Publications

In chronological order, most recent first.



  • European Guideline on IgG4-related digestive disease - UEG and SGF evidence-based recommendations
    Löhr J-MBeuers UVujasinovic MAlvaro DBrøndum Frøkjær JButtgereit FCapurso GCulver ELde-Madaria EDella-Torre EDetlefsen S Dominguez-Muñoz ECzubkowski PEwald NFrulloni LGubergrits NGuney Duman DHackert TIglesias-Garcia JKartalis NLaghi ALammert FLindgren FOkhlobystin AOracz GParniczky APozzi Mucelli RMRebours VRosendahl JSchleinitz NSchneider AFh van Bommel EVerbeke CSPierre Vullierme MWitt HUEG guideline working group.
    PMID: 32552502 DOI: 10.1177/2050640620934911. United European Gastroenterology Journal, July 2020.






Layman summary: The recent recognition of IgG4-related disease as a distinct condition and the absence of a single diagnostic feature justifies the need for classification criteria. An international multispecialty group of 86 physicians assembled by the ACR/EULAR has described classification criteria for IgG4-RD from a cohort of 1879 subjects. It is to be used for inclusion into clinical trials and other studies – not for clinical practice – and is based on obtaining of a score of ≥ 20, calculated accross 3 steps including entry, exclusion and inclusion criteria. This classification has demonstrated excellent test performance with a sensitivity > 80% and a specificity > 90%.
 

Layman summary: The recent recognition of IgG4-related disease as a distinct condition and the absence of a single diagnostic feature justifies the need for classification criteria. An international multispecialty group of 86 physicians assembled by the ACR/EULAR has described classification criteria for IgG4-RD from a cohort of 1879 subjects. It is to be used for inclusion into clinical trials and other studies – not for clinical practice – and is based on obtaining of a score of ≥ 20, calculated accross 3 steps including entry, exclusion and inclusion criteria. This classification has demonstrated excellent test performance with a sensitivity > 80% and a specificity > 90%.
 

Layman summary: IgG4-related disease can affect organs in the abdomen including ducts in the liver (sclerosing cholangitis) and the pancreas (pancreatitis). People with these conditions often have a raised level of antibodies in the blood, known as ‘IgG4’. IgG4 antibodies are produced by immune cells, which in health act as the body’s defence system against infections. In this study we investigated a type of immune cell known to be involved in antibody production called a ‘T follicular helper cell’. We found these cells were active in the blood and in the inflamed tissue of people with IgG4-related disease compared to healthy people. Although further research is needed, these cells could be a target of therapy for IgG4-related disease in the future.

 

Zachary S Wallace, Yuqing Zhang, Cory A Perugino, Ray Naden, Hyon K Choi, John H Stone for the ACR/EULAR IgG4-RD Classification Criteria Committee
PMID: 30612117  DOI: 10.1136/annrheumdis-2018-214603

Layman summary: IgG4-related disease can affect multiple organs in the body. Diagnosing IgG4-related disease can sometimes be very difficult because the symptoms can mimic other conditions, and this can delay diagnosis and treatment. This study aimed to identify people with different subtypes of IgG4-related disease based on the pattern of organs affected. It surveyed IgG4-related disease experts from across the world who submitted over 700 cases of IgG4-related disease. It found that there are four different patterns of IgG4-realting disease where the main organs affected are (i) the pancreas and liver, (ii) scaring of the blood vessels and tissues at the back of the abdomen, (iii) the head and neck or (iv) the salivary glands. Females and persons of Asian descent were more likely to have IgG4-related disease affecting the head and neck than other subtypes. Further study is needed to understand whether there are certain environmental or genetic factors that may influence the development of certain IgG4-realated disease patterns.

 

Layman summary: IgG4-related disease can affect the kidneys directly or can cause tissue scarring at the back of the abdomen which might block kidney drainage. This study looked back at patients with IgG4-related disease affecting the kidneys in two hospitals in the United Kingdom. It describes the symptoms, blood test findings and scan findings of these patients to help other doctors diagnose and treat the condition. It found that in a group of 154 people with IgG4-related disease, 28 (18%) had involvement of the kidney or tissue at the back of the abdomen. In some of these patients their kidney function deteriorated over time. The study highlights the importance of identifying and treating IgG4-related disease affecting the kidney.
 

