characterized by blurred consciousness, unresponsiveness to calls, weakness of the left side of the limbs and gaze of both eyeballs to the right side. During the same period, the EEG showed a background of awake EEG, with medium-amplitude slow waves of 4-5 Hz in the right leads, which gradually slowed down to a medium-amplitude slow wave of 2-2.5 Hz and lasted for 1-2 min, restoring the background of awake EEG. Ultrasound examination on January 2024 (Fig. 4) revealed multiple hypoechoic nodules on the bilateral neck and bilateral supraclavicular region. In addition, enlarged lymph nodes could be considered and the inhomogeneous enlargement of bilateral submandibular glands were observed. IgG4-associated Possibility of submandibular inflammation. There were multiple hypoechoic nodules in bilateral axilla and right subclavian region, with enlarged lymph nodes considered. There were also multiple hypoechoic nodules in bilateral inguinal region, where enlarged lymph nodes were considered. Pathological results on January 2024 showed the following (Fig. 5): In the punctured tissue from the right axillary lymph node, a large number of plasma cell infiltration was seen in lymphatic tissues and combined with the relevant tests, the likelihood of lgG4-RD was high. Immunohistochemical tests showed CD38 (multiple +), CD138 (multiple +), IgG (multiple +) and IgG4 (multiple +, >50/high-powered field) expression. Enhanced MRA images are shown (Fig. 6), which suggested thickening of the wall of the M1 segment of the left middle cerebral artery, narrowing of the lumen, local occlusion and significant enhancement of the wall after enhancement in a circumferential and eccentric manner. In addition, MRA images suggested thickening of the wall of the left middle cerebral artery M1 section, without obvious plaque hemorrhage and lipid deposition. 3D time of flight-MRA images suggest segmental narrowing of the lumen of the left middle cerebral artery M1 with local occlusion. PWI-CBV suggests that the perfusion of the left middle cerebral artery is lower compared with that of the contralateral side. The patient was subjected to standard clinical practice. Prednisone acetate 40 mg qd and other symptomatic supportive therapy was started on January 2024. Based on the information provided by the patient, in accordance with the comprehensive diagnostic criteria for lgG4-RD established in Japan in 2020,⁶ four criteria were met for diagnosing IgG4-RD. According to the IgG4-RD diagnostic criteria established by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2019.⁷ The patient's serum IgG4 was 14g/l, ≥5 times the upper reference limit with a score of 11, the bilateral submandibular gland involvement had a score of 6, dense lymphoid and plasma cell infiltration was seen on the pathology picture with a score of 4, resulting in the cumulative weighted score of 21>20. Therefore, the diagnosis was IgG4-RD. During the period of hormone therapy, the patient's episode frequency was significantly reduced, where the patient requested automatic discharge after 2 days, refusing further treatment. The patient was followed up >1 months after discharge, where the patient's family said that the patient had not experienced any further episodes of TIA since discharge from the hospital. On February 2024, the serum IgG4 level decreased from 14 g/l before treatment to 8.86 g/l and the hormone dosage was now reduced to 30 mg qd, which resulted in good control of the disease. A review of routine blood tests, electrolytes, C-reactive protein, erythrocyte sedimentation rate and other indicators revealed that they were generally normal and no adverse reactions were observed. In May 2024, the patient 's igG4 quantitative determination index was 3.91 g / L, which had been reduced to the normal range.Currently, the subject remains under observation in follow-up.

According to the lgG4-RD diagnostic criteria established by the American College of Rheumatology ( ACR ) / European League Against Rheumatism ( EULAR ) in 2019 and the lgG4-RD comprehensive diagnostic criteria established by Japan in 2020, the patient has been clearly diagnosed as IgG4-RD. IgG4-RD is an inflammatory disease involving multiple organs, but central nervous system involvement is rare. At present, there is no literature reported IgG4-RD combined with TIA.Our report not only documents the patient's clinical manifestations but also delves into the potential pathological links between IgG4-RD and TIA. The exploration of this association is of significant importance for understanding the vascular involvement mechanism in IgG4-RD.

The patient was first admitted to the hospital with recurrent weakness of the left side of the limbs, accompanied by blurred consciousness, right-sided gaze of both eyes and shallow left nasolabial folds, which lasted for ~5 min each time in complete remission, and which could be recalled by following up with the patient after the remission. The patient presented with left-sided limb weakness at the time of the attack, indicating that the lesion involved the right pyramidal fasciculus. Concurrently, the patient exhibited a horizontal gaze of both eyes to the right, indicative of supranuclear oculomotor paralysis. This was presumed to be localized to either the right frontal lateral visual center (posterior part of the middle frontal gyrus) or left lateral visual center of the pons (Paramedian pontine reticular structure). Based on the principle of monism, it was finally located in the right frontal lobe as an involvement of the right middle cerebral artery supply area. The patient's enhanced MRA showed multiple arterial wall thickening and lumen narrowing and cerebral atherosclerosis with possible plaque formation. The process of atherogenesis is influenced by multiple risk factors, including high cholesterol, hypertension and diabetes mellitus, where atherosclerosis typically begins with endothelial cell damage. During the early stages of atherosclerosis, endothelial cells are damaged, which then release adhesion molecules, which attract inflammatory cells (such as macrophages and T-lymphocytes) to accumulate in the vessel wall, releasing inflammatory mediators (such as IL-6), leading to an inflammatory response. IL-6 can activate endothelial cells and exacerbate endothelial cell damage, which in turn promotes plaque formation. Aggregation of leukocytes, including monocytes and T lymphocytes, and accumulation of other inflammatory mediators during the inflammatory response can also contribute to plaque formation. After plaque formation, inflammatory cells in the plaque, such as macrophages, are able to phagocytose oxidized low-density lipoproteins and form foam cells.⁸ These foam cells then release pro-inflammatory cytokines, leading to a further increase in local inflammation. Inflammation in the plaque also involves other immune cells, such as T cells and B cells. The activity of these cells may lead to an aggravation of the inflammatory response within the plaque, ultimately leading to plaque destabilization. Unstable plaques are more likely to rupture, releasing material from the plaque into the lumen of the blood vessel, triggering the formation of blood clots that block the cerebral blood vessels, which can lead to the onset of a TIA and then formation of an ischemic cerebral infarction.⁹ Patients with IgG4-RD typically exhibit increased serum erythrocyte sedimentation rate, CRP and IL-6 levels, suggesting an inflammatory pathological basis.¹⁰ Siddiquee et al ¹¹ previously demonstrated that atherosclerosis does enhance the inflammatory response to IgG4-RD. IL-6 can also be produced by fibroblast subpopulations, which in turn is capable of stimulating fibroblast proliferation and promoting fibrous tissue formation .¹² Zong et al ¹³ showed that IL-6 and fibroblasts may be the cause of pathogenic center formation and fibrosis in the development of IgG4-RD.

