Spinal cord compression by cystic IgG4-related spinal pachymeningitis mimicking neurocysticercosis: a case report.

BACKGROUND: To report a case of IgG4-related pachymeningitis presenting with cystic lesions mimicking neurocysticercosis. CASE PRESENTATION: A 40-year-old female patient with tetraparesis, dysphagia and dysphonia was evaluated with clinical examination, magnetic resonance imaging, and meningeal biopsy. Magnetic resonance imaging (MRI) revealed diffuse pachymeningeal enhancement involving the cranial, cervical, thoracic, and lumbar segments with spinal cord compression and cystic lesions. CSF immunology was initially positive for cysticercus cellulosae. After disease progression a meningeal biopsy was compatible with IgG4 related disease. The patient had partial response to rituximab and needed multiple surgical procedures for spinal cord decompression and CSF shunting. CONCLUSIONS: This case highlights the possibility of IgG4-related disease in patients with diffuse pachymeningitis causing spinal cord compression, even with cystic lesions on MRI. Diagnosis of IgG4-related pachymeningitis is paramount due to the possibility of treatment response to immunotherapy, particularly to anti-CD20 agents.

Beyond diagnosis: exploring the significance of IgG4+ plasma cell count through immunostaining in IgG4-related disease.

OBJECTIVES: To evaluate whether the grade of IgG4+ plasma cell infiltration in biopsies is associated with clinical or serologic outcomes in IgG4-RD. METHODS: We included 57 patients with biopsy proven IgG4-RD according to the Comprehensive Diagnostic Criteria and/or the 2019 ACR/EULAR Classification Criteria. We collected histological, clinical (disease duration, phenotype, remission and relapses) and serological variables. RESULTS: 29 (50.9%) patients were men, mean age 49.9 years, with a median disease duration of 22 months. The distribution among clinical phenotypes were 14% pancreato-hepato-biliary, 12.3% retroperitoneal/aortic, 29.8% head and neck-limited, 29.8% Mikulicz/systemic and 14% undefined. Thirty-nine patients had a proliferative and 18 a fibrotic phenotype. Most biopsies were from lacrimal gland, lymph node, pancreas, orbit, kidney, retroperitoneum and thyroid gland. Thirty-nine (68.4%) patients had <100 IgG4+ plasma cells/HPF and 18 (31.6%) ≥100 IgG4+ plasma cells/HPF. Patients with ≥100 IgG4+ plasma cells/HPF were more likely to belong to the pancreato-hepato-biliary and the proliferative phenotypes, had fewer relapses and a higher remission rate. On multivariate analysis, the OR for remission at last follow-up was 6.7, 95% CI 1.1-4.42, p=0.03. The log-rank test showed a difference in relapse-free survival between the two groups (HR 2.6, 95% CI 1.2-5.6, p=0.01). According to the ROC analysis, patients with more than 61 IgG4+ plasma cells were less likely to relapse. CONCLUSIONS: A count of ≥100 IgG4+ plasma cells/HPF may identify patients with a proliferative phenotype, fewer relapses and a higher remission rate.

IgG4-related disease-rare but you should not forget it.

Immunoglobulin G4-related disease is a systemic immune-mediated disease with insidious evolution characterized by fibroinflammatory lesions over virtually any organ system. Despite the remarkable progression of knowledge, its etiology remains undefined. Due to its relapse-remitting pattern, it could accumulate irreversible damage, increasing comorbidities and mortality. This paper emphasizes key concepts for diagnosing and treating patients with this condition.

Nefropatía por enfermedad relacionada a IGG4 / Nephropathy due to IGG4-related disease

IgG4-related disease (ER-IgG4) is a group of systemic fibro-inflammatory diseases, whose renal involvement is rare and difficult to diagnose. Diagnosis is usually made by serological and histological studies. Treatment is based on systemic corticosteroids. The renal prognosis is determined by the patient's comorbidities and the degree of fibrosis in the renal biopsy. We present the case of an elderly patient with exacerbated chronic kidney disease, whose study showed nephropathy associated with ER-IgG4.

La enfermedad relacionada a IgG4 (ER-IgG4) es un grupo de enfermedades fibro-inflamatorias sistémicas, cuya afectación renal es poco frecuente y de difícil diagnóstico. Habitualmente el diagnóstico se realiza mediante estudios serológicos e histológicos. El tratamiento se basa en corticoides sistémicos. El pronóstico renal está determinado por las comorbilidades del paciente y el grado de fibrosis en la biopsia renal. Se presenta el caso de un paciente adulto mayor con enfermedad renal crónica reagudizada, cuyo estudio demostró nefropatía asociada a ER-IgG4.

