Predictors of Relapse in IgG4-Related Disease

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Abstract and Introduction

Abstract

Objectives: In IgG4-related disease, the relationship between pathological findings and relapse has not been well established. This study aimed to identify the clinical and pathological predictors of disease relapse in IgG4-RD.

Methods: Patients with newly diagnosed IgG4-RD (n = 71) were enrolled between January 2011 and April 2020; all cases were pathologically confirmed. The clinical and pathological features were recorded in a database at baseline and each follow-up visit. Patients were followed up at least once a month via outpatient clinic examinations and telephone calls. Univariate and multivariate Cox regression analyses and receiver operating curve (ROC) analysis were used to identify the predictors of disease relapse and to assess their predictive value.

Results: Over a median follow-up of 26 (range, 6–123) months, 3/71 (4.2%) patients died. Of the remaining 68 patients, 47 (69.1%) patients had achieved clinical remission and 21 (30.9%) had suffered relapse at the last follow-up. The independent predictors of relapse were IgG4 ≥ 6.5 g/L (HR = 2.84, 95% CI: 1.11–7.23), IgG ≥ 20.8 g/L (HR = 4.11, 95% CI: 1.53–11.06), IgG4-RD responder index (RI) ≥ 9 (HR = 3.82, 95% CI: 1.28–11.37), and severe IgG4⁺ plasma cell infiltration (HR = 6.32, 95% CI: 1.79–22.41). A prognostic score developed using three of the identified predictors (IgG ≥ 20.8 g/L, IgG4-RD RI ≥ 9, and severe IgG4⁺ plasma cell infiltration) showed good value for predicting impending relapse (AUC, 0.806).

Conclusions: In patients with IgG4-RD, IgG4 ≥ 6.5 g/L, IgG ≥ 20.8 g/L, IgG4-RD responder index (RI) ≥ 9, and severe IgG4⁺ plasma cell infiltration are predictors of relapse.

Introduction

IgG4-related disease (IgG4-RD) is a newly recognized systemic autoimmune disease that can involve the pancreatobiliary tract, retroperitoneum/aorta, head and neck region, and salivary glands.^[1] The etiology is unknown. Single or multiple organomegaly may be present and, therefore, the disease often has to be differentiated from tumor.^[1] Histopathological examination is one of the major criteria for the diagnosis of IgG4-RD according to the 2019 ACR/EULAR classification criteria, the characteristic findings being IgG4⁺ plasma cell infiltration, storiform fibrosis, and obliterative phlebitis.^[2,3]

Relapse is common in IgG4-RD, occurring in 24–54% of patients after reduction of glucocorticoid dose.^[4–9] The 2-year relapse rates are 23.0–41.4%.^[9,10] Patients with relapse present with reappearance of organomegaly and organ dysfunction (e.g., renal insufficiency, liver cirrhosis, intestinal obstruction). Previous studies have identified high serum IgG4 level, multiple organ involvement, high IgG4-RD responder index (RI) score, high serum IgE, and high eosinophil count at baseline as predictors of long-term relapse.^[11,12] Increase in memory B cell count after corticosteroid treatment and persistence of T-follicular helper cells after rituximab are also reported to be associated with relapse.^[13,14] In addition, our previous study^[8] found serum TNF-α level and IL-2R to be independent predictors of relapse.

Although the pathological diagnostic criteria for IgG4-RD have been established,^[15–21] the pathological features associated with disease relapse are not known. The aim of this study was to investigate the relationship between pathological manifestations and disease relapse in IgG4-RD and to identify the independent predictors of disease relapse.

