Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies

Jürgen Wollenhaupt; Joel Silverfield; Eun Bong Lee; Jeffrey R. Curtis; Susan P. Wood; Koshika Soma; Chudy I. Nduaka; Birgitta Benda; David Gruben; Hiroyuki Nakamura; Yoshihiro Komuro; Samuel H. Zwillich; Lisy Wang; Richard J. Riese

doi:10.3899/jrheum.130683

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Figure 1.
Mean (A) LDL cholesterol, (B) serum creatinine, (C) hemoglobin, (D) neutrophil counts, (E) lymphocyte counts, and (F) proportion of patients with mild neutropenia over time.
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Figure 2.
(A) American College of Rheumatology response rate: ACR20, (B) ACR50, and (C) ACR70 response rates over time.
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Figure 3.
(A) Mean 28-joint Disease Activity Score (DAS28)-4[erythrocyte sedimentation rate (ESR)], (B) DAS-defined remission (DAS28-4-ESR < 2.6), (C) low disease activity (LDA; DAS28-4-ESR ≤ 3.2), and (D) mean Health Assessment Questionnaire Disability Index (HAQ-DI) over time.

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Table 1.

Patient demographics and baseline characteristics.

Characteristic	Tofacitinib All (5 and 10 mg BID ± background DMARD), n = 4102^*	Tofacitinib 5 mg BID ± background DMARD, n = 1421	Tofacitinib 10 mg BID ± background DMARD, n = 2681	Tofacitinib 5 and 10 mg BID + background DMARD, n = 2742	Tofacitinib 5 and 10 mg BID monotherapy, n = 1360
Total patient-yrs of exposure	5963	3215	2748	3684	2279
Mean (maximum) duration of treatment/exposure, days	531 (1844)	826 (1844)	374 (1353)	491 (1822)	612 (1844)
Sex, n (%)
Male	696 (17.0)	235 (16.5)	461 (17.2)	479 (17.5)	217 (16.0)
Female	3406 (83.0)	1186 (83.5)	2220 (82.8)	2263 (82.5)	1143 (84.0)
Mean age, yrs (SD)	53.2 (11.5)	52.8 (11.9)	53.4 (11.3)	53.4 (11.5)	52.8 (11.6)
Race, n (%)
White	2330 (56.8)	648 (45.6)	1682 (62.7)	1652 (60.2)	678 (49.9)
Black	110 (2.7)	22 (1.5)	88 (3.3)	75 (2.7)	35 (2.6)
Asian	1087 (26.5)	624 (43.9)	463 (17.3)	679 (24.8)	408 (30.0)
Hispanic	14 (0.3)	14 (1.0)	0	12 (0.4)	2 (0.1)
Other^†	312 (7.6)	106 (7.5)	206 (7.7)	206 (7.5)	106 (7.8)
Unspecified^‡	249 (6.1)	7 (0.5)	242 (9.0)	118 (4.3)	131 (9.6)
Mean weight, kg (SD)	70.2 (19.2)	65.5 (17.1)	72.9 (19.9)	71.1 (19.5)	68.2 (18.5)
BMI, kg/m² (SD)	26.7 (6.4)	25.4 (5.8)	27.4 (6.6)	26.9 (6.5)	26.1 (6.1)

↵* Baseline values were available for 3783 patients (92.2%) from the index study; 319 patients (7.8%) had new baseline values derived from the last pre-drug visit on entry to the LTE studies, or were missing baseline values as of the data cutoff.
↵† Excluding white, black, Asian, and Hispanic patients.
↵‡ Race was not provided by patients. BID: twice daily; BMI: body mass index; DMARD: disease-modifying antirheumatic drug.

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Table 2.

Summary of safety data.

