Feature

Exploring the Mysteries of IgG4-related Disease

At a 2011 symposium, clinicians and investigators officially categorized the group of immunoglobulin G4-associated diseases as an immunoglobin G4-related disease, or IgG4-RD. The group reached a consensus on the nomenclature in part because Japanese investigators had been using the term, and because the group wanted to drop the term “systemic” in association with diseases of this nature. However, more questions than answers remain about the diagnosis, pathogenesis and treatment of this relatively new group of conditions.

John H. Stone, MD, MPH, professor of medicine at Harvard Medical School and director of Clinical Rheumatology and Edward Fox Chair in Medicine at the Massachusetts General Hospital (MGH), set the stage.

“IgG4-related disease is a fibroinflammatory condition that can affect essentially any organ,” he told Healio Rheumatology, quoting a forthcoming review paper. “The disease shows similar histopathology findings across organ systems, consisting of a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis.”

In another section of the paper, Stone characterized the disease as “a reactive phenomenon,” as opposed to a primary driver of disease. “IgG4-RD is marked by responsiveness to glucocorticoids, but frequent disease relapse, the inability to taper glucocorticoids completely, and steroid toxicity are problematic,” he said. “Targeted treatment approaches against the B cell lineage appear promising, and therapeutic efforts focused upon the CD4+ SLAMF7+ cytotoxic T cell may also be feasible.”

He added, “The precise role of IgG4 in disease pathophysiology, if any, remains unclear. Although elevated serum IgG4 levels were the abnormality that originally called this disease to medical attention, in fact the serum level of IgG4 is elevated in only about two-thirds of IgG4-RD patients. Moreover, serum IgG4 levels are often so high as to trigger concern for a plasma cell dyscrasia, but the performance of IgG4 as a serum biomarker of disease activity is imperfect.”

Antoine G. Sreih, MD, assistant professor of clinical medicine in rheumatology at the University of Pennsylvania, described it this way, “It is a group of multiple diseases and disorders that share similar histopathologic manifestations, serologic findings and some clinical manifestations, grouped around the presence of IgG4+ plasma cells in the tissue with or without elevated IgG4 in the blood,” he said. “It is not one disease.”

The presentation is “most often mimics a malignancy with tumor-like masses,” added Corey Perugino, DO, a graduate assistant in medicine in the division of rheumatology at MGH, an instructor in Medicine at Harvard Medical School and a post-doctoral fellow at the Ragon Institute of MGH, Massachusetts Institute of Technology and Harvard. “It is marked by enlargement of the involved organs, resulting in organ dysfunction and damage.”

Corey Perugino, DO
Corey Perugino

Beyond these basics, with the official designation coming a few years ago, clinicians are still struggling to grasp the boundaries covered by the IgG4 umbrella. It is with this in mind that Healio Rheumatology consulted experts and examined these conditions.

Fundamentals

Akiyama and colleagues described the conditions, writing that IgG4-related disease is “characterized by high serum IgG4 concentrations and infiltration of IgG4+ plasma cells with hyperplastic ectopic germinal centers at affected sites.” They noted uncertainty surrounding the underlying immune mechanism, but that T cells are involved and have been investigated, particularly the role of T follicular helper cells in “IgG4 class-switching, plasmablasts and plasma cell differentiation, and germinal center formation.”

Traditionally, IgG4 was considered to be not only noninflammatory, but an anti-inflammatory antibody, especially in conditions mediated by immunoglobin E (IgE), according to Stone.

“As an example, serum IgG4 concentrations are known to increase over the professional lives of beekeepers, presumably as a guard against anaphylaxis,” he said. “The same observations have been made in patients treated with desensitizing immunotherapy, following which the induction of IgG4 responses corresponds to reduced allergic symptoms.”

There are structural and functional attributes of the IgG4 molecule that make it an unlikely driver of inflammation, Stone added.

“Its Fc portion provides low-binding affinity for activating Fc receptors, but a relatively preserved affinity for binding to FcgRIIb, an inhibitory Fc receptor,” he said. “In addition, the Fc portion binds poorly to C1q, the first component of the complement cascade.”

Another factor, for Stone, is the hinge region of the IgG4 molecule has unique amino acid moieties that facilitate dissociation of its originally paired heavy chains. This permits re-association with similarly split IgG4 molecules of different antigen specificity.

“This process, known as Fab-arm exchange, renders newly formed IgG4 molecules functionally biospecific and incapable of crosslinking antigen or forming immune complexes,” he said. “Such properties allow the IgG4 molecule to serve as an ‘antigen sink,’ competing with other IgG subclasses to bind antigen at sites of inflammation without inciting further inflammation, thereby blunting the inflammatory response of chronic antigenic exposure.”

Stone acknowledged the possibility that a disease-causing IgG fraction produced by a subset of antibody-secreting cells contributes to tissue injury. A possible vehicle for this is through immune complexes or Fc-receptor engagement.

