Immunoglobulin G4 Research Articles

Role of Endoscopic Procedures in the Diagnosis of IgG4-Related Pancreatobiliary Disease.

The emergence of the disease entity of glucocorticoid-responsive systemic immunoglobulin G4 (IgG4)-related pancreatobiliary disease has generated substantial attention among the international gastroenterology society. IgG4-related pancreatobiliary disease includes type 1 autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC). The typical manifestations of IgG4-related pancreatobiliary disease are cholestatic liver dysfunction, obstructive jaundice, and weight loss, although it may present with no clinical symptoms. Since it mimics tumors on imaging, AIP/IgG4-SC may often be misdiagnosed as pancreatic or biliary cancer. The endoscopic armamentarium for the diagnosis of IgG4-related pancreatobiliary disease includes endoscopic ultrasonography, intraductal ultrasonography, endoscopic retrograde cholangiopancreatography, and cholangioscopy. The role of endoscopic tissue acquisition is two-fold in the diagnosis of IgG4-related pancreatobiliary disease: exclusion of cancer and procurement of histopathological proof for diagnosis of AIP/IgG4-SC, which can also be achieved by adding the immunohistochemistry for IgG4. Our review article addresses the role of various endoscopic examinations in diagnosing IgG4-related pancreatobiliary disease, focusing on the differentiation of this condition from pancreatobiliary malingnancies.

Phase I study of pucotenlimab (HX008), an anti-PD-1 antibody, for patients with advanced solid tumors.

Background:Pucotenlimab is a humanized immunoglobulin G4 (IgG4) anti programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) with a S228P hinge mutation and an engineered Fc domain. Preclinical data suggests that pucotenlimab exerts antitumor effects. In this phase I study, which was prospectively registered on www.chinadrugtrials.org.cn (CTR20180125), the safety, maximum tolerated dose, preliminary antitumor activity, pharmacokinetics, and immunogenicity of pucotenlimab were evaluated in patients with advanced solid tumors.Methods:Patients with advanced solid tumors refractory to standard therapies were recruited. In a 3+3 dose escalation study, 13 patients received pucotenlimab intravenously every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurred at doses of 1 mg/kg, 3 mg/kg, 10 mg/kg, and 200 mg. 17 additional patients were assigned in the expansion period.Results:A total of 30 patients were enrolled. No dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common treatment-related adverse events of any grade were proteinuria (40%), fatigue (36.7%), weight loss (26.7%), fever (26.7%), increased aspartate aminotransferase (26.7%), rash (23.3%), and anorexia (20.0%). Partial responses occurred in five patients, with an objective response rate of 16.7%. Pharmacokinetics analysis showed rapid absorption followed by slow terminal elimination, with a mean half-life of 17.1–23.5 days across all dose groups.Conclusions:Pucotenlimab had an acceptable toxicity profile at doses up to 10 mg/kg and the maximum tolerated dose was not reached. Based on the pharmacokinetics, efficacy, and safety profile, 3 mg/kg Q3W or 200 mg Q3W are optimal for further drug development.

Characterization of ASP8374, a fully-human, antagonistic anti-TIGIT monoclonal antibody

The T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) is a validated immune checkpoint protein expressed on memory CD4+T-cellls, Tregs, CD8+T-cell and natural killer (NK) cells. ASP8374 is a fully human monoclonal immunoglobulin (Ig) G4 antibody designed to block the interaction of TIGIT with its ligands and inhibit TIGIT signaling. ASP8374 exhibited high affinity binding to TIGIT and increased interferon (IFN)-γ production of cultured peripheral blood mononuclear cells (PBMCs) in a titratable manner. When used in combination with pembrolizumab, an anti-programmed death-1 (PD-1) antibody, ASP8374 induced higher T-cell activation in vitro than either treatment alone. An anti-mouse TIGIT antibody surrogate, mSEC1, displayed anti-tumor efficacy in an MC38 syngeneic mouse tumor model alone and in combination with an anti-programmed death-ligand 1 (PD-L1) antibody. In an additional syngeneic mouse tumor model (CT26), while mSEC1 alone did not demonstrate anti-tumor efficacy, mSEC1 combined with an anti-PD-1 antibody enhanced anti-tumor efficacy above that of the anti-PD-1 antibody alone. These data provide evidence that ASP8374 has therapeutic potential for advanced malignancies.

