Küttner's Tumor and Autoimmune Pancreatitis as Metachronous Manifestations of IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan, fibro-inflammatory condition that presents with painless organ swelling, lymphoplasmacytic infiltration, and obliterative phlebitis, often showing a favorable response to corticosteroid therapy. The most affected organs include the pancreas, kidneys, retroperitoneum, lacrimal glands, and salivary glands. Diagnosis relies on serological, imaging, and histopathological findings, with glucocorticoids as the primary treatment. Despite its reversible nature and good prognosis in many cases, long-term complications such as organ dysfunction or malignancy can still occur. International collaborative efforts have enhanced the understanding, diagnosis, and management of IgG4-RD, emphasizing the importance of comprehensive diagnostic criteria and appropriate therapeutic strategies. Herein, we present an interesting case of a geriatric male who was referred to our clinic because of concern for pancreatic cancer. We diagnosed the patient with autoimmune pancreatitis, a manifestation of IgG4-RD. The patient experienced a dramatic response to steroid therapy and is currently on maintenance therapy.

Idiopathic hyalinizing fibrosclerosis: A systemic steroid-resistant condition distinct from IgG4-related disease.

Since the concept of IgG4-related disease (IgG4-RD) was proposed, that diagnosis has been considered in idiopathic fibroinflammatory diseases in various organs, particularly in cases with multi-organ involvement. We have recently encountered three cases of fibrosing disease of uncertain etiology with shared microscopic appearances. Case 1 (56-year-old man) had an irregular mass at the base of mesentery. Case 2 (29-year-old woman) presented with obstructive jaundice due to an ill-defined mass at the hepatic hilum and two lung nodules. Case 3 (53-year-old man) had multiple solid nodules in the mediastinum, peritoneum, retroperitoneum, and mesentery; he also had diffuse irregular narrowing of the intra- and extra-hepatic bile ducts in keeping with sclerosing cholangitis. Serum IgG4 concentrations were not elevated. Biopsies from the nodular lesions showed extensive hyalinizing fibrosis with an only focal lymphoplasmacytic infiltrate. Thick collagenous bundles are arranged in an irregular or partly whorl pattern. Typical storiform fibrosis or obliterative phlebitis was not observed. The number of IgG4-positive plasma cells was <10 cells/high-power field; the ratio of IgG4/IgG-positive plasma cells was <30%. After the histological diagnosis of sclerosing mesenteritis, pulmonary hyalinizing granuloma, and mediastinal fibrosis was made, they were treated with a trial of steroids, but none showed a significant response. In conclusion, a hyalinizing fibrotic condition can occur at various anatomical sites. They have shared microscopic findings, and are steroid-resistant. Although the clinical presentation may mimic IgG4-RD, the two conditions are likely distinct. We would propose a diagnostic term of 'idiopathic hyalinizing fibrosclerosis' for this under-recognized, rare, systemic condition.

Coronary periarteritis and pericarditis are rare but distinct manifestations of heart involvement in IgG4-related disease: a retrospective cohort study.

BACKGROUND: The heart can be involved in immunoglobulin (Ig)-G4-related disease (IgG4-RD). This study aimed to summarize the clinical features and efficacy of treatment for IgG4-RD patients with heart involvement. METHODS: We conducted a retrospective study enrolling 42 IgG4-RD patients with heart involvement from the IgG4-RD cohorts of the Peking Union Medical College Hospital and Beijing An Zhen Hospital, from 2010 to 2022. Clinical, laboratory, radiological data were collected, and treatment responses to glucocorticoids and immunosuppressants were analyzed. RESULTS: IgG4-related cardiac involvement is a rare part of the IgG4-RD spectrum. The incidences of coronary periarteritis and pericarditis were 1.2%(13/1075) and 3.1%(33/1075), respectively in our cohort. Valvular disease possibly related to IgG4-RD was detected in two patients. None of the patients with myocardial involvement were identified. The average age was 58.2 ± 12.8 years, with a male predominance (76.7%). Coronary artery CT revealed that mass-like and diffuse wall-thickening lesions were the most frequently observed type of coronary periarteritis. Pericarditis presented as pericardial effusion, localized thickening, calcification and mass. After treatment with glucocorticoid and immunosuppressants, all patients achieved a reduced IgG4-RD responder index score and achieved radiological remission. Two patients with coronary peri-arteritis experienced clinical relapses during the maintenance period. CONCLUSIONS: Cardiac involvement in IgG4-RD is rare and easily overlooked since many patients are asymptomatic, and the diagnosis relies on imaging. Patients showed a satisfactory response to glucocorticoid based treatment.

