Tamsin Cargill

Elevated Serum IgG4 Levels in Diagnosis, Treatment Response, Organ Involvement, and Relapse in a Prospective IgG4-Related Disease UK Cohort.

OBJECTIVES:Elevated serum immunoglobulin G4 (IgG4) levels have been associated with autoimmune pancreatitis and IgG4-related disease (IgG4-RD) for over a decade. However, an elevated serum IgG4 is not specific for the disease. There have been inconsistent reports of its use in diagnosis, as a marker of disease relapse, and its relationship to organ involvement in retrospective cohorts. The aims of this study were to ascertain conditions that are associated with an elevated serum IgG4 and to investigate the role of IgG4 in diagnosis, relapse, and organ involvement in a prospective cohort of patients with IgG4-RD.METHODS:We evaluated serum IgG4 measurements in the Oxford Immunology Laboratory over 6 years. Patients in whom serum IgG4 was requested to differentiate IgG4-RD from other diseases were recruited into a longitudinal follow-up study to determine final diagnosis. In a prospective cohort of IgG4-RD patients, organ involvement, response to therapy, and disease relapse were determined.RESULTS:Two thousand and sixty-seven samples from 1,510 patients had serum IgG4 measured. Of these, IgG4 was elevated (≥1.4 g l−1) in 243 (16.1%) patients. The main indication (85.6%) was to distinguish between IgG4-RD and non-IgG4-RD conditions. Only 5.1% of patients who had serum IgG4 measured for this purpose had a final diagnosis of IgG4-RD. Of those with an elevated serum IgG4, 22.4% met IgG4-RD diagnostic criteria. Serum IgG4 was elevated in 48 (82.8%) of IgG4-RD patients. An IgG4 cutoff of 1.4 g l−1 gave a sensitivity of 82.8% and specificity of 84.7% to diagnose IgG4-RD. Increasing this to 2.8 g l−1 increased specificity to 96.2% and negative predictive value to 97.7%, with a lower sensitivity of 56.9% and positive predictive value of 44.5%. Serum IgG4 levels fell with corticosteroid therapy, but this was not disease-specific. A serum IgG4 of ≥2.8 g l−1 at diagnosis was associated with multi-organ involvement and risk of relapse.CONCLUSIONS:Serum IgG4 levels are elevated in multiple non-IgG4-RD inflammatory and malignant conditions, with less than one-quarter of those with an elevated IgG4 meeting IgG4-RD diagnostic criteria. A serum IgG4 of ≥2.8 g l−1 is useful in distinguishing between IgG4-RD and non-IgG4-RD diagnoses, predicting multiple-organ involvement and risk of relapse in IgG4-RD.

Intravenous artesunate versus intravenous quinine in the treatment of severe falciparum malaria: a retrospective evaluation from a UK centre

Abstract Introduction: Despite evidence from developing world trials that intravenous (IV) artesunate (AS) is superior to IV quinine (Q) in severe falciparum malaria (FM), IV AS remains unlicensed in the UK with national guidelines listing it as an acceptable alternative to IV Q as the drug of choice. We retrospectively evaluate the safety and effectiveness of IV AS in returning travellers with severe FM. Methods: We identified adults admitted to the Infectious Diseases unit with severe FM and treated with IV Q (1991–2009) or IV AS (2009–2011). Outcomes included adverse events, mortality, length of stay, admission to intensive care and, where data were available, parasite/fever clearance time and hypoglycaemic events. Results: Of 167 patients, 24 received IV AS and 143 IV Q. There was one potential AS-associated adverse event, a case of late onset haemolysis. Median length of stay (LOS) was significantly shorter for AS (3·5 versus 5 days, P = 0·017), even after adjusting for African ethnicity (for LOS ⩾3 days, mhor = 0·33, P = 0·027; crude OR = 0·29, P = 0·013). In the AS group, there were no fatalities (versus five in Q group, NS) and fewer intensive care unit (ICU) admissions (NS). Median parasite clearance was significantly faster in AS (65 versus 85 hours in Q, P = 0·0045) with no hypoglycaemic episodes (versus five in Q). Discussion: We found IV AS to be safe and effective, with shorter LOS, faster parasite and fever clearance, no fatalities or hypoglycaemic events, and fewer ICU admissions versus IV Q. This corroborates both developing world trials and smaller European case series (although these lacked comparison groups). As well as obvious benefits for patients, there are potential resource savings. A case of late-onset haemolysis may represent an adverse event, particularly as it has been documented elsewhere, warranting further investigation. Nonetheless, our experience suggests IV AS should be first-line for treating severe FM in the UK.

Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease

Background IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition, characterised by an elevated serum IgG4 concentration and abundant IgG4-positive plasma cells in the involved organs. An important question is whether the elevated IgG4 response is causal or a reflection of immune-regulatory mechanisms of the disease. Objectives To investigate if the IgG4 response in IgG4-RD represents a generalised polyclonal amplification by examining the response to common environmental antigens. Methods Serum from 24 patients with IgG4-RD (14 treatment-naive, 10 treatment-experienced), 9 patients with primary sclerosing cholangitis and an elevated serum IgG4 (PSC-high IgG4), and 18 healthy controls were tested against egg white and yolk, milk, banana, cat, peanut, rice and wheat antigens by radioimmunoassay. Results We demonstrated an elevated polyclonal IgG4 response to multiple antigens in patients with IgG4-RD and in PSC-high IgG4, compared with healthy controls. There was a strong correlation between serum IgG4 and antigen-specific responses. Responses to antigens were higher in treatment-naive compared with treatment-experienced patients with IgG4-RD. Serum electrophoresis and immunofixation demonstrated polyclonality. Conclusions This is the first study to show enhanced levels of polyclonal IgG4 to multiple antigens in IgG4-RD. This supports that elevated IgG4 levels reflect an aberrant immunological regulation of the overall IgG4 response, but does not exclude that causality of disease could be antigen-driven.

Increases in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related Disease.

BACKGROUND & AIMS: IgG subclass 4–related disease (IgG4‐RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4‐positive plasma cells. We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4‐RD. We investigated the association between serum IgE and diagnosis and relapse of this disease. METHODS: We performed a prospective study of 48 patients with IgG4‐RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals (healthy control subjects) recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months (range, 3–73 months). Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4‐RD; levels at diagnosis were compared with baseline levels of control subjects. Allergen‐specific IgEs were measured using the IgE ImmunoCAP. Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4‐RD and disease control subjects were measured by immunohistochemistry. We analyzed data using the Spearman rank correlation and receiver operating characteristic curves. RESULTS: Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4‐RD, respectively, compared with 6% and 16% of healthy control subjects (P < .0001). Peripheral blood eosinophilia was detected in 38% of patients with IgG4‐RD versus 9% of healthy control subjects (P = .004). Of patients with IgG4‐RD, 63% had a history of allergy and 40% had a history of atopy with an IgE‐specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P < .05). Level of IgE at diagnosis >480 kIU/L distinguished patients with IgG4‐RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2. Level of IgE at diagnosis >380 kIU/L identified patients with disease relapse with 88% specificity, 64% sensitivity, and a likelihood ratio of 5.4. IgE‐positive mast cells and eosinophilia were observed in lymphoid, biliary, and pancreatic tissue samples from 50% and 86% of patients with IgG4‐RD, respectively. CONCLUSIONS: In a prospective study, we associated IgG4‐RD with allergy, atopy, eosinophilia, increased serum levels of IgE, and IgE‐positive mast cells in lymphoid, biliary, and pancreatic tissue. An IgE‐mediated allergic response therefore seems to develop in most patients with IgG4‐RD; levels of IgE might be used in diagnosis and predicting relapse.

No evidence to support a role for Helicobacter pylori infection and plasminogen binding protein in autoimmune pancreatitis and IgG4-related disease in a UK cohort

Background and objectives Helicobacter pylori (H.pylori) plasminogen binding protein (PBP) has been proposed as an antigen triggering autoimmune pancreatitis (AIP), the pancreatic manifestation of IgG4-related disease (IgG4-RD). We investigated exposure to H. pylori infection, cytokine response and immunological memory to H. pylori PBP in a prospective IgG4-RD cohort in the UK. Methods Clinical and endoscopic evidence of peptic ulceration, serological H. pylori exposure and serum IgG4 levels were obtained in 55 IgG4-RD patients and 52 disease controls (DC) with autoimmune or inflammatory conditions with an elevated serum IgG4. Gastric and duodenal tissues were assessed for H. pylori and immunostained for IgG4. B and T cell ELISpot and cytokine luminex assays were used to detect immune responses to H. pylori PBP. Results 85% of IgG4-RD patients had pancreatic and/or biliary disease, 89% had extra-pancreatic manifestations, and 84% had an increased serum IgG4. Clinical dyspepsia (35.2%), gastritis (58%), peptic ulceration (7.4%) and H. pylori colonisation (24%) in IgG4-RD was similar to DC. In IgG4-RD, gastric tissue contained a chronic inflammatory infiltrate with a low IgG4+ plasma-cell count (<10/HPF; range 1–4/HPF), and duodenal specimens had an increased IgG4 count (>10/HPF; range 7–54) compared with DC (p < 0.01). Th1 and Th2 cytokine response and immunological B-cell memory to H. pylori PBP did not differ between IgG4-RD and DC. Conclusions In a prospective UK cohort, the prevalence of gastric ulceration, exposure to H. pylori, cytokine response and immunological memory to H. pylori PBP did not differ in IgG4-RD patients compared with DC. This study does not support a role for H. pylori PBP as a microbial antigen in IgG4-RD. Keywords for abstract Peptic ulceration, Antigens, B cells, T cells, Interleukins, Helicobacter pylori.