The Diagnostic Challenges of Autoimmune Pancreatitis – A Case Report

Purpose: Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease that accounts for 4,6–5,0% of chronic pancreatitis and encompasses two entities, one related to a systemic disease referred to as IgG4-related disease (type 1 AIP) and the other generally without immunoglobulin G4-positive cells and without systemic involvement (type 2 AIP). Its association to other autoimmune diseases, namely ulcerative colitis, is known although the exact relationship between the two entities is not completely clarified. The diagnosis of autoimmune pancreatitis requires a multidisciplinary approach. Due to overlap in clinical and radiological features, it is often misdiagnosed as pancreatic cancer. Methods and Aims: This clinical case report describes an uncommon entity highlighting the challenge in the diagnostic approach of a pancreatic mass. Results: A 45-year-old female, with a medical history of ulcerative colitis and arterial hypertension treated with bisoprolol and mesalazine, underwent an abdominal computerized tomography scan (CT scan) for study of a solid liver lesion, which incidentally revealed a tail pancreatic mass. There were no symptoms at all and physical examination was normal. Laboratory analyses showed normal levels of immunoglobulin G4 and negative antinuclear antibodies. Endoscopic ultrasound revealed a homogeneous and hypoechogenic lesion in the pancreatic tail with a “sausage-like” appearance. Endoscopic ultrasound-guided fine needle aspiration was inconclusive (pancreatic adenocarcinoma hypothesis could not be excluded) and the patient underwent a laparoscopic distal pancreatectomy. Histopathology examination confirmed the diagnosis of a type 2 autoimmune pancreatitis. At 12-month follow-up, the patient remained asymptomatic with no evidence of recurrence. Conclusions: The diagnosis of AIP is a clinical challenge, not only due to its rarity, but also due to the need of integrating clinical, laboratory, imaging, and histology data for confirmation. Although the diffuse form of AIP can be easily distinguished from pancreatic cancer on imaging, differentiating focal AIP from pancreatic malignancy is challenging, so a surgical approach is often proposed. The association of AIP with other autoimmune illnesses can be identified in more than half of the cases. Among these, the association with inflammatory bowel disease, and more specifically with ulcerative colitis, has been described being the most common.

Nivolumab-associated Stevens-Johnson syndrome in a patient with lung cancer

Nivolumab is a fully human immunoglobulin G4 immune checkpoint inhibitor antibody approved for use in the treatment of several malignancies such as lung cancer. Cutaneous reactions to checkpoint inhibitors are frequent, appearing in approximately 40% of patients. Although most of the reactions are well tolerated, these drugs can lead to severe cutaneous adverse reactions, but a quick recognition of the symptoms can significantly decrease their mortality. In this case report, we describe a patient with metastatic squamous lung cell carcinoma suffering from nivolumab-induced Stevens-Johnson syndrome with severe skin denudation and mucosal involvement.

Isolated Type Immunoglobulin G4 Sclerosing Cholangitis: The Misdiagnosed Cholangiocarcinoma.

Immunoglobulin G4 sclerosing cholangitis (IgG4-SC), firstly described in 2004, is the biliary manifestation of a recently described multisystem immune-mediated disease known as IgG4-related disease. IgG4-SC is a unique and rare type of cholangitis of unknown etiology and its precise prevalence rate is still unclear. It is characterized by bile duct wall thickening and high levels of systemic serum IgG4 plasma cells. Differential diagnoses for IgG4-SC include benign (primary sclerosing cholangitis) as well as malignant (extra-hepatic cholangiocarcinoma) diseases. Discrimination between these entities is very important, due to the fact that they have different biological behaviors and different therapeutic strategies. The rare IgG4-SC subgroup with its puzzling manifestations carries a hefty diagnostic challenge for the treating physicians, and inaccurate diagnosis can lead to unnecessary morbid surgical procedures. With the paucity and relative weakness of available data in the current literature, one needs to carefully review all available parameters. A low threshold of suspicion is required to try and prevent missing IgG4-SC. IgG4-SC is highly responsive to steroid treatment, especially during the early inflammatory phase, while delay in management could lead to fibrosis and organ dysfunction. On the other hand, cholangiocarcinoma is treated by means of surgery and/or chemotherapeutic agents.

