Normal Immunoglobulin G Levels Research Articles

Multiple Sclerosis, Rituximab, Hypogammaglobulinemia, and Risk of Infections.

B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to estimate how much of this rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors in persons with multiple sclerosis (pwMS). We conducted a retrospective cohort study of rituximab-treated pwMS from January 1, 2008, to December 31, 2020, in Kaiser Permanente Southern California. Cumulative rituximab dose was defined as ≤2, >2 and ≤4, or >4 g. Serious infections were defined as infections requiring or prolonging hospitalizations, and recurrent outpatient infections as seeking care for ≥3 within 12 months. Exposures, outcomes, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHRs) were estimated using Andersen-Gill hazards models, and generalized estimating equations were used to examine correlates of IgG values. Cross-sectional causal mediation analyses of rituximab and hypogammaglobulinemia were conducted. We identified 2,482 pwMS who were treated with rituximab for a median of 2.4 years (interquartile range = 1.3-3.9). The average age at rituximab initiation was 43.0 years, 71.9% were female, 49.7% were White, non-Hispanic patients, and 29.6% had advanced disability (requiring walker or worse). Seven hundred patients (28.2%) developed recurrent outpatient infections, 155 (6.2%) developed serious infections, and only 248 (10.0%) had immunoglobulin G (IgG) < 700 mg/dL. Higher cumulative rituximab dose (>4 g) was correlated with lower IgG levels (Beta = -58.8, p < 0.0001, ref ≤2 g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4 g, aHR = 1.56, 95% CI 1.09-2.24; IgG < 500, aHR = 2.98, 95% CI 1.56-5.72) and outpatient infections (>4 g, aHR = 1.73, 95% CI 1.44-2.06; IgG < 500 aHR = 2.06, 95% CI 1.52-2.80; ref = IgG ≥ 700). Hypogammaglobulinemia explained at most 17.9% (95% CI -47.2-119%) of serious infection risk associated with higher cumulative rituximab exposure but was not significant for outpatient infections. Other independent modifiable risk factors were advanced physical disability for serious (aHR = 5.51, 95% CI 3.71-8.18) and outpatient infections (aHR = 1.24, 95% CI 1.06-1.44) and COPD (aHR = 1.68, 95% CI 1.34-2.11) and obesity (aHR = 1.25, 95% CI 1.09-1.45) for outpatient infections. Higher cumulative rituximab doses increase the risk of infections even in this population where 90% of patients maintained normal IgG levels. Clinicians should strive to use minimally effective doses of rituximab and other B-cell-depleting therapies and consider important comorbidities to minimize risks of infections.

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels

Background and aimsNormal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. MethodsTwo hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. ResultsOne hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. ConclusionsHigh proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Immunoglobulin G4-Seronegative Autoimmune Cholangiopathy With Pancreatic and Hepatic Involvement Mimicking as Primary Sclerosing Cholangitis

Immunoglobulin G4-seronegative autoimmune cholangiopathy is a rare cause of biliary strictures. We describe a 27-year-old man presenting with elevated liver enzymes, recurrent cholangitis/bacteremia, biliary strictures, and normal immunoglobulin G4 levels, who was initially diagnosed with primary sclerosing cholangitis, and later listed for transplantation for recurrent bacteremia. Subsequent surveillance imaging demonstrated morphologic changes consistent with biliary strictures and autoimmune pancreatitis. Initiating corticosteroids resulted in liver enzyme normalization and stricture improvement. Diagnosing seronegative autoimmune cholangiopathy remains challenging given similar presentation to primary sclerosing cholangitis. This case highlights importance of a wide differential for biliary strictures, with increased suspicion in those developing pancreatic changes in this setting.

Factors and cytokine signatures associated with the response to therapy in patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome: a real-world study.

Factors and cytokine signatures associated with the response to therapy in patients with primary biliary cholangitis-autoimmune hepatitis overlap syndrome: a real-world study.

