IgG4-related disease

Purpose of review Remarkable insights have been gleaned recently with regard to the pathophysiology of IgG4-related disease (IgG4-RD). These findings have direct implications for the development of targeted strategies for the treatment of this condition. Recent findings Oligoclonal expansions of cells of both the B and T lymphocyte lineages are present in the blood of patients with IgG4-RD. Oligoclonal expansions of plasmablasts are a good biomarker for disease activity. An oligoclonally expanded population of CD4+ cytotoxic T lymphocytes is found not only in the peripheral blood but also at tissue sites of active disease. This cell elaborates cytokines that may drive the fibrosis characteristic of IgG4-RD. T follicular helper cells (Tfhc), particularly the Tfhc2 subset, appear to play a major role in driving the class switch to IgG4 that typifies this disease. The relationship between malignancy and IgG4-RD remains an area of interest. Summary Advances in understanding the pathophysiology of IgG4-RD have proceeded swiftly, leading to the identification of a number of potential targeted treatment strategies. The completion of classification criteria for IgG4-RD, an effort supported jointly by the American College of Rheumatology and the European League Against Rheumatism, will further facilitate studies on this disease.

Over the past decade and with increasing pace in the last few years, a "new" disease has emerged, gradually affecting a wide range of medical specialties and explaining a host of conditions previously regarded as separate entities. is newly recognized condition is IgG4-related disease (IgG4-RD), a potentially multiorgan disorder that is characterized by elevated serum IgG4 concentrations in the majority of cases. IgG4-RD was recognized in modern times in Japan through a series of seminal observations that occurred during the 1��0s and the �rst few years of this century [1][2][3][4][5], but it is clear in reviewing the medical literature that IgG4-RD has been present and reported upon in various guises going back at least to the 1800s [6][7][8][9][10][11].
In addition to the frequent elevations of serum IgG4 concentrations, certain major pathologic hallmarks are generally present to one degree or another across all organ systems, providing the principal foundation for the belief that the disparate organ manifestations associated with this diagnosis are in fact part of the same systemic disease. ese pathologic features include a lymphoplasmacytic in�ltrate with a high percentage of plasma cells within the lesion staining for IgG4; a peculiar pattern of �brosis known as "storiform" �brosis; a tendency to affect veins in a manner that leads to obliterative phlebitis; and mild to moderate tissue eosinophilia [12].
IgG4-RD appears to sit at an intersection between different in�ammatory pathways. �any but not all patients have substantial allergic or atopic histories, and early indications are that a "modi�ed" 2 response is critical to this condition [13]. Other patients also develop tumefactive lesions leading to misdiagnoses of cancer. Still others have clinical manifestations and serological �ndings that lead to erroneous classi�cations of their diagnoses as "connective tissue diseases. " e full links between the various in�ammatory players in this symphony of in�ammation remain to be fully elucidated. It is likely that a broader understanding of the ways in which B and � cells, �broblasts, plasma cells, immune complexes, and other elements interact in IgG4-RD will provide important insights into the nature of its individual in�ammatory constituents and the broader immune system.
IgG4-RD is now recognized as a worldwide disease [14]. e international community convened in Boston in 2011 to compare notes, share experiences, and plan ways for moving ahead in understanding this condition. Building upon crucial earlier work in Japan, consensus papers pertaining to the nomenclature of this condition and to its pathological features have been published [12,15]. Japanese investigators have also published diagnostic criteria for IgG4-RD [16].
In this special issue, we are pleased to present more than two dozen papers on IgG4-RD that address a number of facets International Journal of Rheumatology of this condition: from its clinical manifestations to its radiologic features; from its pathology hallmarks to its serologic characteristics; and from its diagnostic challenges to early indications of treatment success. ese papers capture the essence of IgG4-RD in 2012 and represent the current stateof-the-art against which future advances will be compared.