Cory A. Perugino

Large vessel involvement by IgG4-related disease.

Objectives: IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs and lead to tumefactive, tissue-destructive lesions. Reports have described inflammatory aortitis and periaortitis, the latter in the setting of retroperitoneal fibrosis (RPF), but have not distinguished adequately between these 2 manifestations. The frequency, radiologic features, and response of vascular complications to B cell depletion remain poorly defined. We describe the clinical features, radiology findings, and treatment response in a cohort of 36 patients with IgG4-RD affecting large blood vessels. Methods: Clinical records of all patients diagnosed with IgG4-RD in our center were reviewed. All radiologic studies were reviewed. We distinguished between primary large blood vessel inflammation and secondary vascular involvement. Primary involvement was defined as inflammation in the blood vessel wall as a principal focus of disease. Secondary vascular involvement was defined as disease caused by the effects of adjacent inflammation on the blood vessel wall. Results: Of the 160 IgG4-RD patients in this cohort, 36 (22.5%) had large-vessel involvement. The mean age at disease onset of the patients with large-vessel IgG4-RD was 54.6 years. Twenty-eight patients (78%) were male and 8 (22%) were female. Thirteen patients (36%) had primary IgG4-related vasculitis and aortitis with aneurysm formation comprised the most common manifestation. This affected 5.6% of the entire IgG4-RD cohort and was observed in the thoracic aorta in 8 patients, the abdominal aorta in 4, and both the thoracic and abdominal aorta in 3. Three of these aneurysms were complicated by aortic dissection or contained perforation. Periaortitis secondary to RPF accounted for 27 of 29 patients (93%) of secondary vascular involvement by IgG4-RD. Only 5 patients demonstrated evidence of both primary and secondary blood vessel involvement. Of those treated with rituximab, a majority responded positively. Conclusions: IgG4-RD is a distinctive, unique, and treatable cause of large-vessel vasculitis. It can also involve blood vessels secondary to perivascular tumefactive lesions. The most common manifestation of IgG4-related vasculitis is aortitis with aneurysm formation. The most common secondary vascular manifestation is periaortitis with relative sparing of the aortic wall. Both primary vasculitis and secondary vascular involvement respond well to B cell depletion therapy.

Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies

IgG4-related disease (IgG4-RD) is a systemic, multi-organ disorder with heterogeneous clinical features but distinctive presentations.1, 2 The classic onset of this disease is subacute, taking the form of tumor-like lesions that develop gradually. These lesions are generally identified either on physical examination (e.g., salivary gland enlargement) or imaging (e.g., a renal, lung, or pancreatic mass), frequently at a time when the patient feels well. In the first years following recognition of IgG4-RD, the diagnosis was often made by pathologists in the complete absence of clinical suspicion for the disease. More recently, because of growing familiarity with typical IgG4-RD presentations and the use of blood IgG4 testing, presumptive diagnoses are often rendered by clinicians before the performance of diagnostic tests. Biopsy confirmation of the diagnosis remains important in most cases. IgG4-RD is not a new disease. Cases of the disease are well documented in medical history going back at least to the late 1800s3 , but the individual organ manifestations were considered to be distinct disease entities for more than a century, each confined to single organs and given eponymic designations: e.g., Riedel’s thyroiditis (circa 1883), Kuttner’s tumor (dacryoadenitis involving the submandibular gland, circa 1896), and Ormond’s disease (circa 1960).4, 5, 6 In 2001, Hamano, Kawa, and colleagues demonstrated that an elevated serum IgG4 level was useful in distinguishing “sclerosing pancreatitis,” now termed type 1 (IgG4-related) autoimmune pancreatitis, from other diseases of the pancreatic and biliary tract.7 In 2003, Kamisawa and Nakajima recognized similar pathology findings in extra-pancreatic organs of patients with sclerosing pancreatitis.8 They described a disease typified by elevated serum IgG4 levels, responsiveness to glucocorticoids, multi-organ involvement, and a fibroinflammatory infiltrate. The name “IgG4-related autoimmune disease” was given to this disorder initially because of the abundance of IgG4-expressing plasma cells within affected tissues, thereby unifying seemingly disparate conditions. The involvement of bile ducts, major salivary glands, lymph nodes, and retroperitoneal tissue was also described in this original case series. Since that time, IgG4-RD has been reported to affect virtually every organ in the body. The lacrimal gland, lung, and kidney are other common sites of disease involvement [Figure 1, A–B].2 The aorta, pachymeninges, and bile ducts comprise exceptions to the tumefactive clinical presentation, presumably because of their tubular structures and/or thin walls.9, 10, 11 Open in a separate window Open in a separate window Figure 1 (A) Head and neck illustration highlighting involvement of the lacrimal and major salivary glands. Lacrimal and salivary gland enlargement is most often bilateral in distribution. (B) Abdomen illustration highlighting typical organ involvement including the pancreas, bile ducts, kidneys, and retroperitoneal tissue. Radiographically, the retroperitoneal fibrosis often extends inferiorly to encase the iliac vessels. Not depicted here, the aorta and lung are other common sites of disease involvement.