HEADACHE AS AN ADVERSE EFFECT OF IMMUNOGLOBULIN ADMINISTRATION FOR SELECTIVE IMMUNOGLOBULIN G DEFICIENCY

INTRODUCTION: IgG subclass deficiency was described by William Terry in a patient with recurrent infections. Selective IgG subclass is defined as a significant decrease in serum concentration of 1 or more IgG subclasses with normal total IgG, IgA and IgM levels. Persistent low serum levels of one or more immunoglobulin G (IgG) subclasses may be found in a high proportion of adult patients with increased susceptibility to infections (17). This deficiency has been described in association with other primary immunodeficiencies, including: selective IgA deficiency, selective IgM deficiency and Ataxia-Telangiectasia, growth hormone deficiency, Down syndrome, cystic fibrosis, among others (1). CLINICAL CASE:We present the clinical case of a 28-year-old female patient with a history of selective immunodeficiency to IgG immunoglobulin, repeated urinary tract infections, repeated vaginal infections and herpes simplex II infection, all of which have been treated, She went to a hospital in Morona Santiago three days ago for presenting, as the apparent cause, administration of immunoglobulin for a basic illness, a mild holocranial headache that evolved into a severe headache, accompanied by nausea that led to vomiting on one occasion, for which she was admitted to the hospital for pain management. Complementary examinations showed that there was no metabolic alteration or neurological deterioration, which is why she was classified as an adverse effect of the administration of immunoglobulin 3 days earlier. EVOLUTION:The patient was admitted for pain management due to severe headaches, multiple analgesics were administered without adequate response, so it was decided to start a tramadol infusion pump. During the following hours of hospitalization she remained with a feeling of nausea and weakness, however, the headache gradually subsided and it was decided to discontinue analgesic medication to assess the response of the clinical picture, and she was discharged 24 hours after admission with a favorable evolution. CONCLUSIONS: IgG subclass deficiency is a pathology characterized by the fact that it occurs in women over 16 years of age, with a very low prevalence; the presence of respiratory pathologies gives rise to the suspicion of this disease. The treatment of this pathology is based solely on the intravenous or subcutaneous administration of Immunoglobulin G, together with the concomitant treatment of the infections that the patient presents. Adverse effects should always be taken into account, as they are temporary, but quite disabling. KEYWORDS: Headache, Immunoglobulin G, Urinary Tract Infections, Herpes Simplex

Immunological evaluation of patients with orthopedic infections: taking the Cierny-Mader classification to the next level.

Introduction: Cierny–Mader osteomyelitis classification is used to label A, B, or C hosts based on comorbidities. This study's purpose was to define the “true” host status of patients with orthopedic infection using serologic markers to quantify the competence of their immune system while actively infected. Methods: Retrospective chart review identified patients at a single-surgeon practice who were diagnosed with orthopedic infection between September 2013 and March 2020 and had immunological laboratory results. All patients were A or B hosts who underwent surgery to eradicate infection. Medical history, physical examination, and Cierny–Mader classification were recorded. Laboratory results included complement total, C3, C4, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), immunoglobulin E (IgE), rheumatoid factor, and antineutrophil cytoplasmic antibodies (ANCA) panel. Clinically significant results were defined as flagged abnormal. Normal complement levels and normal IgG levels were considered abnormal when infection was present. Results: Of 105 patients, 99 (94 %) had documented lab abnormalities. Clinically significant abnormalities were found in 33 of 34 (97 %) type-A hosts and 66 of 71 (93 %) type-B hosts. Eleven of 105 (10.5 %) patients were formally diagnosed with primary immunodeficiency by a hematologist. IgG deficiency, of either low or normal value, in the face of infection comprised 91 % (30 of 34) type-A hosts and 86 % (56 of 71) type-B hosts. Six (5.7 %) patients received IgG replacement therapy. Twenty-eight patients had abnormal total complement levels (low or normal): 7.4 % (2 of 34) A hosts and 40 % (26 of 71) B hosts (). B hosts had statistically significantly lower complement levels and significantly more no-growth cultures (). Thirteen of 14 patients with recurrent infections had low or normal IgG levels. IgM was significantly lower between reinfected patients and those without reinfection (). Conclusions: Adding immunologic evaluation to the Cierny–Mader classification more accurately determines patients' true host status and better quantifies risk and outcome with respect to orthopedic infection. Immunologically deficient A hosts should be quantified as B hosts. IgG deficiencies may be addressed when deemed appropriate by the consulting hematologist/immunologist. Patients with recurrent infections had significantly lower IgM levels than their nonrecurrent infection counterparts.