Layman summary: IgG4-related disease commonly affects the bile ducts in the liver, preventing them from draining and consequently causing yellowing of the skin (jaundice). There are many conditions other than IgG4-related disease that block the bile ducts and it is important that doctors make the correct diagnosis to provide the correct treatment. One test used to find the cause of bile duct blockage is via a camera (endoscope) passed through the mouth and stomach to the site where the bile ducts enter the gut. The bile ducts can be directly visualised, samples can be taken, and the ducts can be unblocked. This article reviews recent advances in the technique of endoscopy.
 

Layman summary: IgG4-related disease often affects the ducts in the liver (IgG4-related sclerosing cholangitis). This article describes the current knowledge of the causes, symptoms, tests treatments and long-term outcomes of the condition.
 

  • An International, Multi-Specialty Validation Study of the IgG4-Related Disease Responder Index.
    Wallace ZS, Khosroshahi A, Carruthers MD, Perugino CA, Choi H, Campochiaro C, Culver EL, Cortazar F, Della-Torre E, Ebbo M, Fernandes A, Frulloni L, Hart P, Karadag O, Kawa S, Kawano M, Kim MH, Lanzillotta M, Matsui S, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Tanasa P, Umehara H, Webster G, Zhang W, Stone JH.
    PMID: 29457382 PMCID: PMC6098740 [Available on 2019-08-18] DOI: 10.1002/acr.23543
Layman summary: The IgG4-responder index is a tool developed for doctors to assess the severity of IgG4-related disease in a person. It can be used over time to monitor the effectiveness of treatment. This study tested the responder index to see how reliably it could be used by different doctors assessing the same person. 26 doctors assessed 12 patient narratives using the index. 3 doctors assessed 15 patients with a new diagnosis of IgG4-related disease and followed them over time. The study found that different doctors agreed on similar scores using the index on the same patients. The score improved after treatment. This shows the IgG4-responder index is a realiable tool to assess the activity of IgG4-related disease and response to treatment.
 

Layman summary: IgG4-related disease can often affect the pancreas. It had been suggested that a common bacterium (Helicobacter pylori) that causes inflammation and ulcers in the stomach might be linked to IgG4-related disease. In this study 55 people with IgG4-related disease were compared to 52 people with different pancreatic or liver conditions. There was no difference between in previous exposure to Helicobacter pylori nor gastric inflammation or ulcers between the two groups, suggesting this bacterium does not trigger IgG4-related disease. 

Layman summary: IgG4-related disease can affect the lungs in a variety of ways. In this study, over 40% of people diagnosed with IgG4-related disease at a specialist centre had evidence of lung involvement either on scans of their chest or by the symptoms they had such as breathlessness. This study highlights to doctors the importance of recognising lung involvement in patients with IgG4-related disease so that it can be treated effectively. 

Layman summary: People with IgG4-related disease sometimes also have allergic conditions. In this study, blood markers associated with allergy were assessed in a group of people newly diagnosed with IgG4-related disease. In over 50% of people an antibody called ‘IgE’, associated with allergy was raised at diagnosis and allergy associated immune cells called ‘eosinophils’ were raised in over 40% of people. Tissue biopsies taken from people with active IgG4-related disease showed allergy related cells in the inflamed regions. Taken together with other parameters, levels of IgE in the blood can be used to help diagnose patients with IgG4-related disease. 

Layman summary: IgG4-related disease lead to inflammatory changes in affected organs that can be viewed under a microscope when a tissue sample is taken. These changes can be used to diagnose the condition, but sometimes other diseases cause similar appearances. This article describes 100 cases of tissue samples from patients with IgG4-related disease that were assessed by a pathologist using the ‘Boston Criteria’, to judge the likelihood of IgG4-related disease. It highlights the importance of tissue samples being used together with symptoms and imaging to make the correct diagnosis of IgG4-related disease. 

Layman summary: This article is an overview of IgG4-related disease, with a particular focus on the liver and pancreas. It explains why IgG4-related disease can be difficult to diagnose because it mimics other diseases and outlines new diagnostic tests that are in development. It explains how research into the cause of the disease has advanced but treatments to fully suppress the disease are still lacking. 

Layman summary: This article reports the unusual symptoms of a patient with IgG4-related disease affecting the large intestine and lymph nodes. It educates other doctors to improve their recognition of IgG4-realted disease.