John H. Stone
John H. Stone

“There are certainly diseases, eg, pemphigus vulgaris and idiopathic membranous glomerulonephropathy, in which IgG4 autobodies themselves appear to be pathogenic,” he said. “Many IgG4-RD patients have concurrent elevations in other IgG subclasses, such as IgG1, that are more likely than IgG4 to form immune complexes, engage Fc-receptors and incite or participate in an ongoing immune response.”

Diagnosis

Zhu and colleagues investigated whether inflammatory myofibroblastic tumor and IgG4-related inflammatory pseudotumors are different diseases, rather than the same disease, as was previously believed. They examined 26 samples for histological characteristics and the expression of IgG, IgG4, SMA and anaplastic lymphoma kinase (ALK)-1 to determine a differential diagnosis. Tumor sizes were 3.47 cm in the myofibroblastic group and 2.22 cm in the pseudotumor group. Diffuse and total destroyed alveoli were also observed in the myofibroblastic group (88.89% vs. 17.65%), as were fewer lymphoid follicles (1.6/HPF vs. 3/HPF) and lower expression of IgG (74.7/HPF vs. 149.1/HPF). Investigators found ALK-positivity demonstrated an association with higher cytological atypia (mean 3.7/HPF) and lesser lymphoid follicles (mean 1.2/HPF), which the researchers described as an exclusion criteria for IgG4-associated inflammatory pseudotumor. A positive correlation also was observed between lymphocyte plus plasma cell count and IgG4-positive plasma cell counts. Conversely, the IgG4-positive plasma cell counts and ALK-1 expression were negatively correlated.

“The significant differences of clinicopathological characteristics between the [inflammatory myofibroblastic tumors] and IgG4-related [inflammatory pseudotumors] indicated that a combination of lymphocytes + plasma cells count, cytological atypia, IgG4 and ALK-1 staining will be helpful in differential diagnosis,” the researchers concluded.

Sreih commented that along with storiform fibrosis, these diseases are also marked by the presence of small lymphocytes, phlebitis obliterans and some degree of eosinophilic infiltration.

Perugino believes it is most accurate to view IgG4-RD as a single immunologic disease entity with various clinical manifestations, similar to the way antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis or systemic lupus erythematosus (SLE) are perceived.

“These varied manifestations share many common denominators such as the insidious onset of symptoms, lack of fever, responsiveness to glucocorticoids, elevated serum IgG4 level, enlarged or tumefactive organs and a typical organ distribution,” he said. There are also unifying histopathologic features, including lymphoplasmacytic infiltrate, fibrosis in a storiform pattern, obliterative phlebitis and greater than 40% of plasma cells expressing IgG4 compared to IgG.

“While elevated serum IgG4 levels are not universally seen — about 60% to 90% depending on the published cohort — and sampling bias could explain the lack of IgG4+ plasma cells on immunostaining, one or the other should be required to be confident in diagnosing IgG4-RD,” Perugino said.

For Perugino, there are a few specific challenges for clinicians. “One is the fact that this disease mimics malignancy with post-Whipple procedure referrals not being uncommon,” he said. “Another is the relatively limited awareness of this disease entity.”

Multi-organ Involvement

A marked characteristic of the IgG4-RD family is that multiple organs may be involved. Perugino compiled a list representing the typical organ distribution of IgG4-RD that included lacrimal glands, salivary glands, lungs/pleura, aorta, kidneys, pancreas and retroperitoneum.

In terms of clinical manifestations, Sreih said much depends on which organ is affected. “IgG4-related disease can affect one organ or multiple organs at the same time,” he said. “One of the most commonly affected organs is the pancreas.”

Sreih focuses much of his attention on patients with IgG4 and present with a form of vasculitis that causes retroperitoneal fibrosis. “Many of the patients I deal with have aortitis or inflammation of other large arteries, such as the iliac arteries,” he said “Aortitis often occurs below the renal arteries and inflammation can be seen around the iliac arteries. You will see sort of an inflammatory mass encasing the aorta. There will be evidence of inflammation around the aorta.”

Mochizuki and colleagues published a report on a 59-year-old man who presented with a host of symptoms, including multiple dark red erythema with induration, anemia and polyclonal hypergammaglobulinemia. After a skin biopsy, the initial diagnosis was multicentric Castleman’s disease. Treatment with glucocorticoids yielded moderate results. After 4 years, clinicians observed enlarged bilateral lacrimal glands, at which point another biopsy revealed dense lymphocyte and plasma cell infiltration with an IgG4+/IgG+ plasma cell ratio of 70%, according to the findings. A diagnosis of IgG4-related disease was made. Rituximab therapy also yielded moderate results.

“This case demonstrates that overlapping features of IgG4-RD and [multicentric Castleman’s disease] may present in a single patient, which suggests a shared pathogenesis,” the researchers concluded.

“The lachrymal glands are inflamed, infiltrated by plasma cells and lymphocytes,” Sreih said. “Patients often present with swelling around the eyes or inflammation of lachrymal glands, along with slowing of parotid glands.”