Efficacy and safety of rituximab induction therapy and effect of rituximab maintenance for IgG4-related disease: a systematic review and meta-analysis.

BACKGROUND: Previous studies have reported that rituximab (RTX) therapy might be beneficial in reducing relapse rates in patients with IgG4-related disease (IgG4-RD). Therefore, we aimed to systematically assess the efficacy and safety of RTX induction treatment and the effect of RTX maintenance in patients with IgG4-RD. METHODS: The protocol was registered in the PROSPERO (CRD42023427352). PubMed, Embase, the Cochrane database, Scopus, and the Web of Science were interrogated to identify studies that evaluated the impact of RTX on prognosis in IgG4-RD. We explored the impact of various subgroups of factors on relapse outcomes and focused on the possible role of maintenance therapy in reducing relapse rates. The pooled incidence of adverse events of RTX therapy and the influencing factors have also been evaluated. RESULTS: Eighteen studies comprising 374 patients (mean age 56.0 ± 8.7 years; male 73.7 %) with a mean follow-up duration of 23.4 ± 16.3 months were included. The pooled estimate of the response rate, complete remission rate, overall relapse rate, adverse event rate, and serious adverse event rate of RTX induction therapy were 97.3 % (95 % CI, 94.7 %-99.1 %), 55.8 % (95 % CI, 39.6 %-71.3 %), 16.9 % (95 % CI, 8.7 %-27.1 %), 31.6 % (95 % CI, 16.7 %-48.9 %) and 3.9 % (95 % CI, 0.8 %-8.9 %), respectively. In subgroup analysis, the pooled relapse rate was significantly lower in studies with maintenance than without maintenance (2.8% vs 21.5 %, p < 0.01). Pooled Kaplan-Meier relapse curves also demonstrated that RTX maintenance therapy provided a better prognosis. CONCLUSIONS: RTX induction therapy appears to have satisfactory efficacy in the induction of remission in IgG4-RD. In addition, prophylactic RTX maintenance therapy after induction may be beneficial in preventing relapse of IgG4-RD.

Systematic analysis for clinical characteristics and outcomes of IgG4-related disease patients during the COVID-19 pandemic.