Layman summary: Most patients with IgG4-related disease will have a raised blood level of the protein ‘IgG4’ when they first present with symptoms. However, a raised blood IgG4 measurement can also occur in many other diseases. This study looked at all the IgG4 measurements done in a hospital over a 6-year period and followed the patients to see if they had IgG4-RD or another condition. Of all the tests that were done (over 2000 tests for over 1000 patients), IgG4 was raised in 16%. Of the patients with a raised IgG4, less than a quarter had IgG4-related disease. Over 80% of patients diagnosed with IgG4-related disease had a raised blood IgG4 level and patients with several affected organs had a much higher level. The study shows that most people with a raised blood IgG4 do not have IgG4-related disease, but very raised levels make the diagnosis of IgG4-related disease more likely. 

Layman summary: The diagnosis of IgG4-related disease can be very difficult to make. This study describes two tests to diagnosis IgG4-related disease affecting the liver or pancreas, that distinguish it from other diseases that have similar symptoms. The first test assesses immune cells called ‘B cells’ that produce the IgG4 protein in the disease. The second test compares the ratio of the protein ‘IgG4’ with the protein ‘IgG’ in the blood. If this test was performed on 100 people where 40 have IgG4-RD, the test would be positive in 39 people and 1 (3%) would not have IgG4-realted disease (false-positives). The test would be negative in 61 people and of these 2 (3%) would have IgG4-related disease (false-negatives). Although more investigation is needed, these tests could be used by doctors to help diagnose IgG4-realted disease.

Layman summary: This article describes IgG4-relating disease that affects the pancreas. It explains how the disease can often present with a yellowing of the skin (jaundice) and can affect other organs as well as the pancreas. It outlines the current way to diagnose the disease with a combination of symptoms, blood tests, images and tissue samples because there is no single test. It advises on treatment with steroids and other drugs that dampen down inflammation and the immune system. It warns that if left untreated, the pancreas can become damaged and this can lead to diabetes (failure to control blood sugar) and difficulties digesting fat in foods.

Layman summary: It can often be difficult to decide on the best course of action when people have problems with the liver or pancreas. Sometimes this is because several conditions give rise to similar symptoms, blood test and imaging findings. Sometimes it is difficult to decide which treatment to give person, especially if previous treatments have not worked effectively. Multidisciplinary team meetings are when a group of expert doctors in different specialties come together and discuss such cases to make personalised management plans. This article discusses how these meetings can benefit treatment decisions.

Layman summary: This article describes guidelines for the treatment of the inflamed pancreas (autoimmune pancreatitis), decided on by a panel of international experts who reviewed the research available. The type of autoimmune pancreatitis associated with IgG4-related disease is especially difficult to treat as it often relapses. This article suggests steroids as initial treatment and discussed the dose and length of treatment time and alternative immune supressing treatments that can be used if steroids do not work. It highlights more research is needed to understand which treatments work best in autoimmune pancreatitis.

Layman summary: This article describes a rare complication after a patient with IgG4-related disease had a stent put in to unblock the duct draining the liver and pancreas. The stent moved through the liver and into the sac around the heart. The stent was removed, and the patient recovered. This article increases awareness of this very rare complication. 

Layman summary: This article describes IgG4-related disease occurring in the brain of 3 patients, which is a rare occurrence. It describes the parts of the brain affected in these individuals and how they were diagnosed and treated.

  • International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease.
    Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, Chari ST, Della-Torre E, Frulloni L, Goto H, Hart PA, Kamisawa T, Kawa S, Kawano M, Kim MH, Kodama Y, Kubota K, Lerch MM, Löhr M, Masaki Y, Matsui S, Mimori T, Nakamura S, Nakazawa T, Ohara H, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Shimatsu A, Shimosegawa T, Takahashi H, Takahira M, Tanaka A, Topazian M, Umehara H, Webster GJ, Witzig TE, Yamamoto M, Zhang W, Chiba T, Stone JH; Second International Symposium on IgG4-Related Disease. PMID: 25809420 DOI: 10.1002/art.39132
Layman summary: This article outlines the guidelines for the treatment of IgG4-related disease (affecting any organ) after a meeting of experts from several medical disciplines met to discuss the available research evidence and the way in which they locally practised. There was high agreement between experts on the ways in which IgG4-related disease should be diagnosed and that steroids should be used as the initial treatment. There was less agreement on whether other treatments were needed in most patients to control the disease in the long-term but all agreed that if disease relapse occurred, steroids should be used as treatment. It highlights that more research is needed to determine which treatments prevent relapse most effectively.