Stone said, “These diverse clinical features of IgG4-RD are linked by shared pathological findings across involved organs: a lymphoplasmacytic infiltrate; storiform fibrosis, obliterative phlebitis; and enrichment with IgG4-expressing plasma cells. Such features, though strongly suggestive of IgG4-RD, should never be regarded in isolation as diagnostic of this condition. Rather, careful correlation of pathology features with clinical, serologic and imaging findings is essential to diagnosis.”

Role of B Cells

Khosroshahi and colleagues assessed the clinical and serologic responses to B lymphocyte depletion therapy in a cohort of 10 patients with steroid- and disease-modified antirheumatic drug (DMARD)-refractory IgG4-related disease. Eligible participants received two infusions of rituximab (Rituxan, Genentech) at 1,000 mg, 15 days apart. Each patient’s ability to taper prednisone to discontinuation or to cease DMARD therapy served as the main clinical outcome. The researchers also assessed total IgG, IgG subclasses and patterns of organ involvement to determine whether the pancreas, biliary tree, aorta, salivary glands, lacrimal glands, lymph nodes, thyroid gland and retroperitoneum were impacted. The IgG4-RD disease activity index and flare tool was developed and retrospectively applied to the patient population.

Results showed what the researchers described as “striking clinical improvement” within 1 month of rituximab initiation in nine of 10 patients. The one patient had Riedel thyroiditis and failed to show improvement in the thyroid gland, but demonstrated no signs the disease had moved to other organs. Successful prednisone and discontinuation of DMARD therapy was reported in the entire cohort. Significant decreases in IgG concentrations occurred only the IgG4 subclasses, but not in total IgG. Re-treatment with rituximab was required in four patients. This re-treatment, however, yielded further reduction in IgG4 concentrations. Other findings showed IgG4 appeared to be a reliable indicator of disease activity among those who presented with IgG4 concentration.

Perugino said, “Targeting B cells in the therapy of IgG4-RD makes sense from what we have learned about the underlying immunology of this disease. While it remains unclear as to what the exact role of antibodies are in IgG4-RD is, it is clear that circulating plasmablasts typify the immune response of the disease and that the B cell compartment is most likely driving disease through the presentation of antigen to T cells in the tissue.”

There exists a somewhat stable clinical consensus surrounding the efficacy of rituximab in these diseases.

“This disease is a chronic one with disease recurrence following sometime remission induction being the norm,” Perugino said. “With that observation and the generally older patient population with multiple comorbidities, long-term suppressive glucocorticoids can be expected to cause more harm than good. The field remains desperately in need of a randomized clinical trial to promote FDA approval of a steroid-sparing agent.”

Other recent studies have looked at interactions between cells of the B cell lineage and a novel CD4+ SLAMF7+ cytotoxic T cells capable of promoting fibrosis, according to Stone. “Plasmablasts appear to play a crucial role along with B cells in the presentation of antigen to this T cell,” he said.

Stone added another approach to inhibiting B cells is XmAb5871, a novel molecule with an antigen-binding site specific for CD19, thereby targeting cells of the B-cell lineage. “However, it differs from the antibody-dependent cellular cytotoxicity (ADCC) mechanism of anti-CD20-directed therapy,” he said. “XmAb5871 capitalizes upon the natural inhibitory mechanism of FcgRIIb, the only Fc receptor expressed by B cells, which acts as a negative regulator in conditions of antigen excess and immune complex formation. When FcgRIIb is co-ligated with CD19, B cell function is inhibited and plasmablasts are rendered dormant.”

Therapeutic Options

Regarding other therapeutic options, Sreih said IgG4-RD are “responsive to steroids,” usually in the form of moderate doses of prednisone. “You can expect a response in about 2 [weeks] to 4 weeks, occasionally earlier.”

The improvements will be seen both clinically and on imaging analyses, according to Sreih. “The problem is that after a period of therapy, we want to taper prednisone, but in many cases, the disease relapses.”

Stone agreed. “IgG4-RD does relapse in most cases, at different rates,” he said. “Patients with multi-organ disease and substantial elevations of IgG4 in their serum are at particular risk for early relapses. We presume that relapses happen because patients continue to be exposed to or are re-exposed to the antigen or antigens that trigger the disease, and the memory elements of the immune system are able to re-initiate the immune response once therapies wane.”

The next step is a steroid-sparing agent. “At this point, we use an immunosuppressant,” Sreih said. “But those medications need more clinical trial data. Currently, there have been no head-to-head randomized, placebo-controlled trials. Most of what we have are case reports, case series and retrospective analyses.”

In addition to rituximab, mycophenolate mofetil and azathioprine have shown some efficacy, according to Sreih. “There is disagreement among experts about whether to start prednisone initially with an immunosuppressant because the relapse risk is high,” he said. A contraindication to prednisone or long-term prednisone is one possible instance where this may occur, but beyond such cases, there is little consensus about using prednisone with other therapies in a first-line setting.