Thoracic involvement in IgG4-related disease in a UK-based patient cohort

IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder with classical histopathological findings, often in the context of elevated serum IgG4 levels. The thoracic manifestations of IgG4-RD are numerous and can mimic several common and better known conditions. The objective of this study was to outline the frequency and nature of thoracic involvement in a prospective cohort of IgG4-RD patients who met defined diagnostic criteria. Over 40% of IgG4-RD patients had clinicoradiological and/or histological evidence of thoracic involvement, predominantly mediastinal lymphadenopathy, the majority associated with multi-system disease outside the chest. Thoracic involvement was associated with a higher serum IgG4 level, potentially representing greater disease activity or spread. Our data highlight the diverse nature of thoracic IgG4-RD, and the importance of knowledge and recognition of the condition among respiratory physicians who are likely to encounter this disease entity on an increasing basis.

The commissioning and provision of advocacy for problem drug users in English DATS: A cross-sectional survey

Aims: This study investigated the commissioning and delivery of advocacy for problem drug users. We aimed to quantify provision, describe the commissioning of advocacy services in Drug Action Teams (DATs) and to identify factors influencing advocacy provision. Methods: A cross-sectional survey of a randomly selected sample of 50 English DATs. The purpose-designed questionnaire comprising a mix of closed and open questions was completed through a telephone interview. Findings: An 86% response rate was achieved. Informants understood ‘advocacy’ as encompassing a range of activities including user involvement and peer support. A range of approaches classified as formal, informal and ad hoc were described. Whilst advocacy was identified as a need in 29 DATs (67%), formal, independent advocacy was commissioned in only four (9%). In eight DATs (19%), there was no advocacy provision of any kind. Conclusions: Advocacy is described by the National Treatment Agency as an essential element of effective drug treatment systems. However, provision in English DATs is inconsistent, poorly integrated with treatment systems and characterized by the absence of strategic planning. Clarification of the concept and purpose of advocacy as either a right adhering to citizenship or a means to achieve treatment targets is an essential first step towards systematic and meaningful integration of advocacy within the treatment system.

P207 Thoracic involvement in IgG4-related disease

Background and objectives IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder originally described in association with autoimmune pancreatitis (AIP), usually but not always in the context of elevated serum IgG4 levels. Thoracic manifestations of IgG4-RD include mediastinal lymphadenopathy, lung nodules or masses, interstitial lung disease, bronchiectasis and pleural disease. The authors’ regional IgG4-RD service is one of the largest UK-based units treating patients with this condition. Specialist clinics and multidisciplinary team meetings operate alongside an active research programme. We aimed to describe the frequency with which thoracic abnormalities – either as a symptomatic presenting feature of IgG4-RD or an incidental asymptomatic finding on imaging – were present in a prospectively recruited patient cohort. Method and results Patients referred to the authors’ IgG4-RD service from 2005 onwards and confirmed as having a diagnosis of IgG4-RD were included. Diagnoses were made using established clinical criteria (HISORt for AIP and Japanese International Consensus Diagnostic Criteria for systemic disease); tissue specimens were assessed using the Boston histopathological consensus criteria where available. Patients were followed prospectively; clinicopathological data relating to presentation and clinical progress were stored in a secure database with the consent of participants. In patients without symptomatic thoracic manifestations of IgG4-RD, routine clinical imaging (CXR and CT) was reviewed where available for evidence of incidental asymptomatic disease. 61 IgG4-RD patients with thoracic imaging available were included; mean age at diagnosis was 60.3 years (SD 14.6). 43 (70.5%) patients were male. The majority of patients (85.2%) presented with features of intra-abdominal disease. 6 patients (9.8%) had evidence of symptomatic thoracic disease on the basis of clinical presentation, radiology and/or histology. A further 15 (24.6%) patients had abnormal imaging suggestive of asymptomatic thoracic IgG4-RD. Conclusion A significant proportion of IgG4-RD patients have evidence of symptomatic and asymptomatic thoracic manifestations of this multi-system disease. Respiratory physicians should consider IgG4-RD in their differential diagnosis for a range of pulmonary presentations, particularly where there is co-existing extra-thoracic organ involvement. Making a diagnosis of IgG4-RD impacts on access to established therapeutic options including corticosteroids and rituximab to which the disease is responsive in the inflammatory phase.