IgG4-related disease
What is it?
IgG4-Related Disease (IgG4-RD) is a recently described fibro-inflammatory condition with systemic involvement characterized by tumefactive lesions and serum IgG4 (immunoglobulin G4) elevation in the majority of patients. IgG4-RD can involve a single organ or multiple organs at the same time and shows a chronic course with a relapsing-remitting behavior.
IgG4-RD typically affects middle-aged to elderly men with only sporadic cases described in the pediatric population. IgG4-RD is considered a rare disease with a prevalence of 5 to 10 affected subjects in 100.000 individuals. Genetic or hereditary predispositions have not been identified yet. A recent study suggests that chronic professional exposure to solvents and metals – as it occurs, for instance, in Blue Collar workers – might represent an important risk factor for the development of IgG4-RD.
Causes and risk factors
IgG4-related diseases are more common in men than in women and are more common after 40-50 years of age. Pediatric cases are rarely described. Although epidemiological data are still incomplete, IgG4-associated disease appears to be more common in Japan.
Which are the symptoms?
IgG4-RD can affect virtually every organ site and many manifestations considered independent clinical entities for decades are now recognized part of the IgG4-RD spectrum. The most frequently affected organs are:
- the pancreas (“IgG4-related autoimmune pancreatitis”) and the biliary tract (“IgG4-related sclerosing cholangitis”);
- the salivary glands (“IgG4-related syaloadenitis”) and the lacrimal glands (“IgG4-related dacryoadenitis”);
- the orbit and the retro-orbital tissue (“IgG4-related orbital pseudotumor”);
- the aorta and the retroperitoneum (“IgG4-related retroperitoneal fibrosis / aortitis”);
- the kidneys (“IgG4-related tubule-interstitial nephritis”).
IgG4-RD typically presents with symptoms and signs arising because of the compression exerted by the fibrotic mass on adjacent anatomical structures. Due to its mass forming aspect and to the lack of accurate disease biomarkers, IgG4-RD is classically misdiagnosed with a solid or haematological tumor. Serum IgG4, for instance, are increased in the majority of patients but, if taken alone, have relevant shortcomings for diagnostic and follow-up purposes. Similarly, imaging studies such as Computed Tomography, Magnetic Resonance, and 18-Fluorodeoxyglucose PET scan are useful to have a complete picture of the organs involved by IgG4-RD, but definitive diagnosis still requires histological examination of affected organs.
How is it diagnosed?
Therefore, a final diagnosis requires a biopsy of the affected tissue and a histological examination. However, there are clinical, radiological, and laboratory elements that can aid in the diagnosis:
- allergy in history;
- visible swelling of the large salivary glands, lacrimal glands, or orbit;
- inflamed pancreas with a "sausage" appearance on CT and MRI;
- increase in the level of immunoglobulins IgG4 and IgE in blood tests.
Suggested exams
How is it treated?
Early recognition of IgG4-RD is extremely important in order to avoid organ failure, chronic morbidities, and overtreatment with unnecessary surgical procedures or chemotherapies. IgG4-RD, in fact, promptly responds to immunosuppressive treatments. Glucocorticoids represent the first line treatment to induce disease remission. Methotrexate or azathioprine are used as steroid sparing agents to maintain remission. Rituximab (a B cell depleting monoclonal antibody for intravenous infusion) has been recently shown to induce remission of IgG4-RD in the majority of case and is now used as the preferred second-line agent in tertiary care referral centers for treating IgG4-RD relapse.
Patients with IgG4-RD referred to San Raffaele Research Hospital are followed in a dedicated Clinic (the IgG4-RD Clinic) by immunologists and rheumatologists with years of expertise in the field. The team was, in fact, the first to describe IgG4-RD and its multifaceted manifestations in Italy and presently follows-up the largest cohort of Italian IgG4-RD patients. IgG4-RD Clinic published more than 100 scientific works on peer-reviewed international journals dealing with IgG4-RD, contributed to the development of international diagnostic and therapeutic guidelines, and received financial support to address the molecular bases of this rare disorder. Because IgG4-RD can affect many different organs, each case is periodically discussed in multidisciplinary teams within San Raffaele Research Hospital to provide the better therapeutic options for each patient. The multidisciplinary team includes gastroenterologists, hepatologists, ENT specialists, ophthalmologists, pulmonologists, neurologists, pancreatic, biliary and thoracic surgeons among others. Being recognized as a national and international referral center for IgG4-RD, the IgG4-RD Clinic at San Raffaele Research Hospital also offers the possibility to be enrolled in research projects, to participate in clinical trials, to benefit from up-to-date off-label treatments, and to discuss social and psychological aspects of IgG4-RD.
Where do we treat it?
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