BACKGROUND: To systematically describe clinical characteristics and investigate factors associated with COVID-19-related infection, hospital admission, and IgG4-related disease relapse in IgG4-RD patients. METHODS: Physician-reported IgG4-RD patients were included in this retrospective study. Using multivariable logistic regression analysis to determine factors for primary outcome (COVID-19-related IgG4-RD relapse) and secondary outcome (COVID-19-related infection and hospital admission). Covariates included age, sex, body mass index, smoking status, comorbidities, IgG4-RD clinical features, and treatment strategies. RESULTS: Among 649 patients, 530 had a diagnosis of COVID-19, 25 had COVID-19-related hospital admission, and 69 had COVID-19-related IgG4-RD relapse. Independent factors associated with COVID-19 infection were age (OR, 0.98; 95% CI, 0.96-1.00), body mass index (1.10, 1.03-1.18), and tofacitinib (0.34, 0.14-0.79). Further analysis indicated that age (1.10, 1.03-1.16), coronary heart disease (24.38, 3.33-178.33), COVID-19-related dyspnea (7.11, 1.85-27.34), pulmonary infection (73.63, 16.22-4615.34), and methotrexate (17.15, 1.93-157.79) were associated with a higher risk of COVID-19-related hospital admission. Importantly, age (0.93, 0.89-0.98), male sex (0.16, 0.03-0.80), ever/current smoking (19.23, 3.78-97.80), COVID-19-related headache (2.98, 1.09-8.17) and psychiatric symptoms (3.12, 1.07-9.10), disease activity before COVID-19 (1.89, 1.02-3.51), number of involved organs (1.38, 1.08-1.76), glucocorticoid dosage (1.08, 1.03-1.13), and methotrexate (5.56, 1.40-22.08) were strong factors for COVID-19-related IgG4-RD relapse. CONCLUSIONS: Our data add to evidence that smoking and disease-specific factors (disease activity, number of involved organs, and specific medications) were risk factors of COVID-19-related IgG4-RD relapse. The results highlight the importance of adequate disease control with b/tsDMARDs, preferably without using methotrexate and increasing glucocorticoid dosages in the COVID-19 era. Key Points • COVID-19-related infection or hospital admission were associated with known general factors (age, body mass index, specific comorbidities and methotrexate) among IgG4-RD patients. • Smoking and disease-specific factors (disease activity, number of involved organs and specific medications) were associated with higher odds of COVID-19-related IgG4-RD relapse. • The results highlight the importance of adequate disease control with b/tsDMARDs, preferably without using methotrexate or increasing glucocorticoid dosages.

IgG4-associated disease with systemic lupus erythematosus: A case report and review.

We report a 67-year-old man who presented with poor dietary intake and fatigue. Laboratory tests showed leukopenia, antinuclear antibody (ANA) positivity, anti-dsDNA antibody (A-dsDNA) and anti-Smith antibody (anti-Sm) negativity, decreased C3 and C4, elevated serum immunoglobulin G (IgG), IgG4, and creatinine, and 1.25 g urinary protein at 24 hours. As his condition worsened, re-examination showed thrombocytopenia and A-dsDNA positivity, and renal biopsy pathology showed IgG4-related tubulointerstitial nephritis. The final diagnosis was IgG4-related disease (IgG4-RD) with systemic lupus erythematosus (SLE). His condition improved with glucocorticoid (GC) combined with hydroxychloroquine (HCQ) and mycophenolate mofetil (MMF) treatment. This case highlights that IgG4-RD and SLE may occur successively or co-exist and may convert into each other.

Mikulicz's disease combined with IgG4-related hypophysitis: a case report.

BACKGROUND: IgG4-related diseases are very uncommon, and its diagnosis and treatment are complicated as it encompasses multiple disciplines. CASE PRESENTATION: A 77-year-old woman was admitted with a jaw mass and nausea and vomiting. Laboratory tests showed elevated serum IgG4, pituitary MRI suggested thickening of the pituitary stalk, and head and neck CT suggested orbital and mandibular masses. Patients with mandibular mass were diagnosed with Mikulicz's disease with IgG4-related hypophysitis. We found no other evidence of causing thickening of the pituitary stalk. She was given oral prednisolone 30 mg daily, and her nausea and vomiting improved significantly, and the mandibular and ocular masses decreased in size. CONCLUSION: Mikulicz's disease combined with IgG4-related hypophysitis is a rare case of IgG4-RD in elderly women. IgG4-RD is one of the causes of head and neck exocrine gland mass and pituitary stalk thickening in the elderly.

Sinonasal immunoglobulin G4-related disease: a case report of an atypical and rare entity.

