Case Reports

An Imposter Twice Over: A Case of IgG4-Related Disease

Fed Pract. 2018 October;35(10):60-64

References

1. Lang D, Zwerina J, Pieringer H. IgG4-related disease: current challenges and future prospects. Ther Clin Risk Manag. 2016;12:189-199.

2. Brito-Zerón P, Ramos-Casals M, Bosch X, Stone JH. The clinical spectrum of IgG4-related disease. Autoimmun Rev. 2014;13(12):1203-1210.

3. Wallace ZS, Deshpande V, Mattoo H, et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 2015;67(9):2466-2475.

4. Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-RD. Ann Rheum Dis. 2015;74(1):14-18.

5. Khosroshahi A, Wallace ZS, Crowe JL, et al; Second International Symposium on IgG4-Related Disease. International consensus guidance statement on the management and treatment of IgG4-Related disease. Arthritis Rheumatol. 2015;67(7):1688-1699.

6. Gupta N, Mathew J, Mohan H, et al. Addition of second-line steroid sparing immunosuppressants like mycophenolate mofetil improves outcome of immunoglobulin G4-related disease (IgG4-RD): a series from a tertiary care teaching hospital in South India. Rheumatol Int. 2017;38(2):203-209.

7. Lin HP, Lin KT, Ho WC, Chen CB, Kuo, CY, Lin YC. IgG4-associated cholangitis mimicking cholangiocarcinoma-report of a case. J Intern Med Taiwan. 2013;24:137-141.

8. Douhara A, Mitoro A, Otani E, et al. Cholangiocarcinoma developed in a patient with IgG4-related disease. World J Gastrointest Oncol. 2013;5(8):181-185.

9. Harada K, Nakanuma Y. Cholangiocarcinoma with respect to IgG4 reaction. Int J Hepatol. 2014;2014:803876.

10. Barbu M, Lindström U, Nordborg C, Martinsson A, Dworeck C, Jeppsson A. Sclerosing aortic and coronary arteritis due to IgG4-related disease. Ann Thorac Surg. 2017;103(6):e487-e489.

11. Kim YJ, Park YS, Koo BS, et al. Immunoglobulin G4-related disease with lymphoplasmacytic aortitis mimicking Takayasu arteritis. J Clin Rheumatol. 2011;17(8):451-452.

12. Khosroshahi A, Digumarthy SR, Gibbons FK, Deshpande V. Case 34-2015: A 36-year-old woman with a lung mass, pleural effusion and hip pain. N Engl J Med. 2015;373(18):1762-1772.

13. Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia and IgE elevation in IgG4-related disease. Allergy. 2014;69(2):191-206.

14. Wallace ZS, Mattoo H, Carruthers M, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis. 2015;74(1):190-195.

Discussion

IgG4-related disease has been found to be a systemic disorder. Typical characteristics include predominance in men aged > 50 years, elevated IgG4 levels, and findings on histology.¹ It has been reported to involve many organs, including pancreas, liver, gallbladder, salivary glands, thyroid, and pleura of the lung.^2,5

This case report begins with a presumptive diagnosis of cholangiocarcinoma, which was treated aggressively with extensive surgery. Several case reports of complex tumefactive lesions in the GI area (mostly pancreatic and biliary) have detailed IgG4-RD as both a risk factor for subsequent development of cholangiocarcinoma and as a separate entity of IgG4-related sclerosing cholangitis.^7-9 It is hypothesized that the induction of IgG4- positive plasma cells has been intertwined with the development of cholangiocarcinoma. Differentiation between IgG4 reaction that is scattered around cancerous nests and IgG4 sclerosing cholangitis without malignancy is challenging. It has been documented that both elevated IgG4 levels and hilar hepatic lesions that resemble cholangiocarcinoma frequently accompany those cases of IgG4 sclerosing chlolangitis without pancreatic involvement.⁹The histologic features of IgG4-RD need to be identified with multiple biopsies and cytology, and superficial biopsy from biliary mucosa cannot reliably exclude cholangiocarcinoma.

Lymphoplasmacytic aortitis and arteritis have been documented in IgG4-RD. In 2017, Barbu and colleagues described how one such case of coronary arteritis presented with typical angina and coronary catheterization revealing coronary artery stenosis.¹⁰ However, during coronary artery bypass surgery, the aorta and coronary vessels were noted to be abnormally stiff. A diffuse fibrotic tissue was identified to be causing the significant stenosis without evidence of atherosclerosis. Pathology showed typical findings of IgG4-RD, and there was a rapid response to immunosuppressive therapy. Involvement of coronary arteries has been described in a small number of cases at this time and is associated with progressive fibrotic changes resulting in an MI, aneurysms, and sudden cardiac death.^2,10,11

IgG4-RD can be an extensively systemic disease. All presentations of fibrosis or vasculitis should be viewed with heightened suspicion in the future as being a facet of his IgG4-RD. Pleural involvement has been reported in 12% of cases presenting with systemic presentation, kidney involvement in 13%.^2,12

Unfortunately, there is no standard laboratory parameter to date that is diagnostic for IgG4-RD. The gold standard remains confirmation of histologic findings with biopsy. According to an international consensus from 2015, 2 out of the 3 major findings need to be present: (1) dense lymphoplasmacytic infiltrate; (2) storiform fibrosis; and (3) obliterative phlebitis in veins and arteries.^1,5 Most patients present with symptoms related to either tumefaction or fibrosis of an organ system.¹ Peripheral eosinophilia and elevated serum IgE are often present in IgG4-RD.¹³ Although IgG4 values are elevated in 51% of biopsy-proven cases, flow cytometry of CD19^lowCD38⁺CD20^-CD27⁺ plasmablasts has been explored recently as a correlation with disease flare.^3,14 These particular plasmablasts mark a stage between B cells and plasma cells and have been reported to have a sensitivity of 95% and a specificity of 82% in association with actual IgG4-RD.¹⁴ Furthermore, blood plasmablast concentrations decrease in response to glucocorticoid treatment, thereby providing a possible quantifiable value by which to measure success of IgG4 treatment.^5,12

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Treatment for this disease consists of immunosuppressive therapy. There is documentation of successful remission with rituximab and azathioprine, as well as methotrexate.^1,5Both 2015 consensus guidelines and a recent small single-center retrospective study support addition of second-line steroid sparing agents such as mycophenolate mofetil.^5,6 For acute flairs, however, glucocorticoids with slow taper are usually utilized. In these cases, they should be tapered as soon as clinically feasible to avoid long-term adverse effects. Untreated IgG4-RD, even asymptomatic, has been shown to progress to fibrosis.⁵