IgG4-RD is readily treatable and responds rapidly to glucocorticoids, rendering steroids recommended as the first-line treatment of this condition. However, long-term steroid therapy is typically required to maintain remission,³ since the majority of patients will relapse after tapering or discontinuation.¹⁴ In relapsed or rare steroid-refractory cases, biologically targeted therapy or disease-improving antirheumatic drugs can be added to steroids.¹⁵ Rituximab, which is an anti-CD20 chimeric antibody that is designed to clear B cells through complement-mediated and antibody-dependent cytotoxicity, is an important drug for the treatment of complex, frequently relapsing, steroid-dependent diseases.¹⁶ B-cell depletion therapy with rituximab has been shown to be effective in inducing remission for the maintenance therapy of IgG4-RD.¹⁴ B-cell depletion not only leads to rapid clinical improvement in the majority of patients but can also maintain long-term remission by avoiding steroid-related toxicity.¹⁷ Obelizumab is a bispecific antibody that binds specifically to two different target molecules, namely Fcγ receptor IIB (FcγRIIB) and CD19, on the surface of B cells. FcγRIIB is expressed by B cells and is a low-affinity IgG receptor on the surface of B cells, making it a reversible inhibitor of B cells. By targeting FcγRIIB and CD19, obelizumab can inhibit the activation and proliferation of B cells whilst removing autoantibody-secreting plasma cells.¹⁸ Perugino et al ¹⁹ demonstrated that the majority of patients were able to achieve the complete remission of their clinical symptoms after 2 months of treatment with obelizumab alone. Belimumab, as an anti-B-cell activating factor monoclonal antibody, has been reported to modulate B cells and to inhibit IgG4-RD episodes, whilst reducing GC doses.²⁰ However, only three patients with IgG4-RD and comorbid SLE have been treated with belimumab, all of which resulted in reduced serum IgG4 levels after treatment, suggesting that belimumab is a promising GC-preserving agent for IgG4-RD.²¹ Tocilizumab is a humanized anti-IL-6 receptor antibody. IL-6 and fibroblasts are involved in the formation of IgG4-RD. Therefore, the use of inhibitors to block the IL-6-associated inflammatory response or to inhibit the proliferation of fibroblasts may prove beneficial for the treatment of IgG4-RD.²² Dupilumab (DUP) is a fully humanized monoclonal antibody that binds to the IL-4 receptor α subunit and is the first biologic to target IL-4R, which induces the conversion of B-cells into plasma cells by stimulation of follicular helper T-cells (Tfh-cells), causing them to secrete IgG4. Therefore, type 2 helper T (Th2) cells can be one of the therapeutic targets for IgG4 -RD.²³ Masatoshi et al ²⁴ previously demonstrated through a clinical trial of patients with IgG4-RD that DUP can improve their condition and that it is safer compared with the long-term use of GC for treating IgG4-RD patients. Although it has been shown that certain IgG4-RD patient conditions will gradually improve after treatment with biologics, there is a lack of large-scale evidence for confirming their efficacy and safety.

In conclusion, to the best of our knowledge, IgG4-RD involvement of the CNS is clinically rare, whereas lgG4-RD manifested by recurrent TIA is even rarer and has not been reported to date. Because of the diverse clinical manifestations of IgG4-RD, large variations in serological indices and imaging, where the diagnosis is mainly based on pathological biopsy as the gold standard, clinical diagnosis of IgG4-RD is difficult. There is no uniform or effective treatment methods with different prognoses. Therefore, the clinician should strengthen the understanding of this disease gradually, further improve the diagnostic criteria of this disease and formulate effective treatment plans, to provide a more accurate prognosis to such patients

Acknowledgements

Not applicable.

Funding

The present report was funded by Jining Key R&D Programme Project Fund (grant nos. 2023YXNS091 and 2023YXNS255) and Shandong Key R&D Programme Project Fund (grant no. 2023YXNS108).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

YTH, RS and HY designed the study. XC, QXK and YLW, collected the data. YTH, RS and QXK contributed to data analysis and interpretation. YTH and HY drafted the manuscript; XC and RS contributed to the revision. YTH and HY confirm the authenticity of all raw data. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by The Ethics Committee of The Affiliated Hospital of Jining Medical University (approval no. 2024-08-C009; Jining, China.The ethical approval date is August 21, 2024).

Patient consent for publication

Written informed consent was obtained from the patient for the publication of this case report and the accompanying images.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

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IgG4-related disease characterized by recurrent episodes of transient ischemic attacks: A case report and literature review

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