Emanuel Della-Torre

International consensus guidance statement on the management and treatment of IgG4-related disease

A. Khosroshahi, Z. S. Wallace, J. L. Crowe, T. Akamizu, A. Azumi, M. N. Carruthers, S. T. Chari, E. Della-Torre, L. Frulloni, H. Goto, P. A. Hart, T. Kamisawa, S. Kawa, M. Kawano, M. H. Kim, Y. Kodama, K. Kubota, M. M. Lerch, M. L€ ohr, Y. Masaki, S. Matsui, T. Mimori, S. Nakamura, T. Nakazawa, H. Ohara, K. Okazaki, J. H. Ryu, T. Saeki, N. Schleinitz, A. Shimatsu, T. Shimosegawa, H. Takahashi, M. Takahira, A. Tanaka, M. Topazian, H. Umehara, G. J. Webster, T. E. Witzig, M. Yamamoto, W. Zhang, T. Chiba, and J. H. Stone

De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease

BACKGROUND IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma cells at disease sites. OBJECTIVE The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. METHODS B-cell populations from the peripheral blood of 84 patients with active IgG4-RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy. RESULTS Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG4(+), are increased in patients with active IgG4-RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive. CONCLUSIONS Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive disease process.

IgG4-Related Hypertrophic Pachymeningitis: Clinical Features, Diagnostic Criteria, and Treatment

IMPORTANCE IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is an increasingly recognized manifestation of IgG4-related disease, a fibroinflammatory condition that can affect virtually any organ. It is estimated that IgG4-RHP may account for a high proportion of cases of hypertrophic pachymeningitis once considered idiopathic. OBJECTIVE To summarize the current knowledge on IgG4-RHP including its pathological, clinical, and radiological presentations. Particular emphasis is placed on diagnostic and therapeutic implications. EVIDENCE REVIEW This review is based on 21 reports published in the English medical literature since 2009. PubMed was searched with the following terms: IgG4, pachymeningitis, IgG4-related pachymeningitis, IgG4-related disease, IgG4-related, and IgG4 meningitis. Only cases with biopsy-proven IgG4-RHP were considered and included in this review. FINDINGS Little is known with certainty regarding the pathogenesis of IgG4-RHP. The presence of oligoclonally restricted IgG4-positive plasma cells within inflammatory meningeal niches strongly suggests a specific response against a still unknown antigen. Clinical presentation of IgG4-RHP is not distinguishable from other forms of hypertrophic pachymeningitis and reflects mechanical compression of vascular or nerve structures, leading to functional deficits. Signs of systemic IgG4-related disease may concomitantly be present. Diagnostic process should rely primarily on magnetic resonance imaging, cerebrospinal fluid analysis, and meningeal biopsy. In particular, hallmark histopathological features of IgG4-RHP are a lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. High-dose glucocorticoids are still the treatment of choice for IgG4-RHP because immunosuppressive agents have shown variable efficacy in reducing the meningeal hypertrophy. Rituximab is a promising therapeutic approach but experience with B-cell depletion strategies remains limited. CONCLUSIONS AND RELEVANCE IgG4-related disease accounts for an increasing proportion of cases of idiopathic hypertrophic pachymeningitis. Clinicians should become familiar with this alternative differential diagnosis because a prompt, specific therapeutic approach may avoid long-term neurological complications.

Immunology of IgG4-related disease.

Immunoglobulin G4‐related disease (IgG4‐RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4+ plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4‐RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4‐RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4‐RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy

IgG4‐related disease (IgG4‐RD) is characterized by a lymphoplasmacytic infiltrate composed of IgG4+ plasma cells, tumefactive lesions, obliterative phlebitis, and mild to moderate eosinophilia. It has been suggested that IgG4‐RD is characterized by allergic manifestations and is potentially driven by enhanced T‐helper type 2 (Th2) responses. We aimed to investigate the potential contribution of atopy to enhanced Th2 responses in IgG4‐RD. Peripheral blood mononuclear cells from 39 patients were isolated and subjected to in vitro mitogenic stimulation with PMA and ionomycin. Following stimulation, gated CD3+CD4+ T cells were analyzed for production of the Th2 cytokines IL‐4, IL‐5, and IL‐13. Among the 39 patients analyzed, only the 18 patients who had a history of atopy showed increases in circulating Th2 memory cells. Our results indicate that Th2 responses that have been reported in IgG4‐RD may result from concomitant atopic manifestations in disease subjects.

B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease

Objectives Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid. Methods Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab. Results The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R2=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition. Conclusions The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.

IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients

Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre. Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as ‘definite’ or ‘possible’ according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with ‘definite’ IgG4-RD and 15 with ‘possible’ IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24–51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking. Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Diagnostic value of IgG4 Indices in IgG4-Related Hypertrophic Pachymeningitis ☆ ☆☆ ★

Diagnosis of IgG4-Related Hypertrophic Pachymeningitis (IgG4-HP) relies on meningeal biopsies, because cerebrospinal fluid (CSF) diagnostic biomarkers are lacking. Here, we determined whether IgG4 intrathecal production could distinguish IgG4-HP from other disorders presenting with HP (OHP). In patients with IgG4-HP, the median CSF IgG4 concentration, IgG4 Index and IgG4Loc were significantly higher than in both controls and OHP. CSF IgG4 levels higher than 2.27mg/dL identified 100% of IgG4-HP and 5% of OHP. An IgG4Loc cut-off of 0.47 identified 100% of IgG4-HP and no cases of OHP. Our results support CSF IgG4 quantification and IgG4 Indices as alternatives to meningeal biopsy for the diagnosis of IgG4-HP when this procedure is contraindicated or uninformative.

Cerebrospinal Fluid Analysis in Immunoglobulin G4-related Hypertrophic Pachymeningitis

To the Editor: Immunoglobulin G4-related disease (IgG4-RD) is characterized by fibrous swelling of affected organs, elevations in serum IgG4 concentrations, and responsiveness to glucocorticoid treatment1. Affected tissues display similar histological features: diffuse lymphoplasmacytic infiltration by numerous IgG4-positive plasma cells, occasional eosinophils, storiform fibrosis, and obliterative phlebitis2. IgG4-related hypertrophic pachymeningitis (IgG4-HP) has been identified as a characteristic central nervous system (CNS) manifestation of IgG4-RD, but comprehensive cerebrospinal fluid (CSF) analyses are substantially lacking3,4. Recently, we demonstrated an intrathecal IgG and IgG4 synthesis in the CSF of a patient with IgG4-HP and suggested IgG4 Indices as safe potential diagnostic tools for IgG4-HP5. Here, we describe 2 new cases of IgG4-HP with CSF evaluation at diagnosis and in response to treatment. In case 1, March 2007, a 56-year-old man was admitted with a 1-year history of right frontal headache. Magnetic resonance imaging (MRI) showed right frontal pachymeningitis. Granulomatous meningeal inflammation was suspected and oral prednisone (1 mg/kg body weight/day) was started with clinical and radiological improvement. Prednisone was discontinued after 8 months, but in July 2008 the headache recurred. Blood and CSF analyses are shown in Table 1. MRI evidenced a right frontotemporal progression of the pachymeningitis (Figure 1A). A meningeal biopsy … Address correspondence to Dr. E. Della-Torre, Department of Medicine and Clinical Immunology, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy. E-mail: dellatorre.emanuel{at}hsr.it

Antineutrophil cytoplasmic antibody positivity in IgG4-related disease: A case report and review of the literature.

Background:IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by serum IgG4 elevation and tissue infiltration of IgG4-positive plasma cells. Substantial overlap between IgG4-RD and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) exists in terms of organ involvement and histopathological features. A positive ANCA assay is regarded as a highly specific finding in favor of an AAV, and generally influences away from a diagnosis of IgG4-RD. Recent reports, however, have raised the possibility that some patients with IgG4-RD are ANCA positive, thus suggesting reconsideration of the role of ANCA in the diagnostic workup. In the present work, we describe the first case of concomitant biopsy-proven IgG4-RD and granulomatosis with polyangiitis (GPA), demonstrating antiproteinase 3 (PR3) ANCA of the IgG4 subclass in the patients serum. We also review the literature in order to provide clinicians with tools for interpreting ANCA positivity in IgG4-RD patients. Case summary:A 51-year-old woman was referred for left exopthalmos due to lacrimal gland enlargement and increased serum IgG4 concentration. IgG4-RD was suspected and further imaging studies disclosed multiple pulmonary masses in the right lung. Histological analysis of the left lacrimal gland was diagnostic for IgG4-RD, but lung biopsy showed typical features of GPA. ANCA assay was positive for anti-PR3 antibodies. Further immunofluorescence studies demonstrated anti-PR3 antibodies of IgG1 and IgG4 subclass. Treatment with rituximab induced swift remission of both IgG4-RD and GPA manifestations. We identified 9 other reports of patients with IgG4-RD and positive ANCA in the English literature, 5 cases with biopsy-proven IgG4-RD and 4 cases in whom IgG4-RD was diagnosed presumptively. Four patients had also histological evidence of concomitant AAV. Conclusion:The present work demonstrates that ANCA positivity in patients with biopsy-proven IgG4-RD should prompt the exclusion of a concomitant vasculitic process; a positive ANCA does not exclude the diagnosis of IgG4-RD; confirmation through immunoenzymatic assays of the ANCA specificity, clinical-pathological correlation, and histopathological evaluation remain crucial steps for the differential diagnosis between AAV and IgG4-RD.