BACKGROUND: Immunoglobulin G4-related disease is marked by extensive inflammation and fibrosis of an unknown autoimmune component, with an overall incidence ranging from 0.78 to 1.39 per 105 person-years. Sinonasal immunoglobulin G4-related disease is atypical and exceedingly uncommon in the existing literature, frequently manifesting clinically as chronic rhinosinusitis, epistaxis, and facial pain. CASE PRESENTATION: This report describes a 25-year-old Iraqi female who has been suffering from symptoms of chronic rhinosinusitis for 8 years. Despite undergoing several surgeries, there has been no improvement in her symptoms. A tissue biopsy that revealed dense lymphoplasmocytosis with noticeable plasma cell infiltration, storiform fibrosis, and obliterative angitis, along with positive immunohistochemical staining for Immunoglobulin G4 plasma cells, finally confirmed the diagnosis of sinonasal immunoglobulin G4-related disease. The patient responded well to oral prednisolone and methotrexate treatments. CONCLUSIONS: The main objective of the current report is to raise awareness among physicians about the significance of promptly identifying and diagnosing this rarity, thus preventing the adverse consequences linked to delayed diagnosis and treatment initiation.

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.

Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review.

Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. A consistent feature of many cases is pulmonary infiltrates, or respiratory failure. This systematic literature review aims to summarise the pulmonary manifestations of IgG4-RD, including clinical outcomes and treatment. This review was registered on PROSPERO (CRD42023416410). Medline, Embase and Cochrane databases were searched for articles discussing IgG4-RD syndrome. Information was extracted on demographics, type and prevalence of pulmonary manifestations, treatment and clinical outcomes. Initially, after deduplication, 3123 articles were retrieved with 18 ultimately included. A pooled total of 724 patients with IgG4-RD were included, 68.6% male, mean age 59.4 years (SD 5.8) at disease onset. The most frequently described pulmonary manifestation was mediastinal lymphadenopathy (n = 186, 48.8%), followed by pulmonary nodules (n = 151, 39.6%) and broncho-vascular thickening (n = 85, 22.3%). Where treatment was reported, the majority of patients received glucocorticoids (n = 211, 93.4%). Other immunosuppressive therapy included cyclophosphamide (n = 31), azathioprine (n = 18), with mycophenolate mofetil (n = 6), rituximab (n = 6), methotrexate (n = 5) and other unspecified immunomodulators (50). Clinical outcomes were reported in 263 patients, where 196 patients had remission of their disease, 20 had relapse, 35 had stable disease, four had progression and eight patients died from complications of IgG4-RD. This systematic review summarises pulmonary manifestations, treatments and outcomes in patients with IgG4-RD. Pulmonary involvement in IgG4-RD is relatively common, leading to high levels of morbidity and mortality. Glucocorticoids remain the mainstay of treatment, but further work is required to explore the management of patients with pulmonary manifestations in association with IgG4-RD.

Bilateral sequential ischemic retinopathy and optic neuropathy in IgG1 heavy chain deposition disease.

PURPOSE: To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal immunoglobulin deposition disease (MIDD). OBSERVATIONS: Our case describes a 74-year-old woman diagnosed with IgG1 lambda HCDD. After treatment with daratumumab and intravenous IVIG therapy, the patient developed worsening ischemic retinopathy and optic neuropathy, neovascular glaucoma, and bilateral sequential vitreous hemorrhages, necessitating surgical intervention. We present multimodal imaging from the onset of ischemic retinopathy to end-stage maculopathy illustrated by optical coherence tomography (OCT) angiography. Despite discontinuing treatment with daratumumab and providing maximal ocular interventions to control the complications of neovascular disease, the patient's condition progressed, resulting in profound vision loss. CONCLUSIONS AND IMPORTANCE: Our case illustrates the potential for HCDD to cause end-organ disease, including ischemic retinopathy and optic neuropathy, possibly worsened by the patient's underlying cardiovascular risk factor status and medications. Daratumumab, a humanized IgG1 kappa monoclonal antibody that binds to CD38 used to treat specific blood cancers, has been reported to cause disturbances in retinal blood flow, including retinal artery and vein occlusions. It remains to be determined whether careful patient selection or dose adjustments and timing of HCDD treatments could protect vision by reducing the risk of these rare yet severe ocular complications.

Immunoglobulin G4 (IgG4) Positive Associated Liver Disease.