A Novel Point-of-Care Rapid Diagnostic Test for Screening Individuals for Antibody Deficiencies

PurposeNo rapid diagnostic test exists to screen individuals for primary antibody deficiencies (PAD) at or near the point of care. In settings at risk for polio where live oral polio vaccine is utilized, undiagnosed PAD patients and cases with delayed diagnosis constitute a potential reservoir for neurovirulent polioviruses, undermining polio eradication.This research aimed to develop a rapid screening test suited for use in resource-limited settings to identify individuals with low immunoglobulin G (IgG) levels, enabling early diagnosis and appropriate treatment.MethodsThree prototype tests distinguishing low and normal IgG levels were evaluated with a blinded panel of serum/plasma specimens from 32 healthy controls and 86 primary immunodeficiency-confirmed patients with agammaglobulinemia, common variable immunodeficiency, and hyper-IgM syndrome, including 57 not receiving IgG therapy. Prototype tests were compared to laboratory reference and clinical case definition.ResultsThe leading prototype correctly identified 32 of 32 healthy controls. Among primary antibody deficiency patients not receiving IgG treatment, 17 of 19 agammaglobulinemia, 7 of 24 common variable immunodeficiency, and 5 of 14 hyper-IgM were correctly identified by the prototype, with 67% agreement with the reference assay.ConclusionThe Rapid IgG Screen (RIgGS) test can differentiate between low IgG levels associated with agammaglobulinemia and normal IgG antibody levels. Differentiating CVID and hyper IgM was challenging due to the wide range in IgG levels and influence of high IgM. This test can facilitate the identification of patients with primary antibody deficiencies and support polio surveillance initiatives.

Specific Antibody Deficiency in Adult Patients With IgG or IgG Subclass Deficiency

PurposeSpecific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine despite having normal immunoglobulin levels. The failure of the polysaccharide response can be observed as a component of various primary antibody deficiencies. However, only a few studies have described the clinical and immunological profiles in SAD and/or other primary immunodeficiencies (PIDs) in adults.MethodsA total of 47 patients who had a clinical history suggestive of antibody deficiency or had already been diagnosed with various antibody deficiencies were enrolled. Polysaccharide responses to 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) were measured using the World Health Organization enzyme-linked immunosorbent assay (WHO-ELISA), and postvaccination immunoglobulin G (IgG) titers were compared to clinical and laboratory parameters.ResultsBased on the American Academy of Allergy, Asthma, and Immunology (AAAAI) criteria for the WHO-ELISA, 11 (23.4%) patients were diagnosed as having SAD. Sixteen-three percent of them had combined with other types of PID, such as IgG subclass deficiency and hypogammaglobulinemia. Postvaccination IgG titers for the serotypes 4/9V/18C correlated with IgG2 (P = 0.012, P = 0.001, and P = 0.004) and for 6B/9V/14 with IgG3 (P = 0.003, P = 0.041, and P = 0.036, respectively). The IgG3 subclass levels negatively correlated with forced expiratory volume in 1 second (FEV1, %) and FEV1/forced vital capacity (P < 0.001 and P = 0.001, respectively).ConclusionSAD can be diagnosed in patients with normal IgG levels as well as in those deficient in IgG or the IgG3 subclass, implicating that restricted responses to Streptococcus pneumoniae polysaccharide antigens commonly exist in patients with predominantly antibody deficiency.

Immunoglobulin deficiency as an indicator of disease severity in patients with COVID-19.

