Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: Text mining of the Japanese postmarketing adverse event-reporting database

Figures & data

Figure 1. Data disposition used to analyze reports of serious infection. ^aSymptoms within 28 days before the date of onset of serious infection. RA: rheumatoid arthritis; SI: serious infection.

Table 1. Patient characteristics.

	All patients with rheumatoid arthritis, N = 7653	All patients who developed serious infections, N = 1221	Patients with known onset dates of serious infections, N = 782
Sex
Female	5959 (77.9)	890 (72.9)	583 (74.6)
Male	1417 (18.5)	301 (24.7)	197 (25.2)
Unknown	277 (3.6)	30 (2.5)	2 (0.3)
Age, mean (SD), years	60.0 (12.7)^a	63.4 (11.7)^b	63.2 (11.8)^c
Age category, n (%)
<65 years	3507 (45.8)	434 (35.5)	315 (40.3)
≥65 years	2322 (30.3)	460 (37.7)	336 (43.0)
Unknown	1824 (23.8)	327 (26.8)	131 (16.8)
Weight, mean (SD), kg	53.5 (11.5)^d	53.1 (11.8)^e	53.1 (11.9)^f
BMI, mean (SD)	22.5 (17.2)^g	22.0 (3.9)^h	22.0 (3.9)^i
Number of days from initiating tocilizumab until initial onset of serious infection, mean (SD)	–	318.0 (423.0)^j	–
Other medications
Concomitant glucocorticoid use
Yes	–	399 (32.7)	300 (38.4)
No	–	822 (67.3)	482 (61.6)
Prednisolone-equivalent glucocorticoid dose (mg/day), mean (SD)	–	7.3 (5.1)^k	7.3 (5.1)^l
Concomitant use of csDMARD
Yes	–	771 (63.1)	547 (69.9)
No	–	450 (36.9)	235 (30.1)
Type of concomitant csDMARD
Methotrexate	–	574 (55.4)	–
Tacrolimus hydrate	–	153 (14.8)	–
Salazosulfapyridine	–	132 (12.7)	–
Bucillamine	–	86 (8.3)	–
Mizoribine	–	37 (3.6)	–
Leflunomide	–	16 (1.5)	–
Cyclosporine	–	8 (0.8)	–
Penicillamine	–	8 (0.8)	–
Iguratimod	–	7 (0.7)	–
Azathioprine	–	6 (0.6)	–
Gold sodium thiomalate	–	5 (0.5)	–
Actarit	–	2 (0.2)	–
Auranofin	–	2 (0.2)	–
Previous use of a biologic
Yes	–	53 (4.3)	42 (5.4)
No	–	1168 (95.7)	740 (94.6)
Type of previous biologic
Etanercept	–	20 (1.6)	21 (2.7)
Adalimumab	–	17 (1.4)	18 (2.3)
Infliximab	–	12 (1.0)	10 (1.3)
Abatacept	–	7 (0.6)	6 (0.8)
Golimumab	–	3 (0.2)	3 (0.4)

BMI: body mass index; SD: standard deviation. All data are n (%) unless otherwise stated. Data for additional medications are available only for patients who developed serious infections.

^a n = 5829.

^b n = 894.

^c n = 651.

^d n = 2246.

^e n = 482.

^f n = 353.

^g n = 1515.

^h n = 380.

ⁱ n = 286.

^j n = 750.

^k n = 378.

^l n = 291.

Table 2. Site of onset for most frequently reported^a serious infections in patients who developed serious infections (N = 1221).

Type of serious infection by SOC and PT^a	Incidence of event, n (%) (total number of events = 1591)
Respiratory tract infections	623 (39.2)
Pneumonia	253 (15.9)
Pneumocystis jirovecii pneumonia	59 (3.7)
Nontuberculosis mycobacterial infection	55 (3.5)
Pneumonia bacterial	44 (2.8)
Pneumonia pneumococcal	25 (1.6)
Infectious pleural effusion	24 (1.5)
Skin infection	329 (20.7)
Cellulitis	158 (9.9)
Herpes zoster	56 (3.5)
Subcutaneous abscess	17 (1.1)
Gastrointestinal infection	183 (11.5)
Peritonitis	48 (3.0)
Diverticulitis	43 (2.7)
Urinary tract infection	72 (4.5)
Pyelonephritis	26 (1.6)
Urinary tract infection	26 (1.6)
Sepsis	137 (8.6)
Sepsis	80 (5.0)
Septic shock	36 (2.3)
Other infection	247 (15.5)
Arthritis bacterial	51 (3.2)
Arthritis infective	17 (1.1)

^a Data for serious infections reported for ≥1% of patients.

Table 3. Signs and symptoms of infection^a that occurred in patients who developed serious infection and had known onset dates of serious infections (N = 782).

Rank	Respiratory tract infection (n = 623 events)	Skin infection (n = 329 events)	Gastrointestinal infection (n = 183 events)	Sepsis (n = 137 events)	Urinary tract infection (n = 72 events)	Other infection (n = 247 events)	All infection (n = 782 patients)
1	Cough	Swelling^b	Abdominal pain	Pyrexia	Vomiting^b	Pain^b	Pyrexia
2	Pyrexia	Pain^b	Pain^b	Pain^b	Pyrexia	Swelling^b	Pain^b
3	Productive cough	Erythema	Diarrhea	Cough^b	Pain^b	Pyrexia	Cough^b
4	Dyspnea	Rash	Pyrexia	Swelling^b	Back pain^b	Erythema^b	Swelling^b
5	Pain^b	Pyrexia	Vomiting	Malaise	Nausea^b	Arthralgia	Productive cough^b

^a MedDRA PT.

^b Previously unknown as a sign or symptom of infection.

Table 4. Laboratory results measured within 7 days of infections becoming serious.

Laboratory test	Result
	Onset date of SI known, N = 782^a	SI reports with signs or symptoms, N = 475^a	No symptoms and unknown signs or symptoms, N = 51^a
	CRP, mean (SD), mg/dL	3.4 (4.4), N = 619^b	NR, N = 433^b	NR, N = 25^b
Incidence <1.0 mg/dL, n (%)	269 (43.5)	181 (41.8)	16 (64.0)
Incidence ≥1.0 mg/dL, n (%)	350 (56.5)	252 (58.2)	9 (36.0)
Body temperature, mean (SD), °C	37.0 (0.8), N = 262^b	NR, N = 202^b	NR, N = 7^b
Incidence <37.0 °C, n (%)	134 (51.1)	107 (53.0)	6 (85.7)
Incidence ≥37.0 °C to <38.0 °C, n (%)	82 (31.3)	60 (30.0)	0
Incidence ≥38.0 °C, n (%)	46 (17.6)	35 (17.4)	1 (14.3)
WBC count, mean (SD), /µL	9716.4 (4484.9), N = 635^b	NR, N = 455^b	NR, N = 22^b
Incidence <10,000/µL, n (%)	363 (57.2)	262 (57.6)	15 (68.2)
Incidence ≥10,000/µL, n (%)	272 (42.8)	193 (42.4)	7 (31.8)
Patients with results of all three laboratory tests, n	186	140	6
Normal results of laboratory tests (CRP <1.0 mg/dL,  body temperature <37.0 °C, and WBC count <10,000/µL), n	68	52	4

NR: not reported; SD: standard deviation; SI: serious infection; WBC: white blood cell. ^aN number of patients. ^bN number of patients with measurements, excluding missing data. All data are number of measurements (%) in the category unless stated otherwise. Not included in the analysis were 272 missing measurements for CRP, 555 missing measurements for temperature, and 262 missing measurements for WBC.