A case of immunoglobulin G4-related lung disease with normal serum immunoglobulin G4 level and hybrid radiological findings

A case of immunoglobulin G4-related lung disease with normal serum immunoglobulin G4 level and hybrid radiological findings

Immunoglobulin G4–related disease of the paratestis: Can we avoid radical treatment?

Immunoglobulin G4–related disease of the paratestis: Can we avoid radical treatment?

Identification of Markers Predicting Clinical Course in Patients with IgG4-Related Ophthalmic Disease by Unbiased Clustering Analysis.

Purpose: To describe the clinical features of patients with immunoglobulin G4 (IgG4)-related ophthalmic disease (IgG4-ROD) grouped by unbiased cluster analysis using peripheral blood test data and to find novel biomarkers for predicting clinical features. Methods: One hundred and seven patients diagnosed with IgG4-ROD were divided into four groups by unsupervised hierarchical cluster analysis using peripheral blood test data. The clinical features of the four groups were compared and novel markers for prediction of clinical course were explored. Results: Unbiased cluster analysis divided patients into four groups. Group B had a significantly higher frequency of extraocular muscle enlargement (p < 0.001). The frequency of patients with decreased best corrected visual acuity (BCVA) was significantly higher in group D (p = 0.002). Receiver operating characteristic (ROC) curves for the prediction of extraocular muscle enlargement and worsened BCVA using a panel consisting of important blood test data identified by machine learning yielded areas under the curve of 0.78 and 0.86, respectively. Clinical features were compared between patients divided into two groups by the cutoff serum IgE or IgG4 level obtained from ROC curves. Patients with serum IgE above 425 IU/mL had a higher frequency of extraocular muscle enlargement (25% versus 6%, p = 0.004). Patients with serum IgG4 above 712 mg/dL had a higher frequency of decreased BCVA (37% versus 5%, p ≤ 0.001). Conclusion: Unsupervised hierarchical clustering analysis using routine blood test data differentiates four distinct clinical phenotypes of IgG4-ROD, which suggest differences in pathophysiologic mechanisms. High serum IgG4 is a potential predictor of worsened BCVA, and high serum IgE is a potential predictor of extraocular muscle enlargement in IgG4-ROD patients.

Autoimmune Pancreatitis and IgG4-related Cholangitis: A Single-center Experience

Background: Autoimmune pancreatitis (AIP) and IgG4-related cholangitis (IRC) are newly-recognized diseases. Reports in Thailand are scarce. Objective: To evaluate clinical presentations, other organ involvement (OOI), serology, radiologic, endoscopic features and treatment of AIP and IRC in one institute. Materials and Methods: Patients with AIP and IRC, who were diagnosed and followed-up at Siriraj Hospital during 2005 to 2016 were retrospectively reviewed. Results: There were 15 patients (75%) with AIP, 7 patients (37%) with IRC (4 isolated IRC and 3 IRC with AIP) and 1 (5%) with IgG4-related disease without AIP or IRC (sialadenitis and retroperitoneal fibrosis). Male to female ratio was 1.9: 1. Median age of onset was 64 years. Among the 15 AIP, all were type 1. Initial presentations were jaundice (60%), abdominal pain (40%), OOI (20%; sialadenitis, orbital pseudotumor), and weight loss (7%). Clinical manifestations during the course were jaundice (80%), abdominal pain (67%), weight loss (47%), OOI (47%; retroperitoneal fibrosis, IRC, sialadenitis, orbital pseudotumor, periurethral mass, lung nodules) and steatorrhea (7%). Serum IgG4 was elevated in all patients. Radiography showed diffuse type in 8 cases (53%), focal type in 5 (33%), and unknown in 2 (13%). More than half were suspicious of AIP before diagnosis. Corticosteroid was required in 10 patients (67%). Maintenance therapy was offered in 5 patients (33%) with steroid and azathioprine. Surgery was performed before diagnosis in 7 patients (47%). Spontaneous remission occurred in 4 patients (27%). Among the 7 IRC, initial presentations were jaundice (57%), weight loss (29%), abdominal pain (14%), prolonged fever (14%), and cholangitis (14%). Clinical manifestations during the course were jaundice (57%), abdominal pain (57%), weight loss (29%), recurrent cholangitis (14%) and retroperitoneal fibrosis (14%). Serum IgG4 was elevated in 5 patients (71%). Prednisolone was prescribed in 6 cases (86%). Five patients (71%) required azathioprine. Surgery was performed before diagnosis in 4 patients (57%). Conclusion: AIP and IRC were uncommon. The most common presentation was jaundice. All AIP were type 1 and more than half were diffuse type. OOI were common. Half of IRC had AIP. Approximately half of AIP/IRC patients underwent surgery before diagnosis. Corticosteroid was mainstay treatment. Keywords: Autoimmune pancreatitis, IgG4, Immunoglobulin G4, Sclerosing cholangitis, Thailand &nbsp;