Arthritis Res Ther. 2022;24(106) © 2022 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Baseline characteristics of the patients, stratified by relapse status
	All patients (n = 68)	Patients in remission (n = 47)	Patients with relapse (n = 21)	p
Age (years)	57 (47–63)	57.5 (46.8–64.0)	55.5 (41.3–62.8)	0.660*
Sex (male)	51 (75)	35 (74)	16 (76)	0.880**
Time from onset of symptoms to diagnosis (months)	7 (2–23)	6 (1–20)	12 (5–27)	0.081*
Organ involvement
≥2	40 (58.8)	24 (51.1)	16 (76.2)	0.045**
≥3	23 (33.8)	13 (27.7)	10 (47.6)	0.112**
Head and neck involvement	24 (35.3)	17 (36.2)	7 (33.3)	0.821**
Visceral organ involvement	46 (67.6)	32 (68.1)	14 (66.7)	0.908**
Allergy history	14 (23.3)	9 (21.95)	5 (26.3)	0.710**
IgG4-RD RI	9 (6–12)	6 (6–12)	9 (6–12)	0.038*
Serum IgG4 (g/L)	3.90 (1.44–10.19)	3.09 (1.12–7.26)	7.26 (2.68–18.85)	0.026*
E (%)	2.05 (0.50–4.25)	2.7 (1.1–4.8)	1.5 (0.4–2.2)	0.074*
ESR (mm/h)	41 (12–83)	41 (13–82)	42 (10–92)	0.783*
CRP (mg/L)	6.1 (0.8–31.5)	6.8 (0.73–28.0)	4.97 (0.55–50.2)	0.955*
Serum IgG (g/L)	16.7 (11.5–22.9)	14.4 (10.9–20.3)	19.9 (15.5–34.3)	0.011*
Serum IgE (IU/mL)	112 (24–294)	112 (22–260)	119 (25–313)	0.831*
C3 (g/L)	0.99 (0.80–1.18)	1.02 (0.81–1.21)	0.92 (0.72–1.15)	0.196*
C4 (g/L)	0.19 (0.13–0.26)	0.23 (0.15–0.27)	0.16 (0.07–0.21)	0.019*
TG (mmol/L)	1.12 (0.82–1.83)	1.15 (0.94–1.87)	0.90 (0.71–1.54)	0.046*
TC (mmol/L)	3.71 (3.38–4.52)	4.18 (3.56–4.91)	3.38 (2.82–3.72)	0.005*
LDL (mmol/L)	2.20 (1.73–2.64)	2.50 (1.98–2.99)	1.92 (1.61–2.27)	0.030*

Data are n (%) or median (interquartile range)
IgG4-RD RI IgG4-related disease responder index, E eosinophils, PLT platelet count, ESR erythrocyte sedimentation rate, CRP C-reactive protein, TC total cholesterol, TG triglycerides, LDL low-density lipoprotein
*Mann–Whitney U test, **chi-square test

Table 2. Comparison of pathological manifestations between the patients in remission and patients with relapse
	Patients in remission (n = 47)	Patients with relapse (n = 21)	p
Number of IgG4⁺ plasma cells/HPF	50 (25–120)	70 (40–290)	0.013*
Ratio of IgG4⁺ cell/IgG⁺ cell (%)	40.0 (30.0–56.0)	40.7 (40.0–59.5)	0.644*
Severe IgG4⁺ plasma cell infiltration (≥60/HPF in visceral organs or ≥200/HPF in head and neck organs)	21 (44.7%)	18 (85.7%)	0.002**
Fibrosis	39 (83.0)	18 (85.7)	0.777**
Storiform fibrosis	7 (14.9)	2 (9.5)	0.546**
Obliterative phlebitis	16 (34.0)	7 (33.3)	0.954**
Eosinophilic infiltration	5 (10.6)	1 (4.8)	0.430**
Lymphoid follicle formation	18 (38.3)	3 (14.3)	0.048**
Germinal center formation	5 (10.6)	1 (4.8)	0.430**

Data are n (%) or median (interquartile range). Statistically significant p values are in bold font
HPF high-power field
*Mann–Whitney U test, **chi-square test

Table 3. Cox regression multivariate analysis showing factors independently associated with IgG4-RD relapse
	HR	95% CI	p
IgG ≥ 20.8 g/L	4.11	1.53–11.06	0.005
IgG4 ≥ 6.5 g/L	2.84	1.11–7.23	0.029
IgG4-RD RI ≥ 9	3.82	1.28–11.37	0.016
Severe IgG4⁺ plasma cell infiltration	6.32	1.79–22.41	0.004

IgG4-RD IgG4-related disease, HR hazard ratio, IgG4-RD-RI IgG4-related disease responder index

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Clinical and Pathological Predictors of Relapse in IgG4-Related Disease

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