Adult ocular adnexal xanthogranulomatous disease associated with immunoglobulin G4-related disease: an unusual association.

Adult-onset xanthogranuloma (AOX) and immunoglobulin G4-related disease (IgG4-RD) are uncommon fibrosing conditions that may exhibit localized ocular manifestations and occasionally systemic symptoms. These conditions exhibit overlapping clinical and histological features, suggesting a potential correlation between them, although their exact relationship remains unclear. This paper presents the case of a black male patient exhibiting typical histological indications of both AOX and IgG4-RD. The patient responded positively to corticosteroid treatment.

Performance of the 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease in a Latin American Cohort.

BACKGROUND/OBJECTIVE: The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria (2019 AECC) for IgG4-related disease (IgG4-RD) is considered a significant advancement in the study of this condition. Most studies evaluating their performance have focused on White and Asian patients, leaving a knowledge gap regarding Latin American populations. Therefore, this study aimed to assess the performance of the 2019 AECC for IgG4-RD in a cohort of Latin American patients. METHODS: A multicenter medical records review study was conducted, involving centers from Argentina, Chile, Mexico, Peru, and Uruguay. Data on IgG4-RD patients and mimicker conditions were collected through a standardized online form. The criterion standard for diagnosing IgG4-RD was based on the fulfillment of the Comprehensive Diagnostic Criteria for IgG4-RD and/or the Consensus Statement on Pathology. The 2019 AECC was retrospectively applied. RESULTS: We included 300 patients, with 180 (60%) having IgG4-RD and 120 (40%) having mimicker conditions. The 2019 AECC had a sensitivity of 66.7% and a specificity of 100%. Sensitivity increased to 73.3% when disease-specific autoantibody items were removed, without affecting specificity. The true-positive cases had more involved organs, a higher availability of biopsy results, and were more likely to belong to the Mikulicz/systemic and proliferative phenotypes. CONCLUSIONS: The use of the 2019 AECC for IgG4-RD in a Latin American population confirms its high specificity in excluding those without the disease. The presence of concomitant autoimmune diseases and clinically nonsignificant disease-specific autoantibodies excludes a significant number of patients from fulfilling the criteria.

IgG4-Related Disease of Temporal Bone Presenting as Unilateral Mastoiditis and Cerebral Thrombosis in a 22-Year-Old Man.

BACKGROUND Immunoglobulin G4-related disease (IgG4-RD) is a rare autoimmune disease that can affect multiple organs and manifest itself as a mass at any region of the body. Due to its several differential diagnoses, investigation and treatment are still challenging. Therefore, imaging, serology, and histopathology are required to confirm the diagnosis. The involvement of the temporal bone is an uncommon presentation, often mistaken for malignancy, with vague symptoms. Therefore, we present a 22-year-old Brazilian man, diagnosed with IgG4-related disease, manifesting with unilateral mastoiditis, sensorineural hearing loss, cerebral venous sinus thrombosis, and a mass in the left temporal bone. CASE REPORT A 22-year-old Brazilian male patient first presented with coughing and precordialgia. Chest scans showed pleural effusion and diffuse areas of ground-glass opacity. A year later, the patient developed severe headache, along with aural fullness, facial pressure, and otorrhea. Imaging detected cerebral thrombosis with failure in the filling of the transverse and left sigmoid sinuses and pachymeningeal thickening in the right cerebral hemisphere, with contrast enhancement. Pure tone audiometry showed thresholds consistent with severe sensorineural hearing loss in the left ear. The patient underwent mastoidectomy with removal of large amounts of inflammatory tissue that were sent to histopathological analysis with compatible signs of IgG4-RD. Corticosteroids and rituximab completed the treatment. CONCLUSIONS Early recognition and appropriate treatment of IgG4-RD are imperative to avoid complications and serious irreversible organ damage. This report has presented an atypical case of IgG4-RD of the left temporal bone that was diagnosed and managed according to current guidelines.

Hypertrophic pachymeningitis due to IgG4-related disease (RD-IgG4). A case report.