Despite the pandemic status of COVID-19, there is limited information about host risk factors and treatment beyond supportive care. Immunoglobulin G (IgG) could be a potential treatment target. Our aim was to determine the incidence of IgG deficiency and associated risk factors in a cohort of 62 critically ill patients with COVID-19 admitted to two German ICUs (72.6% male, median age: 61 yr). Thirteen (21.0%) of the patients displayed IgG deficiency (IgG < 7 g/L) at baseline (predominant for the IgG1, IgG2, and IgG4 subclasses). Patients who were IgG-deficient had worse measures of clinical disease severity than those with normal IgG levels (shorter duration from disease onset to ICU admission, lower ratio of to , higher Sequential Organ Failure Assessment score, and higher levels of ferritin, neutrophil-to-lymphocyte ratio, and serum creatinine). Patients who were IgG-deficient were also more likely to have sustained lower levels of lymphocyte counts and higher levels of ferritin throughout the hospital stay. Furthermore, patients who were IgG-deficient compared with those with normal IgG levels displayed higher rates of acute kidney injury (76.9% vs. 26.5%; P = 0.001) and death (46.2% vs. 14.3%; P = 0.012), longer ICU [28 (6–48) vs. 12 (3–18) days; P = 0.012] and hospital length of stay [30 (22–50) vs. 18 (9–24) days; P = 0.004]. Univariable logistic regression showed increasing odds of 90-day overall mortality associated with IgG-deficiency (odds ratio 5.14, 95% confidence interval 1.3–19.9; P = 0.018). IgG deficiency might be common in patients with COVID-19 who are critically ill, and warrants investigation as both a marker of disease severity as well as a potential therapeutic target.

Real-World IgG Testing Frequency and Characteristics Associated with Hypogammaglobulinemia after Anti-CD20 Exposure in Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: Hypogammaglobulinemia is a known potential adverse event in patients with CLL receiving anti-CD20 monoclonal antibody (mAb) therapy. However, real-world immunoglobulin G (IgG) testing rates have not been extensively studied. We used a real-world database to investigate IgG testing rates in patients with CLL before and after anti-CD20 exposure. We further examined factors that increased the likelihood of new onset hypogammaglobulinemia following anti-CD20 therapy. Methods: The Flatiron Health EHR-derived de-identified database was used to select patients with abstraction-confirmed CLL diagnosed before 6/1/2020 with: (1) Exposure to an anti-CD20 mAb, (2) At least one IgG lab within 180 days prior to first anti-CD20 line start, and (3) No evidence of hypogammaglobulinemia (IgG &amp;lt; 7g/L) within 6 months prior to first anti-CD20 line start. A "hypogammaglobulinemia detection window" was defined for each patient as the time between first anti-CD20 administration through to 365 days thereafter. Patients were grouped into 3 categories: (A) "Unknown status": those with no IgG testing during the window, (B) "Confirmed hypogam": those with hypogammaglobulinemia detected on any test during the window, and (C) "No detected hypogam": those tested for IgG during the window with 0 tests meeting the hypogammaglobulinemia threshold. Demographic and clinical baseline characteristics were compared across the groups. A logistic regression was performed to compare factors associated with higher likelihood of detecting hypogammaglobulinemia among patients with an IgG test in the detection window. Factors included were: patient age at start of detection window, exposure to chemotherapy before detection window (Y/N), concurrent chemotherapy to anti-CD20 during the detection window (Y/N), and whether anti-CD20 was given in the first line (1L) setting (Y/N). We also performed a separate scenario analysis with outcome of severe hypogammaglobulinemia (IgG &amp;lt; 5 g/L, compared to &amp;lt; 7 g/L in primary analysis). Results: We found 5,838 anti-CD20 mAb-exposed patients with CLL, of which 1,927 (33%) had at least 1 IgG lab within 180 days of anti-CD20 start. Of those, 922 (48%) had hypogammaglobulinemia within 6 months prior to starting anti-CD20 therapy, leaving 1,005 patients in the cohort. 526 patients (52%) fell into the 'unknown status' category. 182 (18%) patients fell into the 'confirmed hypogam' category, and 297 (30%) fell into the 'no hypogam detected' category. Patients across these 3 categories had similar baseline characteristics (Table 1). Among the patients with an IgG test in the detection window (N=479), patients with 'confirmed hypogam' had more IgG tests during the window than the patients with 'no detected hypogam' (mean 3.9 vs. 2.8 tests, p&amp;lt;0.001). Results of the logistic regression for IgG &amp;lt; 7 g/L did not yield any factors significantly associated with higher likelihood of hypogammaglobulinemia (Table 2). However, the regression at IgG &amp;lt; 5 g/L (incl. changing cohort inclusion criteria 3, N=703) found that concurrent exposure to chemotherapy was associated with higher likelihood of severe documented hypogammaglobulinemia (odds ratio 1.89; 95% CI 1.23-2.96; p = 0.004). Conclusions: In this real-world cohort of patients with CLL with at least one IgG test within 6 months prior to anti-CD20 mAb initiation, hypogammaglobulinemia was common. A majority of the cohort was not tested for IgG post anti-CD20 mAb initiation, which likely reflects clinical practice of infrequently obtaining IgG levels in patients with normal pre-treatment IgG levels. As clinically expected, patients with hypogammaglobulinemia were tested for IgG more frequently than those who were not. This hypothesis-generating study suggests that administering chemotherapy concurrently to anti-CD20 mAbs increases the likelihood of documented severe hypogammaglobulinemia (IgG &amp;lt; 5g/L) in patients with CLL. Further research should confirm this. Our analyses did not account for patients who may have had transient hypogammaglobulinemia during anti-CD20 treatment, and did not stratify by intravenous immunoglobulin (IVIG) usage in this population. Further research should examine the effect of anti-CD20-associated hypogammaglobulinemia on outcomes, and determine if IgG surveillance should be standardized as part of clinical guidelines. Disclosures Hooley: Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Maignan:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Jacob:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Medina:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Benderoff:Roche Group: Current equity holder in publicly-traded company; Flatiron Health Inc: Current Employment, Research Funding. Chen:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Huntington:AbbVie: Consultancy; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; DTRM: Research Funding; Genentech: Consultancy; Novartis: Consultancy; Pharmacyclics: Honoraria; TG Therapeutics: Research Funding.