Elevated Serum IgG4 Was Found in Eosinophilic Granulomatosis With Polyangiitis.

The aim was to determine the levels and clinical impact of immunoglobulin G4 (IgG4) and other IgG subclasses in a Chinese population with eosinophilic granulomatosis with polyangiitis (EGPA). We enrolled 49 patients who had EGPA, 27 who had granulomatosis with polyangiitis (GPA), 31 who had microscopic polyangiitis (MPA), and 30 healthy controls (HCs). Serum IgG subclasses were measured using commercial immunonephelometric assays and compared among different groups. Fifteen EGPA patients (30.61%) had elevated IgG4 levels, based on a cutoff value of 135 mg/dL. In addition, 2 GPA patients (7.40%) and 1 MPA patient (3.33%) had elevated IgG4 levels. The EPGA group had a higher IgG4 level (65.60 mg/dL) than the GPA group (32.70 mg/dL, p = 0.0021), the MPA group (30 mg/dL, p = 0.0021), and the HC group (28.55 mg/dL, p = 0.0002). The EPGA group also had a higher IgG4/IgG ratio (0.0644) than the GPA group (0.0322, p = 0.13), the MPA group (0.0289, p = 0.0055), and the HC group (0.0212, p < 0.0001). Our results indicate that Chinese patients with EGPA have increased levels of serum IgG4. Further study is needed to determine the pathogenic role of IgG4 and IgG4 antineutrophil cytoplasmic antibodies in EGPA.

Abstract 13337: Increased Serum Immunoglobulin G4 Level is a Novel Predictor of Cardiovascular Events Independent of Established Risk Factors: Results From the Real-cad Study

Background: Inflammation is a mediator of atherosclerosis progression. However, it remains unclear whether immunoglobulin G4 (IgG4)-related immuno-inflammation may play a specific role in cardiovascular disease. Methods: We used a case-cohort design to analyze the association of serum IgG4 levels with future cardiovascular events. The sample included 561 cases of the primary end point, defined as cardiovascular death, myocardial infarction, ischemic stroke, or unstable angina, and a random subcohort of 1688 (1409 males; mean age, 68.1 ± 8.4 years), of whom 73 were also cases, selected from 12413 eligible participants with stable coronary artery disease in the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. Results: This case-cohort study had a median follow-up of 3.9 years (interquartile range [IR] 2.9-4.6). Serum IgG4 levels at baseline were 45.3 mg/dL (IR 37.9-58.9), and 845 (50%) took high-dose statins in the subcohort sample. In Cox regression using age, gender, statin dose, high-sensitivity C-reactive protein (hsCRP), body mass index, estimated glomerular filtration rate (eGFR), hypertension, diabetes, and serum lipid profiles, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, as covariates, the highest IgG4 quartile was predictive of the primary end point at 4 years (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.03-2.00, P=0.031), compared with the lowest quartile. Similar results were observed for the secondary end point, a composite of the primary end point plus coronary revascularization (HR 1.60, 95% CI 1.16-2.20, P=0.004). Conclusions: Elevated serum IgG4 level at baseline predicted long-term cardiovascular outcomes independent of established risk factors and high-dose statin therapy in patients with stable CAD. Serum IgG4 may reflect residual cardiovascular risk.

Eosinophilic esophagitis and asymptomatic esophageal eosinophilia display similar immunohistological profiles.