INTRODUCTION: Hypertrophic pachymeningitis (HP) is a clinico-radiological entity characterized by a thickening of the dura mater that may be focal or diffuse and manifested by a variety of neurological syndromes. Aetiologically, it is classified as infectious, neoplastic, autoimmune, and idiopathic. Many of these formerly idiopathic cases have been shown to fall into the spectrum of IgG4-related disease. OBJECTIVE: To describe the case of a patient attended for neurological involvement due to hypertrophic pachymeningitis with initial diagnosis of inflammatory myofibroblastic tumour and final diagnosis of IgG4-related disease. CASE: A 25-year-old woman with neurological symptoms of 3 years' evolution characterized initially by right hypoacusis, evolving with headache and diplopia. Magnetic resonance imaging (MRI) of the encephalon showed pachymeningeal thickening with involvement of vasculo-nervous structures in the tip of the cerebellum, cavernous sinus, ragged foramen, and optic chiasm. The patient presented for consultation with the result of an incisional biopsy that reported a proliferative lesion combining fibrous elements of fascicular or swirling arrangement with collagenized streaks with dense, lymphoplasmacytic infiltrate and some macrophages, with negative staining for ALK 1, with a diagnosis of inflammatory myofibroblastic tumour. Due to suspicion of IgG4-related disease (IgG4-RD) the biopsy was sent for review and pertinent complementary studies were requested. BIOPSY REVIEW: Non storiform fibrosis, predominantly lymphoplasmacytic infiltrate, histiocytes, and polymorphonuclear infiltrate in sectors, without granulomas or atypia. Staining for germs negative. Immunohistochemistry with 50-60 IgG4+/HPF cells and range of 15%-20%, CD68+ in histiocytes, CD1a-, S100-. The patient presented deterioration of visual acuity due to ophthalmic nerve involvement, so glucocorticoid treatment was started in pulses and rituximab with regression of symptoms and imaging improvement of the lesions. CONCLUSION: HP is a clinical imaging syndrome with variable symptoms and aetiologies that poses a diagnostic challenge. In this case the initial diagnosis was inflammatory myofibroblastic tumour, which is a neoplasm of variable behaviour, locally aggressive, and can metastasize; it is one of the main differential diagnoses of IgG4-related disease because they share anatomopathological features, including storiform fibrosis. IgG4-RD is an immune-mediated condition that can have single or multiple involvement. Its diagnosis is complex when it presents with single organ involvement or in non-typical organs (CNS, meninges) in which data are scarce, as in the case of our patient with single organ involvement of the CNS. Although there are classification criteria to guide non-specialists in the diagnosis, the sum of the clinical picture, imaging, laboratory, pathological anatomy, and immunohistochemistry will always be evaluated together for a definitive diagnosis.

Tear levels of IL-7, IL-1α, and IL-1ß may differentiate between IgG4-related disease and Sjögren's syndrome.

We aim to assess and compare a cytokine and chemokine profile in tears from patients with IgG4-related disease (IgG4-RD) and Sjögren's syndrome (SS), and to see if this profile could aid in differentiating these two diseases. We included 10 patients with IgG4-RD who met the Comprehensive Diagnostic Criteria for IgG4-RD and 17 patients who met the AECG criteria for primary SS. The Schirmer-I test was carried out using two standardized sterile tear strips, which were then immediately frozen at - 86 °C until assayed. The tears were extracted from the strips after they had been defrosted using a buffer containing 0.5 M NaCl and 0.5% Tween-20. The amounts (pg/ml) of the following cytokines and chemokines were then measured using luminometry: IFN-γ, TNF-α, G-CSF, IL-1-α, IL-1ß, IL-4, IL-7, IL-12p40, IL-12p70, IL-13, IL-17A, CCL2, CCL3, CCL4, CCL11, and CXCL10. In the IgG4-RD group, seven patients had lacrimal gland involvement, five had dry eye symptoms, and six had a positive Schirmer-I test. In the SS group, 16 (94.1%) had dry eyes and all had a positive Schirmer-I test. We were able to differentiate between both diseases using levels of IL-7, IL-1α, and IL-1ß; in particular, the IL-7/IL-1α and IL-7/IL-1ß ratios had the best discriminatory potential, with cut-off values of 0.32 (AUC: 0.93, sensitivity: 94%, specificity: 80%, p = 0.0003) and 12.55 (AUC: 0.96, sensitivity: 94%, specificity: 90%, p = 0.0001), respectively. Our results suggest that IL-7, IL-1α, and IL-1ß tear levels could help differentiate IgG4-RD from SS. Key Points • The lacrimal gland is frequently involved in IgG4-RD and SS. This characteristic makes both diseases mimics of one another. • Patients with IgG4-RD and SS have different profiles of tear cytokines and chemokines. • Tear IL-7, IL-1α, and IL-1ß levels may serve as helpful biomarkers in separating IgG4-RD from SS.