Further, Sreih added that different approaches are used in the United States, Europe, China and Japan among other countries.

“We see different local practices depending on local health care system rules and regulations,” he said. “For instance, it is hard to obtain rituximab in Canada, so they do not use it as a first-line agent. It is probably easier to get in the United States.”

For the most part, it comes down to a patient-by-patient, trial-and-error process. There are no curative therapies for IgG4-related disease as of yet.

“We are just not there yet,” Sreih said. “We have started talking about potential cures in rheumatic diseases, but, unfortunately, the majority of autoimmune diseases are non-curable but are treatable.”

Specific Complications

Cao and colleagues retrospectively investigated pulmonary function in a cohort of 17 patients with IgG4-related diseases. They aimed to determine whether pulmonary function tests are valuable in the diagnosis of associated respiratory diseases. The study population was divided into patients with respiratory disease or without extrapulmonary involvement. Pulmonary dysfunction was reported in all patients in the group with respiratory disease. Among those with extrapulmonary involvement, 62.5% had pulmonary dysfunction even with normal CT scan results and no associated respiratory symptoms. Restrictive ventilatory dysfunction and abnormal diffusing capacity occurred in all patients, while two patients in the respiratory disease group reported obstructive ventilatory dysfunction. Patients in the respiratory disease group experienced a significantly higher incidence of diffusing capacity of the lung for carbon monoxide per liter of alveolar volume decrease than those in the extrapulmonary group. Similarly, this volume was significantly higher in the extrapulmonary group.

“We report the first finding of a negative correlation between pulmonary diffusing capacity and total serum concentrations of IgG and IgG subclasses (IgG4, IgG3 and IgG2),” the researchers wrote. “Diffusing capacity of the lung for carbon monoxide per liter of alveolar volume plays an important role for detecting lung involvement in IgG4-RD patients. The patient with high serum IgG may be more prone to respiratory involvement.”

“The pulmonary complications of IgG4-RD are complex and have mostly been described radiologically to include ground-glass opacities, pulmonary nodules, masses, interstitial lung disease or bronchovascular/septal thickening,” Perugino said. “About 20% of our IgG4-RD patients at the Massachusetts General Hospital have some form of pulmonary involvement. The report by Cao and colleagues is interesting and deserves a prospective survey of newly diagnosed IgG4-RD patients to assess such non-radiographic, but functional, alterations. With the concurrence of atopic disease including asthma in approximately 40% of these patients, that is an important consideration in interpreting both the radiographic and pulmonary function findings in IgG4-RD.”

Directions for Future Research

“There are many unanswered questions in regard to IgG4-RD,” Perugino said. “First, ‘Is this an autoimmune disease or rather an aberrant immune response to a foreign (ie, viral or bacterial) antigen?’ Second, and related to the first, ‘What causes IgG4-RD?’”

Perugino suggested an increasing body of large, well-defined cohorts are emerging, which will allow investigators to examine potential risk factors, such as through genome-wide association studies and microbiome comparisons.

“My current research is focused on antigen discovery efforts in IgG4-RD to determine if these antigens are self or foreign in nature, if they are shared between patients and, if of self-origin, could the differential tissue expression explain the observed organ distribution?” he said. “One additional question I am interested in studying, which will have larger medical implications for diseases such as allergies is, ‘What dictates IgG4 vs. IgE class switching?’ While the former bestows the name on this disease, it is generally thought of as an immune-inhibitory immunoglobulin, so it is likely the immune system’s attempt at quelling the underlying process whereas IgE is elevated in approximately 40% of IgG4-RD patients and correlated to likelihood of flaring but still with unclear pathologic significance.”

Stone is looking in a different direction.

“The Fc portion of XmAb5871 was engineered to have 400-fold increased affinity for FcgRIIb, permitting it to compete effectively for this binding site,” he said. He added this molecule has demonstrated efficacy in suppressing B-cell activation and proliferation, along with disease activity in rheumatoid arthritis. “We recently completed enrollment on an open-label, single-arm study on its efficacy in IgG4-RD. Preliminary analyses of this approach are promising and have been reported,” Stone said.

Perugino is encouraged by the attention being paid to IgG4-RD. “With time and further published literature on the topic, more clinicians are considering this diagnosis based on clinical signs and measuring serum IgG subclasses as a screening measure,” he said.

For his part, Stone is encouraged that the ACR/EULAR classification criteria for IgG4-related disease are scheduled for completion in 2017.

“International consensus statements on the nomenclature of IgG4-RD, its pathologic findings and clinical management have been published,” he said. “The IgG4-RD responder index, designed to serve as a clinical trials outcome measure, is now undergoing a worldwide validation study.” – by Rob Volansky

Disclosures: Perugino reports no relevant financial disclosures. Sreih reports no relevant financial disclosures. In the last 2 years, he has received compensation for consulting for Krogg and Partners, Rupert Case Management and Naxion. Stone reports he receives research grants from and is a consultant for Genentech, Roche and Xencor in the area of IgG4-RD.