Layman summary: Attention is drawn to the newly described entity: IgG4-related sclerosing sialadenitis, which usually occurs in the sixth decade, with a male preponderance. An elevated IgG4 level, although not sufficient, can help for the diagnosis. A pathway for investigation of IgG4-related chronic sclerosing sialadenitis by the ENT surgeon is proposed in this article. The necessity and urgency of treatment depends on the organ involvement and the first-line treatment is corticosteroids. It is important that patients benefit from multidisciplinary management.

Layman summary: Is the elevated IgG4 response in IgG4-related disease causal or a reflexion of immune-regulatory mechanisms? This article investigates the possibility of the elevated IgG4 being an indirect consequence of the expansion of pre-existing IgG4-switched B cells. 24 patients with IgG4-RD, 9 with PSC and an elevated serum IgG4 and 18 healthy controls were tested against egg white and yolk, milk, banana, cat, peanut, rice and wheat antigens. The IgG4 response to several of these antigens was higher in patients with IgG4-RD than in healthy controls and higher in treatment naive compared with treatment-experienced patients. There was a strong correlation between serum IgG4 and antigen-specific responses. This study is the first to show an enhanced polyclonal IgG4 response to multiple non-infectious environmental antigens in IgG4-RD.  Elevated levels of IgG4 in patients with IgG4-RD may be the result primarily of a polyclonal expansion of many IgG4 B cells irrespective of their specificity and may reflect the abnormal immunological regulation of the overall IgG4 response in the disease. 
 



Layman summary: Chronic antigenic stimulation could underlie the elevated levels of serum IgG4 in IgG4-related disease. The investigation of the job history of IgG4-RD patients from 2 cohorts revealed 88 and 61% of manual work with chronic exposure to antigens. The rates were higher in comparison of 2 disease control cohorts of PSC patients, showing 14 and 22% of patients with a history of manual work. Chronic exposure to occupational antigens may play a role in the initiation and/or maintenance of IgG4-RD in susceptible individuals.








  • Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis.
    Hart PA, Kamisawa T, Brugge WR, Chung JB, Culver EL, Czakó L, Frulloni L, Go VL, Gress TM, Kim MH, Kawa S, Lee KT, Lerch MM, Liao WC, Löhr M, Okazaki K, Ryu JK, Schleinitz N, Shimizu K, Shimosegawa T, Soetikno R, Webster G, Yadav D, Zen Y, Chari ST
    PMID: 23232048 PMCID: PMC3862979 DOI: 10.1136/gutjnl-2012-303617


Layman summary: The Organizing Committee, consisting of 35 IgG4-RD experts, met in Boston in 2011 to discuss the terminology for this newly-emerged disease. Japanese investigators had reached a consensus to refer to it as IgG4-related disease, and the Organizing Committee approved of that term. This paper gives recommendations about general and individual organ involvement terminology.















Books and Book Chapters

1.      EL Culver & G Webster. Chapter 6: Clinical manifestations of type II autoimmune pancreatitis. 3rd Edition Pancreatology. In Press,   March 2016.
2.      T Cargill, EL Culver, RW Chapman. Chapter 5: IgG4-related sclerosing cholangitis. L Forman, Eds. Primary Sclerosing Cholangitis: Current Understanding, Management, and Future Developments, 1st Edition. March 2016.
3.      EL Culver & G Webster. Chapter 14: IgG4-related sclerosing cholangitis. G. Hirschfield Eds. Biliary disease: from Science to Clinic, 1st Edition. Sept 2015.
4.      EL Culver & AC Bateman. Chapter 8: IgG4-related disease. C Probert, Eds. Recent Advances in Gastroenterology, 1st Edition.  JP Medical. Aug 2013.
5.      S Almamari, EL Culver, RW Chapman. Chapter 5: IgG4 associated cholangitis. Carey & Lindor's Cholestatic Liver Disease, 2nd Edition. Humana Press. Sept 2013.