Enfermedad relacionada a IgG4. Serie clínica de pacientes chilenos / IGG4-related disease. Report of 52 patients

BACKGROUND: IgG4-related disease (IgG4 RD) is an immune-mediated fibro-inflammatory disorder, with tissue infiltration of IgG4+ plasma cells. It causes pseudotumors, tumors, and a wide spectrum of clinical manifestations. AIM: To report the clinical, laboratory, histopathological and treatment characteristics of a group of Chilean patients with IgG4 RD. MATERIAL AND METHODS: Review of medical records of 52 patients aged 18 to 76 years with IgG4 RD seen at six medical centers. RESULTS: Elevated IgG4 serum levels (> 135 mg/dl) were found in 18 of 44 (41%) patients. There was histological confirmation of the disease in 46 patients. The most common sites of involvement were lungs, eyes and kidneys. Eighteen (35%) patients had only one organ involved, 34 (65%) patients had two organs and 13 (25%) patients had three or more organs. The involvement of two organs was significantly more common in men (p < 0.05). In patients with only one organ involvement, the most frequent location was orbital and meningeal. All patients with kidney or lung disease had multiorgan involvement. All patients received corticosteroid therapy, 67% synthetic immunosuppressants, and 16% rituximab. CONCLUSIONS: ER-IgG4 can affect any tissue. Multiorgan involvement was more common in this series, with preference for lungs, eyes and kidneys. An excellent response to steroids is characteristic of the disease, but with a high relapse rate that requires additional immunosuppression.

Oral and maxillofacial manifestations of IgG4-related disease: A clinicopathological study.

BACKGROUND: IgG4-related disease is a fibroinflammatory and immune-mediated condition, which has extremely variable clinical manifestations. In this study, we aim to investigate the clinicopathological features of IgG4-related disease involving the oral and maxillofacial region. METHODS: Cases of IgG4-related disease manifesting in the oral and maxillofacial region were retrieved from three Brazilian institutions. Clinical and serological data were obtained from the patients' medical charts, while microscopic and immunohistochemical findings were revised by oral pathologists. Diagnosis followed the American College of Rheumatology/European League against Rheumatism criteria. RESULTS: Seven patients diagnosed with IgG4-related disease were included in this study. Women were affected in all analysed cases, with a mean age of 55.4 years. Two patients presented with the clinical involvement of more than one oral and maxillofacial anatomic site. Therefore, our sample comprised nine oral and maxillofacial anatomic sites affected by IgG4-related disease. The submandibular gland was affected in four cases, the tongue and the parotid gland in two cases each, and the palate in one case. In a few cases, exploratory lower lip biopsy was used as a diagnostic approach. A moderate-to-severe lymphoid infiltrate containing plasma cells and lymphocytes, with an increased IgG4/IgG ratio, was common. Treatment varied and steroids were the most frequently used (57.4%). Six patients remained alive, while one died from unknown causes. CONCLUSION: Although major salivary glands are commonly affected by IgG4-related disease, the oral cavity can also be involved, and lower lip biopsy may be an auxiliary diagnostic tool.

Immunoglobulin G4-related retroperitoneal fibrosis.

Some patients diagnosed with idiopathic retroperitoneal fibrosis could be reclassified as IgG4-related disease (IgG4-RD). Classification criteria have not been uniform and prevalence of IgG4-related retroperitoneal fibrosis (IgG4-RPF) is unknown in our region. We aimed to describe IgG4-RPF frequency relying on criteria published recently and comparing clinical, histopathologic and radiologic features with non-IgG4-RPF. From January, 2005 to December, 2020, nineteen adults with histopathologic diagnosis of idiopathic retroperitoneal fibrosis were included in a dynamic retrospective cohort at Hospital Italiano de Buenos Aires. Pathology slides were reviewed and immunohistochemistry was performed and assessed for each case. We used classification criteria described in 2019 American College of Rheumatology/European League Against Rheumatism to identify IgG4-RD cases. Ten of 19 patients met criteria for IgG4-RPF. Median age was similar in two subsets (61 versus 55, p = 0.2) and both had male predominance. Three out of 10 patients (p = 0.2) featured other manifestations of IgG4-RD in the IgG4-RPF group, and periaortic fibrosis was the most significant finding in images (p = 0.01). Corticosteroids were mostly used as therapy, followed by azathioprine and rituximab. Most patients did not receive specific treatment. IgG4-RPF patients had dense lymphocytic infiltrate and 8 out of 10 showed storiform fibrosis (p = 0.02). IgG4+ cells/hpf and IgG4/IgG ratio were significantly higher (p = 0.01). Over half of the patients in our cohort met the criteria of IgG4-RPF. New criteria may harmonize the identification of IgG4-RD. As IgG4-RD may be reversible at initial stages, these findings may lead to early recognition, treatment and integral follow-up.