Low immunoglobulin G level is associated with poor outcomes in patients with sepsis and septic shock.

Despite studies on low immunoglobulin G (IgG) levels in critically ill patients, their association with clinical outcomes in sepsis patients remains disputed. Herein, we determined the association between low IgG levels and clinical outcomes and investigated the 28-day mortality in patients with low IgG levels. We retrospectively identified 238 patients whose serum IgG levels were measured upon intensive care unit admission using medical record data collected between January 2013 and August 2018. We extracted data on patient characteristics, severity scores (APACHE II, SOFA score), neutrophil-lymphocyte ratio (NLR), procalcitonin levels, and serum IgG levels and calculated the cut-off value for the IgG level according to the evaluated clinical outcomes. The primary outcome was 28-day mortality. There were no significant differences in NLR and procalcitonin levels between survivors and non-survivors; serum IgG levels were significantly higher in survivors than in non-survivors (P=0.004). A serum IgG cut-off value of 670mg/dL was calculated from receiver operating characteristic curve analysis, and serum IgG levels significantly predicted survival with an area under the curve of 0.63 (95% CI, 0.54-0.72) (P=0.004). Patients with low IgG levels (<670mg/dL) had significantly higher mortality rates than those with normal IgG levels (≥670mg/dL) (P<0.001). Our results reveal that low IgG levels (<670mg/dL) in critically ill patients are associated with poor clinical outcomes related to 28-day mortality. In patients with sepsis, low IgG levels could be a predictor of poor outcome.

Features and outcome of AIH patients without elevation of IgG.

