Systemic Amyloidosis as a Rare Complication of IgG4 Related Disease: Case Report and Literature Review

Immunoglobulin 4 Related Disease (IgG4-RD) is immune-mediated broinammatory disease and despite recent advances the immunological process involved in the disease pathogenesis is still unclear. Serum amyloid A (SAA) the precursor protein in AA amyloidosis is induced by inammatory mediators such as IL-1, IL-6 and TNF cytokines. The treatment of AA amyloidosis is directed by the theoretical cytokine involved in the underlying inammatory condition. Many inammatory conditions has already been associated to AA amyloidosis and secondary to IgG4-RD seems to be rare. Here we report the case of a Brazilian patient with IgG4-RD with a fatal evolution of systemic amyloidosis. We also revised the cases already reporte in the literature with IgG4-RD and systemic amyloidosis.


Introduction
Immunoglobulin G4 -related disease (IgG4-RD) is an uncommon systemic in ammatory condition mediated by in ltration of IgG4-producing plasma cells (1). De nitive diagnosis is stablished in biopsies of affected tissues with proven and variable intensity of IgG4 positive plasma cells in ltration. Up to 50% of patients do not have increased serum IgG4 levels 2. Serum IgG4-plasmablast is the gold standard marker for diagnosis and disease remission. Rituximab is the gold standard in order to achieve clinical control, reducing progression of brosis and decreasing in ammatory markers (1,2).
Amyloidosis comprises a group of diseases that are the product of the deposition of unfolded amyloid protein in tissues. In amyloid A amyloidosis (AA amyloidosis), pro-in ammatory cytokines such as interleukin 1, interleukin 6 and TNF-α seems to interact synergistically for the serum amyloid A proteins (SSA) synthesis in the liver, which can be deposited in various organs leading to tissue damage.
Prolonged or recurrent episodes of systemic in ammation, as observed in systemic autoimmune, autoin ammatory or infectious disease, is the main cause of AA amyloidosis. Unexpectedly, systemic AA amyloidosis has no speci c treatment and it is recommended to block the likely underlying cytokine involved in the process (3).
Amyloidosis is a rare complication of IgG4-RD with few cases already reported. The immunology process involved in amyloid formation in patients with IgG4-RD is not yet elucidated neither the phenotypes more susceptible to systemic amyloidosis. This paper aims to report the case of a Brazilian patient with IgG4-RD refractory to treatment who has evolved dramatically to systemic amyloidosis, and to review the cases already reported in the literature.

Material And Methods
We retrieved patient's data from clinical records. We performed a literature review of cases already reported with both IgG4-RD and systemic amyloidosis.
Case Report of persistent night fever and night sweating, associated with pain in the right hypochondrium radiating to the epigastrium. The patient also presented iron de ciency anemia refractory to iron replacement, high platelet counts and positive in ammatory markers (CRP and ESR).
Initially all infectious, autoimmune and neoplastic known causes were excluded. An abdominal CT revealed hepatosplenomegaly and retroperitoneal mass. High-dose corticosteroids prescribed empirically at high doses were only partially effective.Histopathological analysis of retroperitoneal mass was compatible with IgG4-RD. Steroid-sparing agents were not effective in controlling symptoms, as well as tapering steroids dosage was also not able to reduce the levels of in ammatory markers. For this reason, B cell depletion therapy was initiated (ritutximab 1g/dose every 4 weeks in two doses). Clinical control could be observed but without considerable reduction in in ammatory markers.
Due to the socioeconomic context, the patient had low adherence to the proposed treatments and to following the check-up routine.
Six years after diagnosis, he was admitted to the emergency room with severe right hypochondrium pain, after presenting hematochezia for twenty days.
Laboratory ndings included a signi cant increase in in ammatory markers, hypogammaglobulinemia, hypoalbuminemia, high pro-BNP levels and nephrotic proteinuria with normal renal function. Imaging exams showed increased hepatosplenomegaly (Fig. 1). Also, hemorrhagic gastroduodenitis was diagnosed during an upper gastrointestinal endoscopy. Multiple specimen biopsies were obtained from esophagus, stomach, duodenum and liver. Amorphous material deposits were identi ed in all biopsy tissue samples, with a positive Congo red stain (Fig. 1). Subsequently, it was observed a serum amyloid A protein of 186 mg/L (reference value below 6.4 mg/L). Empirical treatment with colchicine was initiated and anti-IL6 was proposed. However, after two months of hospital discharge, and before anti-IL 6 could be started, he developed septic shock refractory to clinical measures progressing to death. All relevant laboratory data and treatment used are shown in Fig. 1.

Discussion
We described the case of a patient with recalcitrant IgG4-RD with persistently high in ammatory biomarkers and a sudden worsening of his clinical condition, leading to the diagnosis of AA systemic amyloidosis.
The immunopathogenesis of IgG4-RD interestingly provokes mechanist insights into systemic in ammation that can lead to amyloid formation once IgG4 has an anti-in ammatory property rather compared to other immunoglobulin G sybtypes. Cytokines, that are key pieces for amyloid formation also accounts for IgG4 related disease.
Cytokines derived from innate immune system seems to be involved in the pathogenesis of IgG4-RD.
From one side IL−6 seems to be associated to vascular forms of IgG4-RD whereas Type I IFN, specially Type I IFN-α, was related to IgG4-RD pancreatitis. Also in vitro studies revealed that IgG4 class-switch DNA recombination is enhanced in the presence of IL−4 and BAFF (B cell activation factor) or APRIL (proliferation-inducing ligand), which strongly suggests that BAFF and APRIL are involved in B cell survival as well as in IgG4 production.
Several reports suggests that IL−6 does not play a major role in the in ammatory responses in IgG4-RD. As IgG4-RD is characterized by Th2 rather than Th1 cytokines, differentiation and activation of M2 macrophages is more likely to be induced in this disease.Thus, M2 macrophages can contribute to tissue brosis via IL−10 and IL−13 production in IgG4-RD (4).
Amyloidosis following IgG4-RD is a rare complication. We identi ed six cases of IgG4-RD and amyloidosis in the literature, all summarized in Table 1. All patients were adult and 66% were female. There was no speci c subtype of IgG4-RD more likely to be involved in amyloidosis formation. Time from the IgG4-RD presentation to the diagnosis of amyloidosis vary in cases reported from 5 months to 20 years and mass spectrometry was performed in just one case to subtype the amyloid protein. Successful treatment after amyloidosis was installed could be obtained using high doses of systemic steroids and anti-CD20 monoclonal antibodies. Two cases with localized breast Rosai-Dorfman IgG4-RD were successfully treated with tumor resection and both reported to be disease free after a long follow-up.
Based on this case series herein reported, we strongly suggests systematic screening of this complication on follow-up of patients with IgG4-RD, specially for those who: 1 -don't achieve disease's control with the usual theraphy; and/or 2 -have persistent high levels of in ammatory markers. We also raise discussions on the physiopatology of SAA formation in patients with IgG4-RD.

Declarations
Funding: There was no funding supporting this paper

Con icts of interest/Competing interests:
All authors declare no con icts/competing interests related to this paper Ethics approval: this paper was approved by the Ethical Committee at the University of São Paulo Consent to participate: We obtained consent to participate previously of the patient died Table   Due to technical limitations, table 1