A 44‐year‐old man with eye, kidney, and brain dysfunction

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of TREX1 (3‐prime repair exonuclease‐1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patients multisystem presentation, retinal involvement interpreted as “retinal vasculitis,” and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy. Ann Neurol 2016;79:507–519

A CD8α− Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment

An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7–positive (SLAMF7+) cytotoxic effector memory T (TEM) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4‐related disease (IgG4‐RD). Glucocorticoids represent the first‐line therapeutic approach in patients with IgG4‐RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4‐RD.

Pathophysiology-Based Approaches to Treatment

IgG4-related disease (IgG-RD) is capable of causing great morbidity and even mortality if the condition remains undiagnosed or poorly treated yet is typically a treatment-responsive disorder. Glucocorticoids have not been studied rigorously, and practices with regard to dosing and duration of treatment remain largely empiric. In addition, IgG4-RD patients are often particularly susceptible to and intolerant of the deleterious effects of glucocorticoid therapy. B cell depletion with anti-CD20 monoclonal antibodies appears to be a rapid, effective means of obtaining disease control and limiting patients’ glucocorticoid exposure, but this option is frequently available. Other therapies targeting the B cell lineage may also be efficacious, and one is under study. The means by which depletion or inhibition of B cells and their progeny ameliorate IgG4-RD are coming into focus now through careful mechanistic studies of samples from treated patients.

Identification of Galectin-3 as an Auto-Antigen in IgG4-Related Disease

Background: The antigenic trigger that drives expansion of circulating plasmablasts and CD4+ cytotoxic T cells in patients with IgG4‐related disease (IgG4‐RD) is presently unknown. Objective: We sought to sequence immunoglobulin genes from single‐cell clones of dominantly expanded plasmablasts and generate recombinant human mAbs to identify relevant antigens in patients with IgG4‐RD by using mass spectrometry. Methods: Paired heavy and light chain cDNAs from dominant plasmablast clones were expressed as mAbs and used to purify antigens by using immunoaffinity chromatography. Affinity‐purified antigens were identified by using mass spectrometry and validated by means of ELISA. Plasma levels of the antigen of interest were also determined by using ELISA. Results: mAbs expressed from the 2 dominant plasmablast clones of a patient with multiorgan IgG4‐RD stained human pancreatic tissue sections. Galectin‐3 was identified as the antigen specifically recognized by both mAbs. Anti–galectin‐3 autoantibody responses were predominantly of the IgG4 isotype (28% of the IgG4‐RD cohort, P = .0001) and IgE isotype (11% of the IgG4‐RD cohort, P = .009). No significant responses were seen from the IgG1, IgG2, or IgG3 isotypes. IgG4 anti–galectin‐3 autoantibodies correlated with increased plasma galectin‐3 levels (P = .001), lymphadenopathy (P = .04), total IgG level increase (P = .05), and IgG4 level increase (P = .03). Conclusion: Affinity chromatography using patient‐derived mAbs identifies relevant autoantigens in patients with IgG4‐RD. IgG4 galectin‐3 autoantibodies are present in a subset of patients with IgG4‐RD and correlate with galectin‐3 plasma levels. The marked increases in levels of circulating IgG4 and IgE observed clinically are, at least in part, caused by the development of IgG4‐ and IgE‐specific autoantibody responses.

Getting with the program in type 1 diabetes mellitus

Transcriptomic studies reveal defective costimulation via PD-L1 to explain the autoreactive phenotype seen in type 1 diabetes mellitus. Transcriptomic studies reveal defective costimulation via PD-L1 to explain the autoreactive phenotype seen in type 1 diabetes mellitus.

An International Multispecialty Validation Study of the IgG4-Related Disease Responder Index

IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4‐RD Responder Index (RI) was developed to help investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation.