Background & AimsHigh IgG levels are considered a hallmark of autoimmune hepatitis (AIH). A subgroup of patients with AIH has IgG within the normal range despite evidence of clinical disease activity. The clinical significance of this biomarker has not been explored.MethodsIn a European multicentre study we compared biochemical, clinical and histological features from patients with AIH and normal IgG-values at diagnosis to an age- and sex-matched control group of patients with typical AIH presenting with elevated IgG. Data were assessed at diagnosis, after 12 months of therapy and at last follow-up.ResultsOut of 1,318 patients with AIH, 130 (10%) had normal IgG at presentation. Histological and biochemical parameters at diagnosis, as well as treatment response, showed no difference between groups. Stable remission off treatment was achieved more commonly in the normal IgG group than in the typical AIH group (24 vs. 8%; p = 0.0012). Patients of the control group not only had higher IgG levels (29.5 ± 5.8 vs. 12.5 ± 3.2 g/L; p <0.0001), but also a higher IgG/IgA ratio (9.3 ± 6.9 vs. 5.4 ± 2.4; p <0.0001) at diagnosis. The IgG/IgA ratio only declined in patients with typical AIH and was no longer different between groups after 12 months (6.3 ± 4.3 vs. 5.5 ± 2.2; p = 0.1), indicating a selective increase of IgG in typical AIH and its suppression by immunosuppression. Autoantibody titres were higher in the typical AIH group, but not when controlled for IgG levels.ConclusionsCompared to AIH with typical biochemical features, patients with normal IgG levels at diagnosis (i) show similar biochemical, serological and histological features and comparable treatment response, (ii) appear to lack the selective elevation of serum IgG levels observed in typical active AIH disease, (iii) may represent a subgroup with a higher chance of successful drug withdrawal.Lay summaryA characteristic feature of autoimmune hepatitis (AIH) is an elevation of immunoglobulin G (IgG), which is therefore used as a major diagnostic criterion, as well as to monitor treatment response. Nevertheless, normal IgG does not preclude the diagnosis of AIH. Therefore, we herein assessed the features of patients with AIH and normal IgG in a large multicentre study. This study demonstrates that about 10% of all patients with AIH have normal IgG; these patients are indistinguishable from other patients with AIH with respect to biochemical markers, liver histology, disease severity and treatment response, but might represent a subgroup with a higher chance of remission after drug withdrawal.

Rituximab-induced IgG hypogammaglobulinemia in children with nephrotic syndrome and normal pre-treatment IgG values.

BACKGROUNDIn paediatric patients with complicated nephrotic syndrome (NS), rituximab (RTX) administration can induce persistent IgG hypogammaglobulinemia among subjects showing low basal immunoglobulin G (IgG) levels.AIMTo evaluate the effect of RTX on IgG levels and infections in patients with complicated NS and normal basal IgG levels.METHODSWe consecutively enrolled all patients with complicated NS and normal basal IgG levels undergoing the first RTX infusion from January 2008 to January 2016. Basal IgG levels were dosed after 6 wk of absent proteinuria and with a maximal interval of 3 mo before RTX infusion. The primary outcome was the onset of IgG hypogammaglobulinemia during the follow-up according to the IgG normal values for age [mean ± standard deviation (SD)].RESULTSWe enrolled 20 patients with mean age at NS diagnosis of 4.2 ± 3.3 years. The mean age at the first RTX infusion was 10.9 ± 3.5 years. Eleven out of twenty patients (55%) developed IgG hypogammaglobulinemia. None of these patients showed severe or recurrent infections. Only one patient suffered from recurrent acute otitis media and underwent substitutive IgG infusion. Three patients undergoing only the two “starting doses” experienced normalization of IgG levels. Using Kaplan-Meier analysis, the cumulative proportion of patients free of IgG hypogammaglobulinemia was 57.8% after the first RTX dose, 51.5% after the third dose, 44.1% after the fourth dose, and 35.5% after the fifth dose.CONCLUSIONRTX can induce IgG hypogammaglobulinemia in patients with pre-RTX IgG normal values. None of the treated patients showed severe infections.

Long-term clinical outcomes in patients with autoimmune hepatitis according to treatment response in Asian country.

As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long-term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain. A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (<1year) and late CBR (≥1year) by the timing of remission. Liver-related adverse outcomes including liver-related death, liver transplantation and hepatocellular carcinoma were evaluated. With immunosuppressive treatment, 222 (76.3%) patients achieved CBR (early CBR: 168 and late CBR: 54). BR was achieved in 55 (18.9%) patients and 14 (4.8%) patients remained non-remission. With a median follow-up duration of 6.6years, the risk of liver-related mortality was the lowest in patients with CBR, followed by patients with late CBR, BR and non-response. The cumulative risk of liver-related adverse outcomes was the highest in patients with non-response (8.51/100 person-years [PYs]), followed by BR (1.95/100 PYs), late CBR (1.89/100 PYs) and early CBR (0.75/100 PYs). By multivariable analysis, age, cirrhosis and treatment responses were independently associated with liver-related adverse outcomes. Patients with CBR within 1year after treatment initiation had the lowest risk of liver-related adverse outcomes. Patients with late CBR and those with only BR had a comparable risk of long-term outcomes.

