Demographic characteristics of IgG4-RD with PAO/PA
Among 587 IgG4-RD patients, 89 patients (76 men and 13 women) were enrolled IgG4-related PAO/PA group and 498 patients were enrolled non-PAO/PA group. Of the IgG4-RD patients with PAO/PA, 24 (27.0%) had PAO/PA alone, while other. patients (n=65, 73.0%) had multiple organs 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. 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 allergic history. The median follow-up time was 30(15, 52) months.
Of 89 patients with PAO/PA, 35(39.3%) patients were diagnosed as definite IgG4-RD, 1(1.1%) was probable, 53(59.6%) patients were possible. Nine(10.1%) patients received perivascular mass biopsy, while the rest patients received biopsy from other involved organs, including submandibular gland, lacrimal gland, kidney, lymph node, lung, et al.
Symptoms at disease onset of IgG4-RD 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 with PAO/PA
Of IgG4-RD with PAO/PA, serum creatinine 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 were 44 (18-75) mm/h and 6.72 (2.14-24.65) mg/L, respectively. Serum IgG, IgG4 and T-IgE 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 with/without PAO/PA
Compared with non-PAO/PA patients, PAO/PA patients were older at disease onset, had higher male/female ratio, but had shorter disease duration and lower percentage of allergy 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 was comparable in patients with/without PAO/PA. However, patients with PAO/PA had higher percentage of single organ involvement than patients without PAO/PA, P<0.001.
PAO/PA patients had higher percentage of back pain, abdominal pain, and lower limb edema than those with PAO/PA (4.2%, 15.9%, and 1.6%, P<0.001, P=0.005, and P<0.001, respectively). On the contrary, PAO/PA patients had lower percentage of submandibular gland enlargement, lacrimal gland enlargement, parotid gland enlargement, and nasal congestion than those without (42.8%, 45.6%, 13.3%, and 21.3%;P<0.001, P<0.001, P=0.042, and P<0.001, respectively) (Table 2). Consistent with onset symptoms, PAO/PA patients had lower percentage of submandibular gland, lacrimal gland, and paranasal involvement (all P<0.001) (Table 2).
Compared with those with PAO/PA, PAO/PA patients had higher levels of ESR, hsCRP, and IgA(P=0.014, P<0.0001, P<0.0001, and P=0.02, respectively)(Table 3). However, IgG4-related PAO/PA had lower levels of serum IgG4 and IgE levels than those without [8310(3250, 17075) mg/L, 332 (119, 720.5) KU/L;P<0.0001 and P=0.025, respectively)(Table 3). In addition, serum IgG4 levels were higher in patients with PAO/PA and other organs affected [5270(2395, 11910) mg/L] than in patients with PAO/PA only [2418(1583, 4638) mg/L] (P=0.001).
CD19+CD24-CD38hiplasmablast/plasma cells
Overall, 93 patients were detected of 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. However, the percentage of CD19+CD24-CD38hi plasmablast/plasma was lower in patients with PAO/PA only [2.22%(Q1-Q3, 1.87%-5.90%)] than patients 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).
Vessels distribution of IgG4 related PAO/PA
Characteristic imaging findings IgG4-related PAO/PA are shown in Figure 2. Of the 89 IgG4-RD patients with PAO/PA, abdominal aorta was the most affected vessel (74, 83.1%), followed by iliac artery (63, 70.8%), thoracic aorta (12, 13.5%), and other vessels, including 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. Moreover, beside soft tissue around vessels, 27 patients had calcification in the aortic wall, 22.5% of patients had diffuse thickening of the abdominal aortic wall, and 10.1% of patients 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). Besides, female patients had 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). In addition, no statistical significance in vessel distribution was found between patients with PAO/PA alone and patients with PAO/PA and other organ involvement.
Further, 55 (61.8%) PAO/PA patients had hydronephrosis, including 47(61.8%) male patients and 8 (61.5%) female patients. Caused by ureteral obstruction, 43 (48.3%) patients suffered impairment of renal function. 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).
Treatment efficacy in PAO/PA patients
PAO/PA patients were treated with glucocorticoids(GCs) or glucocorticoids combined with immunosuppressant agents (GCs plus IM).
Except 18(20.2%) patients received GC monotherapy, other patients were treated with GCs plus cyclophosphamide(CYC) (n=52,58.4%), GCs plus mycophenolate mofetil(MMF) (n=18, 20.2%), GCs plus leflunomide (n=1,1.1% ). 41(46.1%) patients were treated combined with tamoxifen (TMX).
After 6 months of treatment, 34 (38.2%) patients achieved reduction of perivascular soft tissues >70%, 39 (43.8%) patients achieved reduction between 31%-70%, and 16 (18.0%) patients had reduction <30%. Compared with male PAO/PA patients, 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 extubating 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, serum creatinine normalized during the follow-up. 12(27.9%) serum creatinine decreased but was kept above the normal range.
IgG4-RD RI, ESR, hsCRP, serum IgG4, and IgE levels reduced significantly after treatment. Serum IgG4 returned to normal range in 57.3% PAO/PA patients, and serum IgE returned to normal range in 33.7% patients after 6 months of treatment.
Five (5.6%) patients relapsed during follow-up with median recurrence time 21(15.5-33) months, all of them had two or multiple organs involved at baseline and relapsed in other organ beyond blood vessels. No significant difference in relapse rate was found between male and female patients.