At a 2011 symposium, clinicians and investigators officially categorized the group of immunoglobulin G4-associated diseases as an immunoglobin G4-related disease, or IgG4-RD. The group reached a consensus on the nomenclature in part because Japanese investigators had been using the term, and because the group wanted to drop the term “systemic” in association with diseases of this nature. However, more questions than answers remain about the diagnosis, pathogenesis and treatment of this relatively new group of conditions.

John H. Stone, MD, MPH, professor of medicine at Harvard Medical School and director of Clinical Rheumatology and Edward Fox Chair in Medicine at the Massachusetts General Hospital (MGH), set the stage.

“IgG4-related disease is a fibroinflammatory condition that can affect essentially any organ,” he told Healio Rheumatology, quoting a forthcoming review paper. “The disease shows similar histopathology findings across organ systems, consisting of a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis.”

In another section of the paper, Stone characterized the disease as “a reactive phenomenon,” as opposed to a primary driver of disease. “IgG4-RD is marked by responsiveness to glucocorticoids, but frequent disease relapse, the inability to taper glucocorticoids completely, and steroid toxicity are problematic,” he said. “Targeted treatment approaches against the B cell lineage appear promising, and therapeutic efforts focused upon the CD4+ SLAMF7+ cytotoxic T cell may also be feasible.”

He added, “The precise role of IgG4 in disease pathophysiology, if any, remains unclear. Although elevated serum IgG4 levels were the abnormality that originally called this disease to medical attention, in fact the serum level of IgG4 is elevated in only about two-thirds of IgG4-RD patients. Moreover, serum IgG4 levels are often so high as to trigger concern for a plasma cell dyscrasia, but the performance of IgG4 as a serum biomarker of disease activity is imperfect.”

Antoine G. Sreih, MD, assistant professor of clinical medicine in rheumatology at the University of Pennsylvania, described it this way, “It is a group of multiple diseases and disorders that share similar histopathologic manifestations, serologic findings and some clinical manifestations, grouped around the presence of IgG4+ plasma cells in the tissue with or without elevated IgG4 in the blood,” he said. “It is not one disease.”

The presentation is “most often mimics a malignancy with tumor-like masses,” added Corey Perugino, DO, a graduate assistant in medicine in the division of rheumatology at MGH, an instructor in Medicine at Harvard Medical School and a post-doctoral fellow at the Ragon Institute of MGH, Massachusetts Institute of Technology and Harvard. “It is marked by enlargement of the involved organs, resulting in organ dysfunction and damage.”

PAGE BREAK
Corey Perugino, DO
Corey Perugino

Beyond these basics, with the official designation coming a few years ago, clinicians are still struggling to grasp the boundaries covered by the IgG4 umbrella. It is with this in mind that Healio Rheumatology consulted experts and examined these conditions.

Fundamentals

Akiyama and colleagues described the conditions, writing that IgG4-related disease is “characterized by high serum IgG4 concentrations and infiltration of IgG4+ plasma cells with hyperplastic ectopic germinal centers at affected sites.” They noted uncertainty surrounding the underlying immune mechanism, but that T cells are involved and have been investigated, particularly the role of T follicular helper cells in “IgG4 class-switching, plasmablasts and plasma cell differentiation, and germinal center formation.”

Traditionally, IgG4 was considered to be not only noninflammatory, but an anti-inflammatory antibody, especially in conditions mediated by immunoglobin E (IgE), according to Stone.

“As an example, serum IgG4 concentrations are known to increase over the professional lives of beekeepers, presumably as a guard against anaphylaxis,” he said. “The same observations have been made in patients treated with desensitizing immunotherapy, following which the induction of IgG4 responses corresponds to reduced allergic symptoms.”

There are structural and functional attributes of the IgG4 molecule that make it an unlikely driver of inflammation, Stone added.

“Its Fc portion provides low-binding affinity for activating Fc receptors, but a relatively preserved affinity for binding to FcgRIIb, an inhibitory Fc receptor,” he said. “In addition, the Fc portion binds poorly to C1q, the first component of the complement cascade.”

Another factor, for Stone, is the hinge region of the IgG4 molecule has unique amino acid moieties that facilitate dissociation of its originally paired heavy chains. This permits re-association with similarly split IgG4 molecules of different antigen specificity.

“This process, known as Fab-arm exchange, renders newly formed IgG4 molecules functionally biospecific and incapable of crosslinking antigen or forming immune complexes,” he said. “Such properties allow the IgG4 molecule to serve as an ‘antigen sink,’ competing with other IgG subclasses to bind antigen at sites of inflammation without inciting further inflammation, thereby blunting the inflammatory response of chronic antigenic exposure.”

Stone acknowledged the possibility that a disease-causing IgG fraction produced by a subset of antibody-secreting cells contributes to tissue injury. A possible vehicle for this is through immune complexes or Fc-receptor engagement.