Patients with asymptomatic esophageal eosinophilia (aEE) do not exhibit clinical symptoms because of esophageal dysfunction, although they have endoscopic and histological findings similar to those of eosinophilic esophagitis (EoE). The cause of the symptoms and the differences between aEE and EoE are unclear. The aim of this study is to determine whether aEE and EoE are same disease entities by comparing immune-related tissue biomarkers using immunohistological staining. Esophageal biopsy specimens from 61 patients, including 18 with aEE and 43 with EoE, were analyzed. Immunofluorescence staining was performed to quantify the immune-related tissue biomarkers such as major basic protein, eosinophil-derived neurotoxin, eotaxin-3, and immunoglobulin G4. Data are presented as median (interquartile range). There were no significant differences in clinical, endoscopic, or histological features, between patients with aEE and EoE, with the exception of body mass index. There were no significant differences in all immune-related tissue biomarkers between both groups. In conclusions, EoE and aEE displayed similar immunohistological profiles. Hence, they may be similar disease entities with some common pathogenic mechanisms. Our findings suggest that patients with aEE also have histopathological esophageal inflammation.

Quantification of nivolumab in human plasma by LC-MS/HRMS and LC-MS/MS, comparison with ELISA

Nivolumab is a fully human immunoglobulin G4 used for the treatment of several advanced solid cancers as immune checkpoint inhibitors. There are some challenges for the quantification of mAb in plasma because IgG are present intrinsically in complex biologic matrices and this determination must be based on reliable, selective, and accurate analytical methods. This study described two validated methods carried out in two separate laboratories, one developed with a triple quadrupole tandem mass spectrometry (LC-MS/MS) and the other with high resolution mass spectrometry with an orbitrap system (LC-MS/HRMS). Both methods used full-length stable isotope-labeled nivolumab-like (Arginine 13C6–15N4 and Lysine 13C6–15N2) as internal standard. The sample preparation was based on IgG immunocapture, then trypsin digestion was performed and one surrogate peptide was quantified in positive mode. Assays showed good linearity over the range of 5–100 μg/mL and 5–150 μg/mL for LC-MS/HRMS and LC-MS/MS, respectively. The limit of quantification was set at 2 and 5 μg/mL for LC-MS/HRMS and LC-MS/MS, respectively. Acceptable accuracy (from - 13.6% to 3.0%) and precision (within 20%) values were also obtained with both methods. The two LC-MS methods showed a very different matrix effect linked to the use of different analytical columns and elution gradients. Nivolumab plasma concentrations from 60 cancer outpatients were compared with the two mass spectrometry methods and also with a home-made ELISA method. The Bland–Altman analysis did not show any significant bias between the three methods. The Passing–Bablock linear regression analysis showed a good agreement between the three methods with a better correlation between the two mass spectrometry methods.

Developing and validating a clinical algorithm for the diagnosis of podoconiosis.

BackgroundDifficulties in reliably diagnosing podoconiosis have severely limited the scale-up and uptake of the World Health Organization–recommended morbidity management and disability prevention interventions for affected people. We aimed to identify a set of clinical features that, combined into an algorithm, allow for diagnosis of podoconiosis.MethodsWe identified 372 people with lymphoedema and administered a structured questionnaire on signs and symptoms associated with podoconiosis and other potential causes of lymphoedema in northern Ethiopia. All individuals were tested for Wuchereria bancrofti–specific immunoglobulin G4 in the field using Wb123.ResultsBased on expert diagnosis, 344 (92.5%) of the 372 participants had podoconiosis. The rest had lymphoedema due to other aetiologies. The best-performing set of symptoms and signs was the presence of moss on the lower legs and a family history of leg swelling, plus the absence of current or previous leprosy, plus the absence of swelling in the groin, plus the absence of chronic illness (such as diabetes mellitus or heart or kidney diseases). The overall sensitivity of the algorithm was 91% (95% confidence interval [CI] 87.6 to 94.4) and specificity was 95% (95% CI 85.45 to 100).ConclusionsWe developed a clinical algorithm of clinical history and physical examination that could be used in areas suspected or endemic for podoconiosis. Use of this algorithm should enable earlier identification of podoconiosis cases and scale-up of interventions.