The clinical utility of immunoglobulin G4 in the evaluation of autoimmune pancreatitis and pancreatic adenocarcinoma

BackgroundElevation in the serum immunoglobulin-G4 (IgG4) level has been used as a diagnostic marker to distinguish autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC), but its true utility is ill-defined. This study evaluates the clinical utility of IgG4 in differentiating AIP from PDAC. MethodsAll patients evaluated in the hepatopancreaticobiliary surgery clinics with measured serum IgG4 were included. Patients were divided into normal IgG4 (<135 mg/dL) and elevated IgG4 (≥135 mg/dL) groups. The final diagnosis was determined by operative pathology when available or by clinical outcome. The sensitivity, specificity, PPV, and NPV of IgG4 for diagnosing AIP was assessed. ResultsBetween 1997 and 2015, 298 patients were identified. Normal IgG4 levels were present in 85% of patients (254/298), while 15% (44/298) were elevated. The overall prevalence of AIP was 17% (52/298). The sensitivity and specificity of IgG4 for AIP was 67% and 96%, respectively; however, the PPV was only 80%, including a 9% occurrence of PDAC in patients with an elevated IgG4. ConclusionIn this study of selected patients who underwent IgG4 testing, 9% of elevated IgG4 patients had PDAC. The overreliance on IgG4 as diagnostic for AIP may lead to mis-diagnosis and delayed treatment for PDAC.

Author response: Teaching NeuroImages: Idiopathic hypertrophic pachymeningitis.

As discussed by Dr. Budhram, immunoglobulin G4 (IgG4)–related disease (RD) must be considered in patients with hypertrophic pachymeningitis (HP) as it accounts for a high proportion of cases originally thought to be idiopathic.1 IgG4-related HP is pathologically characterized by a lymphoplasmacytic infiltration of IgG4-positive plasma cells.2 The patient we presented had normal IgG4 levels in both serum and CSF.1 Dural biopsy was consistent with a chronic lymphohistiocytic pachymeningitis without substantial plasma cell infiltrate to suggest IgG4-RD. In addition, immunohistochemistry performed on the dural biopsy specimen was IgG4-negative. Our case highlights the steroid responsiveness of idiopathic HP and the excellent response to immunotherapy with methotrexate.1 We agree with Dr. Budhram that immunostaining of dural specimens should be done in patients with HP, as this may help guide treatment for steroid-refractory HP when IgG4 disease can be identified.

Prevalence of IgG-4-associated cholangiopathy based on serum IgG-4 levels in patients with primary sclerosing cholangitis and its relationship with inflammatory bowel disease.

Autoimmune cholangiopathy is part of a fibro-inflammatory immunoglobulin G-4 (IgG-4)-related systemic disease that causes biliary tract strictures. Its clinical presentation is quite similar to that of more common diseases such as primary sclerosing cholangitis (PSC) and pancreatobilliary malignancies. The aims of the present study were to evaluate the prevalence of IgG-4-associated cholangiopathy (IAC) in patients diagnosed with PSC and its relationship with inflammatory bowel disease (IBD). Serum IgG-4 levels were measured in 73 patients. Laboratory data and imaging and endoscopic results were collected from their medical records. The diagnosis of PSC was based on the results of imaging and laboratory data as well as clinical presentation. Serum IgG-4 levels were elevated in 12 patients (16%); half of these patients had IBD. In the group of patients with normal serum IgG-4 levels, 39 patients (63.9%) had IBD (p=0.364). There were no significant statistical differences between PSC patients with normal and elevated serum IgG-4 levels in terms of age, smoking, presence of IBD, extension and severity of IBD, esophageal and gastric varices, Child and the model for end-stage liver disease (MELD) scores, and anatomical location of the biliary stricture (p>0.05). The prevalence of ascites was higher in patients with elevated serum IgG-4 levels (p=0.029). Compared with previous reports, high serum IgG-4 levels were detected in a higher percentage of patients with a preliminary diagnosis of PSC (12% versus 16%). However, there were no clinical or imaging characteristics that could differentiate PSC patients with normal IgG-4 levels from PSC patients with higher IgG-4 levels.