John H. Stone
John H. Stone

“There are certainly diseases, eg, pemphigus vulgaris and idiopathic membranous glomerulonephropathy, in which IgG4 autobodies themselves appear to be pathogenic,” he said. “Many IgG4-RD patients have concurrent elevations in other IgG subclasses, such as IgG1, that are more likely than IgG4 to form immune complexes, engage Fc-receptors and incite or participate in an ongoing immune response.”

PAGE BREAK

Diagnosis

Zhu and colleagues investigated whether inflammatory myofibroblastic tumor and IgG4-related inflammatory pseudotumors are different diseases, rather than the same disease, as was previously believed. They examined 26 samples for histological characteristics and the expression of IgG, IgG4, SMA and anaplastic lymphoma kinase (ALK)-1 to determine a differential diagnosis. Tumor sizes were 3.47 cm in the myofibroblastic group and 2.22 cm in the pseudotumor group. Diffuse and total destroyed alveoli were also observed in the myofibroblastic group (88.89% vs. 17.65%), as were fewer lymphoid follicles (1.6/HPF vs. 3/HPF) and lower expression of IgG (74.7/HPF vs. 149.1/HPF). Investigators found ALK-positivity demonstrated an association with higher cytological atypia (mean 3.7/HPF) and lesser lymphoid follicles (mean 1.2/HPF), which the researchers described as an exclusion criteria for IgG4-associated inflammatory pseudotumor. A positive correlation also was observed between lymphocyte plus plasma cell count and IgG4-positive plasma cell counts. Conversely, the IgG4-positive plasma cell counts and ALK-1 expression were negatively correlated.

“The significant differences of clinicopathological characteristics between the [inflammatory myofibroblastic tumors] and IgG4-related [inflammatory pseudotumors] indicated that a combination of lymphocytes + plasma cells count, cytological atypia, IgG4 and ALK-1 staining will be helpful in differential diagnosis,” the researchers concluded.

Sreih commented that along with storiform fibrosis, these diseases are also marked by the presence of small lymphocytes, phlebitis obliterans and some degree of eosinophilic infiltration.

Perugino believes it is most accurate to view IgG4-RD as a single immunologic disease entity with various clinical manifestations, similar to the way antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis or systemic lupus erythematosus (SLE) are perceived.

“These varied manifestations share many common denominators such as the insidious onset of symptoms, lack of fever, responsiveness to glucocorticoids, elevated serum IgG4 level, enlarged or tumefactive organs and a typical organ distribution,” he said. There are also unifying histopathologic features, including lymphoplasmacytic infiltrate, fibrosis in a storiform pattern, obliterative phlebitis and greater than 40% of plasma cells expressing IgG4 compared to IgG.

“While elevated serum IgG4 levels are not universally seen — about 60% to 90% depending on the published cohort — and sampling bias could explain the lack of IgG4+ plasma cells on immunostaining, one or the other should be required to be confident in diagnosing IgG4-RD,” Perugino said.

For Perugino, there are a few specific challenges for clinicians. “One is the fact that this disease mimics malignancy with post-Whipple procedure referrals not being uncommon,” he said. “Another is the relatively limited awareness of this disease entity.”

Multi-organ Involvement

A marked characteristic of the IgG4-RD family is that multiple organs may be involved. Perugino compiled a list representing the typical organ distribution of IgG4-RD that included lacrimal glands, salivary glands, lungs/pleura, aorta, kidneys, pancreas and retroperitoneum.

PAGE BREAK

In terms of clinical manifestations, Sreih said much depends on which organ is affected. “IgG4-related disease can affect one organ or multiple organs at the same time,” he said. “One of the most commonly affected organs is the pancreas.”

Sreih focuses much of his attention on patients with IgG4 and present with a form of vasculitis that causes retroperitoneal fibrosis. “Many of the patients I deal with have aortitis or inflammation of other large arteries, such as the iliac arteries,” he said “Aortitis often occurs below the renal arteries and inflammation can be seen around the iliac arteries. You will see sort of an inflammatory mass encasing the aorta. There will be evidence of inflammation around the aorta.”

Mochizuki and colleagues published a report on a 59-year-old man who presented with a host of symptoms, including multiple dark red erythema with induration, anemia and polyclonal hypergammaglobulinemia. After a skin biopsy, the initial diagnosis was multicentric Castleman’s disease. Treatment with glucocorticoids yielded moderate results. After 4 years, clinicians observed enlarged bilateral lacrimal glands, at which point another biopsy revealed dense lymphocyte and plasma cell infiltration with an IgG4+/IgG+ plasma cell ratio of 70%, according to the findings. A diagnosis of IgG4-related disease was made. Rituximab therapy also yielded moderate results.

“This case demonstrates that overlapping features of IgG4-RD and [multicentric Castleman’s disease] may present in a single patient, which suggests a shared pathogenesis,” the researchers concluded.

“The lachrymal glands are inflamed, infiltrated by plasma cells and lymphocytes,” Sreih said. “Patients often present with swelling around the eyes or inflammation of lachrymal glands, along with slowing of parotid glands.”