Muchos pacientes con diagnóstico de fibrosis retroperitoneal idiopática (FRI) pueden ser reclasificados como enfermedad relacionada con IgG4 (ER- IgG4). Los criterios diagnósticos no han sido uniformes y la frecuencia de fibrosis retroperitoneal relacionada con IgG4 en nuestra región es desconocida. El objetivo fue describir la frecuencia de ER-IgG4 en pacientes clasificados como FRI y comparar características clínicas, histopatológicas y de laboratorio con aquellos que no reunían criterios de la enfermedad. Se incluyeron 19 adultos en un estudio de cohorte retrospectiva dinámica con diagnóstico anatomopatológico de FRI, en el Hospital Italiano de Buenos Aires, desde enero de 2005 hasta diciembre de 2020. Se revisaron las biopsias y se realizó inmun ohistoquímica en cada una. Se consideró caso al paciente que reunía los criterios de la American College of Rheumatology/European League Against Rheumatism 2019. Diez pacientes reunieron criterios de ER-IgG4. La mediana de edad fue similar en ambos grupos (61 vs. 55, p = 0.2) y en ambos hubo predominio masculino. Tres de 10 pacientes (p = 0.2) tuvieron otras manifestaciones de ER-IgG4 y la fibrosis periaórtica fue el hallazgo más significativo en los estudios por imágenes (p = 0.01). Los corticoides fueron las drogas más utilizadas seguidos por azatioprina y rituximab, pero la mayoría no recibió tratamiento específico. Todos los pacientes con fibrosis retroperitoneal relacionada con IgG4 presentaron infiltrado linfocitario denso y 8/10 fibrosis estoriforme (p = 0.01), así como las células IgG4+/hpf y ratio IgG4/IgG fueron significativamente mayores (p = 0.01). Más de la mitad de los pacientes con FRI cumplieron criterios de ER-IgG4. Los nuevos criterios diagnósticos podrían contribuir a homogeneizar la identificación de ER-IgG4. Dado que esta enfermedad puede ser reversible en estadios tempranos, estos resultados promueven aumentar el conocimiento de la entidad para tratamiento precoz y seguimiento integral.

IgG4-related lung disease as a differential diagnosis of a lymphoproliferative disease: atypical presentation of an atypical disease.

IgG4-related disease (IgG4-RD) is an immunomodulated inflammatory disease that usually affects the pancreas and parotid glands. Although lung involvement is rare, it has been recently reported and could mimic various other diagnoses. We present a case of IgG4-RD whose symptoms and images raised the suspicion of a malignant lymphoproliferative lung neoplasm. It is imperative to differentiate both diseases, since their treatment and prognosis vary.

IgG4-Related Disease: Mimickers and Diagnostic Pitfalls.

BACKGROUND: The tendency of IgG4-related disease (IgG4-RD) to form pseudotumors, as well as its multisystemic nature, makes it the perfect mimicker of many conditions. Moreover, some clinical, serological, radiological, or histological features of the disease might be shared with some mimickers.Recently, 4 clinical phenotypes have been identified, and patients grouped in each phenotype have distinctive demographic, clinical, and serological features and outcomes, and, as expected, for each phenotype, a set of differential diagnoses should be considered. SUMMARY OF THE LITERATURE: The main differential diagnoses for the pancreato-hepato-biliary phenotype are pancreatic adenocarcinoma and cholangiocarcinoma. Other differential diagnoses include type 2 autoimmune pancreatitis and primary sclerosing cholangitis. In patients with retroperitoneal/aortic phenotype, inflammatory conditions such as idiopathic retroperitoneal fibrosis and large vessel vasculitides should be ruled out, and most of the time, a biopsy will be needed to exclude malignancies. In head and neck limited phenotype, autoimmune conditions (eg, granulomatosis with polyangiitis, Graves orbitopathy, sarcoidosis), malignancies, and histiocytosis should be ruled out, whereas the main differential diagnoses of the Mikulicz/systemic phenotype are Sjögren syndrome, granulomatosis with polyangiitis, and multicentric Castleman disease. CONCLUSIONS: Approaching a patient with probable IgG4-RD through a clinical phenotype framework will ease the diagnostic algorithm and facilitate the prompt recognition of the disease. There are certain clinical, serological, radiological, and histological features in each clinical phenotype that, if present, increase the likelihood that a patient may have IgG4-RD instead of the mimicker condition. Those clues that point toward IgG4-RD diagnosis should be actively sought in the workup of patients.