Disease Damage and Acute Phase Reactants in IgG4-Related Disease

1. Perugino CA, Mattoo H, Mahajan VS, Maehara T, Wallace ZS, Pillai S, et al. IgG4-related disease: insights into human immunology and targeted therapies. Arthritis Rheumatol 2017;69:1722–32. 2. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol 2015;67:2466–75. 3. Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med 2007;356:2361–71. 4. Bunker D, Gorevic P. AA amyloidosis: Mount Sinai experience, 1997–2012. Mt Sinai J Med 2012;79:749–56. 5. Karim F, Clahsen-van Groningen M, van Laar JA. AA amyloidosis and IgG4-related disease. N Engl J Med 2017;376:599–600. 6. Carruthers MN, Stone JH, Deshpande V, Khosroshahi A. Development of an IgG4-RD Responder Index. Int J Rheumatol 2012; 2012:259408.

FRI0588 Interim results of a phase 2 study of XMAB®5871, a reversible B cell inhibitor, in IGG4-related disease

Background IgG4-related disease (IgG4-RD) is an immune-mediated condition causing fibro-inflammatory lesions that can lead to irreversible organ damage. No approved therapies for IgG4-RD exist. We report the use of a novel monoclonal antibody, XmAb5871, in IgG4-RD. XmAb5871 is a humanized anti-CD19 antibody with an Fc portion engineered for increased affinity (up to 400-fold over native IgG1) to FcgRIIb, the only Fc receptor on B cells. Co-ligation of CD19 and FcgRIIb leads to inhibition of B lineage cells bearing these targets. Reversible inhibition of B cell function without B cell ablation is one potential advantage of this approach. Methods The trial is an open-label investigation of XmAb5871 in active IgG4-RD, defined by an IgG4-RD Responder Index (RI) of ≥3. XmAb5871 (5 mg/kg) is administered IV every 14 days for 12 doses. The primary outcome measure is the proportion of patients on day 169 (2 weeks following the last dose) with a decrease in the IgG4-RD RI of 2 or more points compared to baseline. Glucocorticoids are permitted but not required at entry and must be discontinued by two months. Other immunosuppressive medications are not allowed. Imaging and mechanistic studies are performed at baseline and at selected intervals. Results Fifteen patients were enrolled between March 2016 and January 2017. As of October 31, 2016, 12 patients had received at least one infusion of XmAb5871. The median age of the 12 patients is 58 years (range: 43 to 78 years). Two-thirds of the patients are male. Nine of the 12 patients had elevated serum IgG4 concentrations at baseline with a mean serum IgG4 of 499 mg/dL (range: 25–2415; normal <86 mg/dL). The median baseline IgG4-RD RI score was 10 (range: 2–30), with active inflammatory disease in at least one organ system (median 4, range: 1–10). The organs most commonly affected were lymph nodes (75% of patients), submandibular glands (67%), parotid glands (58%), and lacrimal glands (50%). Four patients (33%) had kidney involvement and 3 (25%) had heart/pericardium findings. Nine of 11 patients (82%) have had an initial response to XmAb5871 therapy of at least a three-point reduction in the IgG4-RD RI within two weeks of the first dose. As of Oct 31st, 2016, five patients attained disease remission (an IgG4-RD RI of 0 and no prednisone treatment after 2 months) during the study. Efficacy outcomes will be updated as more patients complete the study. One patient had been on glucocorticoid treatment for 2 years and was on prednisone of 15 mg/day at baseline, but was able to discontinue prednisone by 2 months after starting treatment. Three patients experienced minor, transient gastrointestinal side-effects during the 1st infusion. One patient had infusion-related GI symptoms on the 5thinfusion and subsequently developed rash and arthritis. She was found to have anti-drug antibodies and has discontinued the study. Mechanistic studies show that both peripheral B cells and plasmablasts decrease substantially following therapy in the majority of patients. Studies of the mechanism of this decrease and functional B cell assays are under way. Conclusions XmAb5871 is tolerated well in patients with active IgG4-RD and is a promising treatment approach for IgG4-RD. Disclosure of Interest J. Stone Grant/research support from: Genetech/Roche, Xencor, Consultant for: Genentech/Roche, Xencor, Z. Wallace: None declared, C. Perugino: None declared, A. Fernandes: None declared, P. Patel: None declared, P. Foster Shareholder of: Full time employee of Xencor, Employee of: Full time employee of Xencor, D. Zack Shareholder of: Full time employee of Xencor, Employee of: Full time employee of Xencor