BACKGROUND: The goal was to explore the cognition of diagnosis and treatment level of IgG4-related diseases mainly involving lymph nodes. METHODS: The clinical manifestations, laboratory indicators, histopathology, and therapeutic effects of a patient with IgG4-RD suspected of lymphoma were analyzed and the relevant literature was reviewed. RESULTS: Lymph node biopsy showed reactive hyperplasia of lymph node tissue. The liver biochemical indexes were abnormal and the bone marrow smear showed atypical lymphocytes. Lymph node section: IgG4+ cells > 100/HPF (IgG4/IgG > 40%). The serum IgG4 level was 17,200 mg/L, and the diagnosis was IgG4-RD. Oral glucocorticoids took effect after 2 weeks, and no significant enlargement of lymph nodes was observed. CONCLUSIONS: For the diagnosis of IgG4-RD, at present, histopathology is still the gold standard, but a single result cannot diagnose the disease. Comprehensive judgment should be made by combining clinical symptoms, serum IgG4 level and imaging results to prevent misdiagnosis and missed diagnosis, and to avoid over-diagnosis. Short-term hormonal diagnostic therapy may be used in highly suspected patients who cannot be diagnosed. Once diagnosed, standardized medication, adhere to follow-up, regular review, to prevent recurrence and adverse drug reactions.

A case of IgG4-related disease associated with ulcerative colitis that was successfully treated with a JAK inhibitor.

Glucocorticoids (GC) are the standard of care for the induction and maintenance of remission in immunoglobulin G4 (IgG4)-related diseases. However, IgG4-related diseases often relapse with GC dose reduction, not only making GC dose reduction difficult but also necessitating GC dose escalation in many cases. Therefore, other immunosuppressive drugs are required to maintain remission. Here, we report a 39-year-old man with ulcerative colitis and IgG4-related disease who experienced a relapse of both diseases despite treatment with tacrolimus and 6-mercaptopurine. Following the initiation of tofacitinib, a Janus-associated kinase inhibitor, it was possible to reduce the GC dose while maintaining remission of both diseases. This case highlights the potential utility of Janus-associated kinase inhibitors in managing complex cases of IgG4-related disease, especially those with concurrent conditions such as ulcerative colitis.

The clinical outcomes and healthcare resource utilization in IgG4-related disease: a claims-based analysis of commercially insured adults in the United States.

OBJECTIVES: IgG4-related disease (IgG4-RD) can affect nearly any organ and is often treated with glucocorticoids, which contribute to organ damage and toxicity. Comorbidities and healthcare utilization in IgG4-RD are poorly understood. METHODS: We conducted a cohort study using claims data from a US managed care organization. Incident IgG4-RD cases were identified using a validated algorithm; general population comparators were matched by age, sex, race/ethnicity and index date. The frequency of 21 expert-defined clinical outcomes associated with IgG4-RD or its treatment and healthcare-associated visits and costs were assessed 12 months before and 36 months after the index date (date of earliest IgG4-RD-related claim). RESULTS: There were 524 cases and 5240 comparators. Most cases received glucocorticoids prior to (64.0%) and after (85.1%) the index date. Nearly all outcomes, many being common glucocorticoid toxicities, occurred more frequently in cases vs comparators. During follow-up, the largest differences between cases and comparators were seen for gastroesophageal reflux disease (prevalence difference: +31.2%, P < 0.001), infections (+17.3%, P < 0.001), hypertension (+15.5%, P < 0.01) and diabetes mellitus (+15.0%, P < 0.001). The difference in malignancy increased during follow-up from +8.8% to +12.5% (P < 0.001). Some 17.4% of cases used pancreatic enzyme replacement therapy during follow-up. Over follow-up, cases were more often hospitalized (57.3% vs 17.2%, P < 0.01) and/or had an emergency room visit (72.0% vs 36.7%, P < 0.01); all costs were greater in cases than comparators. CONCLUSIONS: Patients with IgG4-RD are disproportionately affected by adverse outcomes, some of which may be preventable or modifiable with vigilant clinician monitoring. Glucocorticoid-sparing treatments may improve these outcomes.

