IgG4-related disease: what a hematologist needs to know

Abstract

IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This review focuses on the hematologic manifestations of IgG4-related disease, including lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia. The disease can easily be missed by unsuspecting hematologists, as patients may present with clinical problems that mimic disorders such as multicentric Castleman disease, lymphoma, plasma cell neoplasms and hypereosinophilic syndromes. When IgG4-related disease is suspected, serum protein electrophoresis and IgG subclasses are helpful as initial tests but a firm histological diagnosis is essential both to confirm the diagnosis and to rule out mimickers. The central histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), storiform fibrosis, and obliterative phlebitis. Importantly for hematologists, the latter two features are seen in all tissues except bone marrow and lymph nodes, making these two sites suboptimal for histological confirmation. Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly morbid or fatal complications such as periaortitis, severe retroperitoneal fibrosis or pachymeningitis. Corticosteroids are effective but cause new or worsening diabetes in about 40% of patients. Initial response rates to rituximab are high but durable remissions are rare. More intensive lymphoma chemotherapy regimens may be required in rare cases of severe, refractory disease, and targeted therapy against plasmablasts, IgE and other disease biomarkers warrant further exploration.

Response to letter to editor regarding Immunoglobulin G4‐related disease in a dog

“…Multiple studies confirm that the incidence of peripheral eosinophilia in all humans with IgG4-RD, including both atopic and nonatopic cases, is~40%. 6 The eosinophilia of IgG4-RD in humans is commonly of the same magnitude as was observed in our dog with IgG4-RD case and responds well to steroids, similar to our IgG4-RD case. 6 Description of atopy is not needed to explain peripheral eosinophilia and lack of findings of atopy does not rule out IgG4-RD in our case.…”

“…Immunoglobulin G4-related disease in humans has been misdiagnosed as hypereosinophilia syndrome but the two diseases are not mutually exclusive; concurrent hypereosinophilia syndrome and IgG4-RD have been reported in humans. 6 Bone marrow evaluation in our dog with IgG4-RD case was inconsistent with a myeloid clonal process and a T-cell clone was not found by polymerase chain reaction (PCR) for antigen receptor rearrangements (PARR) to support a paraneoplastic cause of the hypereosinophlia. 6 Additionally, lesion distribution in our case was inconsistent with hypereosinophilia syndrome in dogs, in our experience.…”

“…6 Bone marrow evaluation in our dog with IgG4-RD case was inconsistent with a myeloid clonal process and a T-cell clone was not found by polymerase chain reaction (PCR) for antigen receptor rearrangements (PARR) to support a paraneoplastic cause of the hypereosinophlia. 6 Additionally, lesion distribution in our case was inconsistent with hypereosinophilia syndrome in dogs, in our experience. We do not know the relationship of IgG4-RD in dogs and cases previously diagnosed as hypereosinophilia syndrome but suspect that at least some cases of canine IgG4-RD have been diagnosed as idiopathic hypereosinophilia syndrome in the past.…”

IgG4-Related Disease as Mimicker of Malignancy

“…to IgG4-RD, as it can often be elevated in conditions such as multicentric Castleman disease, hypereosinophilic syndrome, and vasculitis (1,10). The serum IgG4 level in both our group of patients were elevated above the upper limit of normal (6.83 g/L in the "yes malignancy" group, and 8.77 g/L in "no malignancy" group).…”

Pediatric IgG4‐related lymphadenopathy: A rare condition associated with autoimmunity and lymphoproliferative disorders

“…1 Interstitial fibrosis and vein lesions are lacking in some anatomic sites (eg, lymph nodes), making the diagnosis of IgG4-RD a true challenge. [1][2][3] Despite the vast majority of IgG4-RD has been reported in adults, 4 this condition is increasingly documented also in the pediatric population. To date, 36 cases of childhood IgG4-RD have been published, most of which encompass solid lesions in extra-nodal sites.…”