Stone said, “These diverse clinical features of IgG4-RD are linked by shared pathological findings across involved organs: a lymphoplasmacytic infiltrate; storiform fibrosis, obliterative phlebitis; and enrichment with IgG4-expressing plasma cells. Such features, though strongly suggestive of IgG4-RD, should never be regarded in isolation as diagnostic of this condition. Rather, careful correlation of pathology features with clinical, serologic and imaging findings is essential to diagnosis.”

Role of B Cells

Khosroshahi and colleagues assessed the clinical and serologic responses to B lymphocyte depletion therapy in a cohort of 10 patients with steroid- and disease-modified antirheumatic drug (DMARD)-refractory IgG4-related disease. Eligible participants received two infusions of rituximab (Rituxan, Genentech) at 1,000 mg, 15 days apart. Each patient’s ability to taper prednisone to discontinuation or to cease DMARD therapy served as the main clinical outcome. The researchers also assessed total IgG, IgG subclasses and patterns of organ involvement to determine whether the pancreas, biliary tree, aorta, salivary glands, lacrimal glands, lymph nodes, thyroid gland and retroperitoneum were impacted. The IgG4-RD disease activity index and flare tool was developed and retrospectively applied to the patient population.

PAGE BREAK

Results showed what the researchers described as “striking clinical improvement” within 1 month of rituximab initiation in nine of 10 patients. The one patient had Riedel thyroiditis and failed to show improvement in the thyroid gland, but demonstrated no signs the disease had moved to other organs. Successful prednisone and discontinuation of DMARD therapy was reported in the entire cohort. Significant decreases in IgG concentrations occurred only the IgG4 subclasses, but not in total IgG. Re-treatment with rituximab was required in four patients. This re-treatment, however, yielded further reduction in IgG4 concentrations. Other findings showed IgG4 appeared to be a reliable indicator of disease activity among those who presented with IgG4 concentration.

Perugino said, “Targeting B cells in the therapy of IgG4-RD makes sense from what we have learned about the underlying immunology of this disease. While it remains unclear as to what the exact role of antibodies are in IgG4-RD is, it is clear that circulating plasmablasts typify the immune response of the disease and that the B cell compartment is most likely driving disease through the presentation of antigen to T cells in the tissue.”

There exists a somewhat stable clinical consensus surrounding the efficacy of rituximab in these diseases.

“This disease is a chronic one with disease recurrence following sometime remission induction being the norm,” Perugino said. “With that observation and the generally older patient population with multiple comorbidities, long-term suppressive glucocorticoids can be expected to cause more harm than good. The field remains desperately in need of a randomized clinical trial to promote FDA approval of a steroid-sparing agent.”

Other recent studies have looked at interactions between cells of the B cell lineage and a novel CD4+ SLAMF7+ cytotoxic T cells capable of promoting fibrosis, according to Stone. “Plasmablasts appear to play a crucial role along with B cells in the presentation of antigen to this T cell,” he said.

Stone added another approach to inhibiting B cells is XmAb5871, a novel molecule with an antigen-binding site specific for CD19, thereby targeting cells of the B-cell lineage. “However, it differs from the antibody-dependent cellular cytotoxicity (ADCC) mechanism of anti-CD20-directed therapy,” he said. “XmAb5871 capitalizes upon the natural inhibitory mechanism of FcgRIIb, the only Fc receptor expressed by B cells, which acts as a negative regulator in conditions of antigen excess and immune complex formation. When FcgRIIb is co-ligated with CD19, B cell function is inhibited and plasmablasts are rendered dormant.”

Therapeutic Options

Regarding other therapeutic options, Sreih said IgG4-RD are “responsive to steroids,” usually in the form of moderate doses of prednisone. “You can expect a response in about 2 [weeks] to 4 weeks, occasionally earlier.”

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The improvements will be seen both clinically and on imaging analyses, according to Sreih. “The problem is that after a period of therapy, we want to taper prednisone, but in many cases, the disease relapses.”

Stone agreed. “IgG4-RD does relapse in most cases, at different rates,” he said. “Patients with multi-organ disease and substantial elevations of IgG4 in their serum are at particular risk for early relapses. We presume that relapses happen because patients continue to be exposed to or are re-exposed to the antigen or antigens that trigger the disease, and the memory elements of the immune system are able to re-initiate the immune response once therapies wane.”

The next step is a steroid-sparing agent. “At this point, we use an immunosuppressant,” Sreih said. “But those medications need more clinical trial data. Currently, there have been no head-to-head randomized, placebo-controlled trials. Most of what we have are case reports, case series and retrospective analyses.”

In addition to rituximab, mycophenolate mofetil and azathioprine have shown some efficacy, according to Sreih. “There is disagreement among experts about whether to start prednisone initially with an immunosuppressant because the relapse risk is high,” he said. A contraindication to prednisone or long-term prednisone is one possible instance where this may occur, but beyond such cases, there is little consensus about using prednisone with other therapies in a first-line setting.