Fibrotic phenotype of IgG4-related disease.

A prompt response to glucocorticoids is a clinical hallmark of IgG4-related disease. However, manifestations characterised by prominent tissue fibrosis on histological examination can be less responsive to glucocorticoid therapy than other types of IgG4-related disease. These manifestations include retroperitoneal fibrosis, fibrosing mediastinitis, Riedel thyroiditis, orbital pseudotumor, and hypertrophic pachymeningitis, among others. To explain this discrepancy, a preliminary distinction into proliferative and fibrotic phenotypes of IgG4-related disease has been proposed on the basis of clinical presentation, pathological features, and response to immunosuppressive therapy. Implications of this classification for patient management remain an important area of investigation. In this Series paper, we aim to dissect the pathophysiology of tissue fibrosis in IgG4-related disease and discuss how clinicians should approach the management of fibrotic manifestations of IgG4-related disease based on the most recent diagnostic and therapeutic developments.

Case of IgG4-related Disease with Crescentic Glomerulonephritis: An Unusual Presentation of the Disease.

IgG4-related disease (IgG4-RD) is a chronic systemic inflammatory  disease, characterized by tissue infiltration of lymphocytes and  IgG4-secreting plasma cells, presenting by fibrosis of different  tissues, which is usually responsive only to oral steroids therapy.  Kidneys are the most commonly involved organs, exhibiting renal  insufficiency, tubulointerstitial nephritis, and glomerulonephritis.  Here, we describe a patient with acute renal insufficiency who  was presented with edema, weakness, anemia and multiple  lymphadenopathies. Kidney and lymph node biopsy showed  crescentic glomerulonephritis in kidneys and lymphoplasmacytic  infiltration in lymph nodes. After a course of treatment with an  intravenous pulse of corticosteroid and cyclophosphamide, the  patient's symptoms subsided, and kidney function improved. DOI: 10.52547/ijkd.7788.

Effectiveness of tofacitinib monotherapy for patients with IgG4-RD or idiopathic retroperitoneal fibrosis.

OBJECTIVES: To explore the effectiveness of tofacitinib for immunoglobulin G4-related disease (IgG4-RD) and idiopathic retroperitoneal fibrosis (IRF), and investigate the expression of JAKs in the lesion of these diseases. METHODS: Clinical data of patients with IgG4-RD or IRF who were administered with tofacitinib monotherapy were collected. IgG4-RD responder index (IgG4-RD RI) was assessed. The expression of JAK1, JAK2, JAK3, and TYK2 were analysed with immunohistochemistry staining in three salivary glands specimens of IgG4-RD and one retroperitoneal tissue of IRF. RESULTS: Two patients with IRF and two patients with IgG4-RD used tofacitinib monotherapy. Two patients with IRF achieved complete remission with diminished retroperitoneal mass and decreased CRP, as IgG4-RD RI decreased from 6 to 1 in both of them. One with IgG4-RD achieved complete remission with alleviated enlargement of pancreas and IgG4 level decreased from 13.7 g/L to 2.4 g/L, as IgG4-RD RI decreased from 12 to 1. One with IgG4-RD achieved partial response with IgG4 level decreased from 77.1g/L to 25.8g/L as IgG4-RD RI from 18 to 6. JAK1, JAK2, JAK3, and TYK2 expression were detected in biopsy tissues. The staining intensity of the JAK family on the lesion from one IRF patient was similar to those from IgG4-RD patients. CONCLUSIONS: Tofacitinib is a potentially effective treatment for IgG4-RD and IRF and it is reasonable to conduct clinical trial to validate its efficacy. The JAKs were expressed in the inflammatory lesions of IgG4-RD and IRF and they may share a common pathogenesis pathway that is independent of IgG4 production.

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.