Demographic characteristics of IgG4-RD with PAO/PA
Among 587 IgG4-RD patients, 89 patients (76 men and 13 women) were included in the IgG4-related PAO/PA group and 498 patients were included in the non-PAO/PA group. Of the IgG4-RD patients with PAO/PA, 24 (27.0%) had PAO/PA alone, while the other patients (n=65, 73.0%) had multiple organ involvement Demographic features of IgG4-RD with/without PAO/PA are shown in Table 1. The age of PAO/PA patients was 58.3±11.1 years, with a male/female ratio of 5.85/1. The IgG4-RD RI was 10.8±5.3 at baseline. Male patients (59.5±9.7 years) were older than female patients (51.3±16.1 years) at disease onset (P=0.015). Moreover, 25 (28.1%) PAO/PA patients had an allergic history. The median follow-up time was 30 (15, 52) months.
We compared the prevalence of allergic diseases in IgG4-PAO/PO patients with/without extra-glandular involvement. The results showed that allergic diseases were more common in patients with lacrimal and/or salivary gland lesions than in those without (53.6% versus 16.4%, P<0.001).
Of 89 patients with PAO/PA, 35 (39.3%) patients were diagnosed as having definite IgG4-RD, 1 (1.1%) was probable, and 53 (59.6%) patients were possible. Nine (10.1%) patients underwent perivascular mass biopsy, while the rest of the patients underwent biopsy of other involved organs, including the submandibular gland, lacrimal gland, kidney, lymph node, lung, etc.
Symptoms at disease onset in IgG4-RD patients with PAO/PA
Symptoms at disease onset in IgG4-RD patients with PAO/PA are shown in Table 2. Pain was the most prevalent symptom observed; among all patients, 57 (64.0%) patients had onset symptoms of back pain (32, 36.0%) and abdominal pain (25, 28.1%). Fourteen patients (15.7%) had lower limb edema. Other onset symptoms included lymph node swelling (22, 24.7%), submandibular gland enlargement (18, 20.2%), cough (11, 12.4%), lacrimal gland enlargement (10, 11.2%), jaundice (8, 9.0%), parotid gland enlargement (5, 5.6%), and nasal congestion (4, 4.5%).
Laboratory parameters of IgG4-RD patients with PAO/PA
Among IgG4-RD patients with PAO/PA, the serum creatinine level increased in 43 (48.3%) patients (131 [117, 179] µmol/L) (Table 3), including 39 (51.3%) male patients and 4 (30.8%) female patients. ESR and hsCRP values were 44 (18-75) mm/h and 6.72 (2.14-24.65) mg/L, respectively. Serum IgG, IgG4, and T-IgE levels were 19.88±8.20 g/L, 4240 2015,7730) mg/L, and 170 (95.3, 463.5) KU/L, respectively.
Comparison of IgG4-RD patients with/without PAO/PA
Compared with non-PAO/PA patients, PAO/PA patients were older at disease onset, had a higher male/female ratio, but had shorter disease duration and lower percentage of an allergic history (P<0.001, P<0.001, P<0.001, and P<0.001, respectively; Table 1). The number of organs involved and IgG4-RD RI were comparable in patients with/without PAO/PA. However, patients with PAO/PA had a higher percentage of single organ involvement than those without PAO/PA (P<0.001).
Patients with PAO/PA had a higher percentage of back pain, abdominal pain, and lower limb edema than those with PAO/PA (4.2% [P<0.001], 15.9% [P=0.005], and 1.6% [P<0.001], respectively). In contrast, patients with PAO/PA had a lower percentage of submandibular gland enlargement, lacrimal gland enlargement, parotid gland enlargement, and nasal congestion than those without PAO/PA (42.8% [P<0.001], 45.6% [P<0.001], 13.3% [P=0.042], and 21.3% [P<0.001], respectively) (Table 2). Consistent with onset symptoms, patients with PAO/PA had a lower percentage of submandibular gland, lacrimal gland, and paranasal involvement (all P<0.001) (Table 2).
Compared to patients with PAO/PA, those with PAO/PA had higher levels of ESR, hsCRP, and IgA (P<0.0001, P<0.0001, and P=0.02, respectively) (Table 3). However, patients with IgG4-related PAO/PA had lower levels of serum IgG4 and IgE than those without IgG4-related PAO/PA (8310 [3250, 17075] mg/L, 332 [119, 720.5] KU/L; P<0.0001 and P=0.025, respectively) (Table 3). Additionally, serum IgG4 levels were higher in patients with PAO/PA and other organs affected (5270 [2395, 11910] mg/L) than in those with only PAO/PA (2418 [1583, 4638] mg/L) (P=0.001).
CD19+CD24-CD38hiplasmablast/plasma cells
Overall, 93 patients showed CD19+CD24-CD38hi plasmablast/plasma cells at baseline. No statistical significant difference in CD19+CD24-CD38hi plasmablast/plasma cell was found between PAO/PA and non-PAO/PA patients. However, the percentage of CD19+CD24-CD38hi plasmablast/plasma cells was lower in patients with only PAO/PA (2.22% [Q1-Q3, 1.87%-5.90%]) than in those with PAO/PA and other organ involvement (8.5% [Q1-Q3, 4.52%-16.90%]) or non-PAO/PA (5.58% [Q1-Q3, 2.99%-10.50%]) (P=0.015 and P=0.023, respectively).