CTIM-10. PHASE II STUDY OF PEMBROLIZUMAB PLUS SurVaxM FOR GLIOBLASTOMA AT FIRST RECURRENCE

Abstract BACKGROUND Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 2 (PD-L2). Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell cycle progression. Survivin has also been shown to modulate the function of a number of terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis. METHODS This is a Phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of 10 patients who have failed prior anti-PD1 therapy. The ongoing study is a phase II clinical study with a 10 patient, toxicity run-in. All patients will receive the study drug combination consisting of SurVaxM and pembrolizumab with no randomization, stratification or dose escalation. RESULTS So far ten patients have been enrolled on the study as safety run in. Primary endpoint is Progression free survival at 6 months. Safety and tolerability of Pembrolizumab and SurVaxM, Response rates of Pembrolizumab and SurVaxM determined using RANO criteria are secondary endpoints. Additional secondary endpoints include Overall survival and Progression Free survival Exploratory endpoints include Cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. CONCLUSION This is an ongoing clinical trial.

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study

Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Patients with Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)

Liposomal Cytarabine and Daunorubicin (CPX-351) in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Patients with Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)

Pancreatic solid focal lesions: autoimmune pancreatitis or pancreatic cancer?

Purpose: The diagnosis of pancreatic ductal adenocarcinoma (PDAC) in treatable early stages continues to be challenging. Autoimmune pancreatitis (AIP) can, similarly to PDAC, present as a focal mass and, therefore, an accurate differential diagnosis is of crucial importance. Raised serum immunoglobulin G4 (IgG4) levels, over the twice the normal value, are considered to be one of the significant diagnostic features of type 1 AIP. However, IgG4 can also be increased in patients with PDAC, but levels usually do not exceed twice the normal value. Materials and methods: In the years 2012 - 2018, IgG4 serum levels were examined in 117 patients with histologically confirmed PDAC. Histological resection specimens or bioptic specimens were taken from the pancreatic lesions of patients with both PDAC and an elevated IgG4 level (above 135mg/dL). These were then tested for the presence of IgG4 and plasmocytes in the pancreatic tissue, and changes characteristic for type 1 AIP were also searched for. Results: In 14/117 PDAC patients (11.9 %) the plasmatic IgG4 levels were higher than 135 mg/dL. In 2 patients (1.7 %) the serum IgG4 levels were more than double the normal value, and thus suggestive of AIP according to the guidelines. Of these two patients - one of them met the histological criteria for diagnosis of AIP in the simultaneous presence of PDAC. Conclusions: Differentiating AIP from PDAC can be sometimes problematic since these diseases can both present as focal pancreatic mass/ lesions. IgG4 has been considered useful for AIP diagnosis, however, IgG4 levels can be slightly elevated, as is the case with PDAC. IgG4 levels of over the twice of the upper limit are rare among PDAC patients (1.7% in our study group). However, cases of simultaneous presentation of PDAC and AIP have been documented and should not be neglected. Therefore, targeted biopsy of the pancreas is the method of choice in cases suspected of being a focal form of AIP, and we recommend it over other modalities, such as e.g. response to steroid therapy.

In Reply to the Letter to the Editor Regarding “15-Year Institutional Retrospective Case Series of Decompressive Craniectomy for Malignant Middle Cerebral Artery Infarction (mMCAI)”

Spinal immunoglobulin G4–related hypertrophic pachymeningitis (IgG4-HP) is a rare disease. Little information is known regarding the diagnosis, management, and prognosis of patients with spinal IgG4-HP.The authors present a case of spinal IgG4-HP with a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant studies (up to April 2020) that reported patients with spinal IgG4-HP, based on the criteria of Japan College of Rheumatology, were identified from the PubMed and Cochrane Library databases.This systematic review identified 33 patients, including the present case, of whom 21 were male and 12 were female. The mean value of age was 51.2 (±12.6) years. Eight patients had systemic involvement. In addition, among 33 patients, 13 patients had an elevated serum IgG4. Surgery was performed in 31 patients. Steroid therapy alone and steroid therapy with immunosuppressants were effective in 94% and 100% of the cases, respectively. Furthermore, 31 of 33 patients reported improved outcomes, 1 patient died due to infection, and in 2 patients the data were not available.Spinal IgG4-HP is a rare entity. In addition, it should be considered in the differential diagnosis of space-occupying lesions around the spinal cord. Histopathology with immunohistochemistry results provides the most reliable evidence for diagnosis. Steroid therapy is the first line of treatment. Surgical decompression may be required in patients presenting with nerve root and/or spinal cord compression. Long-term follow-up is necessary for patients with spinal IgG4-HP.