Further, Sreih added that different approaches are used in the United States, Europe, China and Japan among other countries.

“We see different local practices depending on local health care system rules and regulations,” he said. “For instance, it is hard to obtain rituximab in Canada, so they do not use it as a first-line agent. It is probably easier to get in the United States.”

For the most part, it comes down to a patient-by-patient, trial-and-error process. There are no curative therapies for IgG4-related disease as of yet.

“We are just not there yet,” Sreih said. “We have started talking about potential cures in rheumatic diseases, but, unfortunately, the majority of autoimmune diseases are non-curable but are treatable.”

Specific Complications

Cao and colleagues retrospectively investigated pulmonary function in a cohort of 17 patients with IgG4-related diseases. They aimed to determine whether pulmonary function tests are valuable in the diagnosis of associated respiratory diseases. The study population was divided into patients with respiratory disease or without extrapulmonary involvement. Pulmonary dysfunction was reported in all patients in the group with respiratory disease. Among those with extrapulmonary involvement, 62.5% had pulmonary dysfunction even with normal CT scan results and no associated respiratory symptoms. Restrictive ventilatory dysfunction and abnormal diffusing capacity occurred in all patients, while two patients in the respiratory disease group reported obstructive ventilatory dysfunction. Patients in the respiratory disease group experienced a significantly higher incidence of diffusing capacity of the lung for carbon monoxide per liter of alveolar volume decrease than those in the extrapulmonary group. Similarly, this volume was significantly higher in the extrapulmonary group.

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“We report the first finding of a negative correlation between pulmonary diffusing capacity and total serum concentrations of IgG and IgG subclasses (IgG4, IgG3 and IgG2),” the researchers wrote. “Diffusing capacity of the lung for carbon monoxide per liter of alveolar volume plays an important role for detecting lung involvement in IgG4-RD patients. The patient with high serum IgG may be more prone to respiratory involvement.”

“The pulmonary complications of IgG4-RD are complex and have mostly been described radiologically to include ground-glass opacities, pulmonary nodules, masses, interstitial lung disease or bronchovascular/septal thickening,” Perugino said. “About 20% of our IgG4-RD patients at the Massachusetts General Hospital have some form of pulmonary involvement. The report by Cao and colleagues is interesting and deserves a prospective survey of newly diagnosed IgG4-RD patients to assess such non-radiographic, but functional, alterations. With the concurrence of atopic disease including asthma in approximately 40% of these patients, that is an important consideration in interpreting both the radiographic and pulmonary function findings in IgG4-RD.”

Directions for Future Research

“There are many unanswered questions in regard to IgG4-RD,” Perugino said. “First, ‘Is this an autoimmune disease or rather an aberrant immune response to a foreign (ie, viral or bacterial) antigen?’ Second, and related to the first, ‘What causes IgG4-RD?’”

Perugino suggested an increasing body of large, well-defined cohorts are emerging, which will allow investigators to examine potential risk factors, such as through genome-wide association studies and microbiome comparisons.

“My current research is focused on antigen discovery efforts in IgG4-RD to determine if these antigens are self or foreign in nature, if they are shared between patients and, if of self-origin, could the differential tissue expression explain the observed organ distribution?” he said. “One additional question I am interested in studying, which will have larger medical implications for diseases such as allergies is, ‘What dictates IgG4 vs. IgE class switching?’ While the former bestows the name on this disease, it is generally thought of as an immune-inhibitory immunoglobulin, so it is likely the immune system’s attempt at quelling the underlying process whereas IgE is elevated in approximately 40% of IgG4-RD patients and correlated to likelihood of flaring but still with unclear pathologic significance.”

Stone is looking in a different direction.

“The Fc portion of XmAb5871 was engineered to have 400-fold increased affinity for FcgRIIb, permitting it to compete effectively for this binding site,” he said. He added this molecule has demonstrated efficacy in suppressing B-cell activation and proliferation, along with disease activity in rheumatoid arthritis. “We recently completed enrollment on an open-label, single-arm study on its efficacy in IgG4-RD. Preliminary analyses of this approach are promising and have been reported,” Stone said.

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Perugino is encouraged by the attention being paid to IgG4-RD. “With time and further published literature on the topic, more clinicians are considering this diagnosis based on clinical signs and measuring serum IgG subclasses as a screening measure,” he said.

For his part, Stone is encouraged that the ACR/EULAR classification criteria for IgG4-related disease are scheduled for completion in 2017.

“International consensus statements on the nomenclature of IgG4-RD, its pathologic findings and clinical management have been published,” he said. “The IgG4-RD responder index, designed to serve as a clinical trials outcome measure, is now undergoing a worldwide validation study.” – by Rob Volansky

Disclosures: Perugino reports no relevant financial disclosures. Sreih reports no relevant financial disclosures. In the last 2 years, he has received compensation for consulting for Krogg and Partners, Rupert Case Management and Naxion. Stone reports he receives research grants from and is a consultant for Genentech, Roche and Xencor in the area of IgG4-RD.