Vessels distribution of IgG4-related PAO/PA
Characteristic imaging findings IgG4-related PAO/PA are shown in Figure 2. Of 89 IgG4-RD patients with PAO/PA, the abdominal aorta was the most affected vessel (74, 83.1%), followed by the iliac artery (63, 70.8%), thoracic aorta (12, 13.5%), and other vessels, including the superior mesenteric artery (6, 6.7%), renal artery (6, 6.7%), common carotid artery (3, 3.4%), and subclavian artery (2, 2.2%), revealing vascular stenosis in 3 patients. Beside soft tissue around the vessels, 27 patients had calcification of the aortic wall, 22.5% had diffuse thickening of the abdominal aortic wall, and 10.1% had aneurysmal dilation of the aorta (Table 4). Abdominal aorta and iliac artery lesions were more common in male patients than in female patients (P=0.024 and P=0.035, respectively; Table 4). However, the ratio of patients with thoracic aorta and other large vessels affected was higher in female patients than in male patients (P=0.048 and P=0.004, respectively; Table 4). Moreover, female patients had a lower percentage of aortic wall calcification than male patients (P=0.047; Table 4).
According to the distribution of IgG4-related PAO/PA, type 2, involvement of abdominal aorta and iliac artery, was the most prevalent (74, 83.1%), especially type 2b (52, 58.4%), followed by type 2a (15, 16.9%), type 2c (7, 7.9%), type 3 (7, 7.9%), type 1 (5, 5.6%), and type 4 (3, 3.4%) (Table 4). Additionally, no statistical significance in vessel distribution was found between patients with PAO/PA alone and those with PAO/PA and other organ involvement.
Further, 55 (61.8%) patients with PAO/PA had hydronephrosis, including 47 (61.8%) male patients and 8 (61.5%) female patients. Forty-three (48.3%) patients developed impairment of renal function caused by ureteral obstruction. Of patients with severe obstruction, double J (D-J) stent drainage was the first option to relieve obstruction, and 31 (34.8%) PAO/PA patients had D-J stent drainage. With regard to other organs affected, the rates of lymph node, pancreas, submandibular gland, lung, prostate, bile duct, lacrimal gland, parotid gland, paranasal sinus, and thyroid gland involvement were 37.1%, 29.2%, 27.0%, 16.9%, 15.8%, 12.4%, 12.4%, 10.1%, 9.0%, and 2.2%, respectively (Table 2).
Clinical features among the four types of vessel involvement groups
We compared the clinical characteristics at baseline of IgG4-related PAO/PA patients with different vessel distributions (type 1, type 2a, type 2b, type 2c, type 3, and type 4) in supplementary table 1. The results indicated that male patients were predominant in type 2 than in type 1 (P=0.018). Among all the groups, IgG4-RD RI was highest in type 2a (P=0.047). The percentage of creatinine elevation caused by ureter obstruction was much higher in type 2 and type 3 than in the others. There was no statistical significance in the other clinical features among the four groups.
Treatment efficacy in patients with PAO/PA
Patients with PAO/PA were treated with glucocorticoids (GCs) or GCs combined with immunosuppressant agents (GCs plus immunosuppressant agent).
Except for 18 (20.2%) patients who received GC monotherapy, the other patients were treated with GCs plus cyclophosphamide (CYC) (n=52, 58.4%), GCs plus mycophenolate mofetil (MMF) (n=18, 20.2%), and GCs plus leflunomide (n=1, 1.1%). Forty-one (46.1%) patients received combined treatment with tamoxifen.
After 6 months of treatment, 34 (38.2%) patients achieved reduction of perivascular soft tissues >70%, 39 (43.8%) achieved reduction between 31% and 70%, and 16 (18.0%) had reduction <30%. Compared with male patients with PAO/PA, a higher percentage of female patients had reduction of perivascular soft tissues <30% (P=0.01). In 31 (34.8%) patients who had D-J stent drainage, 22 (71.0%) patients had successful stent extubation, and the median time of extubation was 6 (3-13.5) months. Of 43 patients with renal function impairment, 72.1% patients with renal insufficiency at baseline showed normalization of the serum creatinine during the follow-up. Twelve (27.9%) patients’ serum creatinine level decreased but was remained above the normal range. The eGFR before treatment was 46.0±18.0 ml/min/1.73 m2, and it increased to 66.7±18.8 ml/min/1.73 m2 after therapy (supplementary figure 1).
Nine (10.1%) patients who had aneurysmal dilatation at baseline received initial dose of GCs (0.5mg/kg) combined with immunosuppressant agent. We monitored changes of the dilated vessels by CT scan every 3~6 months in the first year after diagnosis. After treatment, no significant change in the dilatation scope and dilated diameter of PAO/PA. No patient experienced aneurysmal rupture.
The IgG4-RD RI and ESR, hsCRP, serum IgG4, and IgE levels reduced significantly after treatment. The serum IgG4 level returned to the normal range in 57.3% of patients with PAO/PA, and the serum IgE level returned to the normal range in 33.7% of patients after 6 months of treatment.
Five (5.6%) patients relapsed during the follow-up with a median recurrence time of 21 (15.5-33) months; all of them had two or multiple organs involved at baseline and relapsed in other organs beyond the blood vessels. No significant difference in the relapse rate was found between male and female patients.
Comparison between IgG4-related PAO/PA patients with shrinkage of soft tissues around vessels >70% and <30%
In order to clarify the differences of IgG4-related PAO/PA patients who had significantly different treatment efficacy, we compared the clinical features between the more than 70% responder group (Group A) and less than 30% responder group (Group B) (supplementary table 2). Patients in Group A were older and more predominantly male than those in Group B. Regarding organ involvement, the percentage of lymphadenopathy was higher in Group A than in Group B (P=0.01), while other organs involvement was comparable between Group A and Group B. The IgG3 level was higher in Group A than in Group B (P=0.006). There was no statistical significance in other clinical features between the two groups.