Relationship between dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor and paranasal sinusitis.

To determine the clinical features of the dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor and its relationship with paranasal sinusitis. A retrospective analysis of 46 patients who received surgical treatment at the Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University for the dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor from October 2010 to December 2012. Each patient underwent magnetic resonance imaging (MRI) of the orbits and the 4 paranasal sinuses. Disease status and the level of serum immunoglobulin G4 (IgG4) was measured before and 6mo after surgery. The initial clinical feature of the idiopathic dacryoadenitis type of orbital inflammatory pseudotumor was redness or swelling of the eyelids. Masses were palpated in the area of the lacrimal gland in some patients. Of the 46 patients, 16 also suffered from sinusitis (34.8%), with 14 cases of ethmoid sinusitis, 8 cases of maxillary sinusitis, 9 cases of sphenoid sinusitis, and 8 cases of frontal sinusitis. Of the 16 patients with sinusitis, 4 patients had a medical history of rhinitis (range: 10mo to 15y previously), 10 patients had occasional nasal congestion, and 2 patients had no nasal congestion. Thirteen of the 46 patients had elevated serum IgG4 levels. Nine of these 13 patients had MRI signs of sinusitis. All patients (n=46) received oral glucocorticoid treatment for approximately 3mo after surgery. No sign of recurrence was found in the orbital MRI 6mo after surgery. Of the 16 patients with sinusitis, 9 cases of elevated serum IgG4 levels improved after treatment with decreased serum IgG4 level and 7 cases of normal serum IgG4 levels remained unchanged. Some patients with the dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor may also suffer from paranasal sinusitis. The incidence of paranasal sinusitis was much higher in patients with IgG4-elevated dacryoadenitis subtype orbital inflammatory pseudotumor than in those with normal IgG4 levels. Dacryoadenitis subtype orbital inflammatory pseudotumor and paranasal sinusitis may both the clinical manifestations of IgG4-related disease involved in different locations.

Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: Natural history, clinical correlates, and outcomes.

Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III-IV; P = .001) and higher expression of CD49d (P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long-term follow-up. The presence of hypogammaglobulinemia does not appear to impact overall survival.

Clinical Characteristics of Adults With Chronic Rhinosinusitis and Specific Antibody Deficiency

Specific antibody deficiency (SAD) involves a deficient response to a polysaccharide vaccine in the setting of normal immunoglobulin G (IgG) levels and chronic infections. Patients with chronic rhinosinusitis (CRS) are often evaluated for SAD. There are limited data that describe patients with CRS and SAD. The objective of this study was to better characterize the role of SAD in CRS. We reviewed electronic records of adults with CRS who were evaluated for immunodeficiency with quantitative Ig levels and pre- and postantibody titers to a pneumococcal polysaccharide vaccine (PPV). Fourteen pneumococcal serotypes were determined in 239 subjects from 2002 to 2009. Of these subjects, 64 had adequate protective titers of 1.3 μg/mL or higher in 7 or more serotypes of the 14 serotypes checked; 56 (23%) had less than 7 protective titers post-PPV and were diagnosed with SAD; and 119 had an adequate response to the vaccine with 7 or more serotypes being higher than 1.3 μg/mL (>50% response) and were characterized as "responders." Subjects with SAD received more antibiotic courses relative to responders in the 2 years after immunization (3.19 ± 2.64 vs 2.19 ± 2.24, P < .05). Of 56 subjects with SAD, 10 (17.9%) received Ig replacement therapy. Subjects who received Ig had fewer numbers of protective pneumococcal titers post-PPV and had more pneumonia (40.0%) versus subjects with SAD who did not receive Ig (10.9%). Of the 239 patients with CRS with normal IgG levels evaluated for immunodeficiency, 56 (23.4%) had SAD. A majority of patients with SAD may not need Ig replacement; however, a subset of patients with SAD benefit from Ig replacement.