	Tofacitinib All (5 and 10 mg BID ± background DMARD), n = 4102	Tofacitinib 5 mg BID ± background DMARD, n = 1421	Tofacitinib 10 mg BID ± background DMARD, n = 2681	Tofacitinib 5 and 10 mg BID + background DMARD, n = 2742	Tofacitinib 5 and 10 mg BID monotherapy, n = 1360
Total patient-yrs of exposure^*	5963	3215	2748	3684	2279
Events, n (events per 100 patient-yrs)
Patients with AE	3152 (52.9)	1181 (36.7)	1971 (71.7)	2051 (55.7)	1101 (48.3)
Discontinuations due to AE	437 (7.3)	211 (6.6)	226 (8.2)	284 (7.7)	153 (6.7)
Patients with serious AE	630 (11.1)	295 (9.8)	335 (12.6)	400 (10.9)	230 (10.1)
Patients with malignancies exc. NMSC	60 (1.0)	33 (1.0)	27 (1.0)	36 (1.0)	24 (1.0)
Mortality	31 (0.5)	21 (0.6)	10 (0.4)	22 (0.6)	9 (0.4)
Most frequently reported treatment-emergent (all-causalities) AE by MedDRA preferred term, n (events per 100 patient-yrs)
Nasopharyngitis	521 (8.7)	303 (9.4)	218 (7.9)	296 (8.0)	225 (9.9)
Upper respiratory tract infection	432 (7.2)	141 (4.3)	291 (10.6)	290 (7.9)	142 (6.2)
Urinary tract infection	271 (4.5)	95 (3.0)	176 (6.4)	195 (5.3)	76 (3.3)
Bronchitis	270 (4.5)	127 (4.0)	143 (5.2)	181 (4.9)	89 (3.9)
Herpes zoster	245 (4.1)	127 (4.0)	118 (4.3)	133 (3.6)	112 (4.9)
Influenza	162 (2.7)	92 (2.9)	70 (2.5)	104 (2.8)	58 (2.5)
Hypertension	229 (3.8)	128 (4.0)	101 (3.7)	149 (4.0)	80 (3.5)
Headache	185 (3.1)	94 (2.9)	91 (3.3)	106 (2.9)	79 (3.5)
Diarrhea	179 (3.0)	85 (2.6)	94 (3.4)	112 (3.0)	67 (2.9)
Fall	133 (2.2)	73 (2.3)	60 (2.2)	83 (2.3)	50 (2.2)
Infection events, n (events per 100 patient-yrs; 95% CI)
Serious infection events^‡	184 (3.1; 2.66, 3.55)	84 (2.6; 2.11, 3.24)	100 (3.6; 2.96, 4.38)	111 (3.0; 2.50, 3.62)	73 (3.2; 2.53, 4.01)
Opportunistic infections (including tuberculosis)^‡	27 (0.4; 0.31, 0.65)	13 (0.4; 0.23, 0.69)	14 (0.5; 0.30, 0.85)	18 (0.5; 0.31, 0.77)	9 (0.4; 0.20, 0.75)
Tuberculosis^‡	10 (0.2; 0.09, 0.31)	5 (0.2; 0.06, 0.37)	5 (0.2; 0.08, 0.43)	NR	NR
Herpes zoster^‡	250 (4.3; 3.83, 4.90)	128 (4.2; 3.51, 4.97)	122 (4.5; 3.77, 5.38)	137 (3.8; 3.23, 4.52)	113 (5.2; 4.29, 6.20)
Adverse cardiovascular events of special interest, n (%)
Nonfatal myocardial infarction	3 (0.05)	3 (0.1)	0	NR	NR
Nonfatal cerebrovascular accident	10 (0.2)	3 (0.1)	7 (0.3)	NR	NR
Nonfatal congestive heart failure	5 (0.1)	2 (0.1)	3 (0.1)	NR	NR
Composite adverse cardiovascular events^§	16 (0.3)	8 (0.3)	8 (0.3)	NR	NR
Discontinuations due to AE (all causalities), n (%)
Blood and lymphatic system disorders	14 (0.3)	7 (0.5)	7 (0.3)	11 (0.4)	3 (0.2)
Hepatobiliary disorders	11 (0.3)	6 (0.4)	5 (0.2)	8 (0.3)	3 (0.2)
Infections and infestations	156 (3.8)	69 (4.9)	87 (3.2)	89 (3.2)	67 (4.9)
Investigations (e.g., blood, creatinine increased, ALT increased, AST increased)	66 (1.6)	31 (2.2)	35 (1.3)	50 (1.8)	16 (1.2)
Neoplasms (benign, malignant, and unspecified)	59 (1.4)	34 (2.4)	25 (0.9)	34 (1.2)	25 (1.8)
Temporary discontinuations / dose reduction of study medication due to AE (all-causalities), n (%)
Any AE	1032 (25.2)	446 (31.4)	586 (21.9)	639 (23.3)	393 (28.9)
Blood and lymphatic system disorders	29 (0.7)	9 (0.6)	20 (0.7)	20 (0.7)	9 (0.7)
Hepatobiliary disorders	16 (0.4)	6 (0.4)	10 (0.4)	9 (0.3)	7 (0.5)
Infections and infestations	590 (14.4)	264 (18.6)	326 (12.2)	358 (13.1)	232 (17.1)
Neoplasms (benign, malignant and unspecified)	12 (0.3)	3 (0.2)	9 (0.3)	8 (0.3)	4 (0.3)
Laboratory variable observations
Decreased hemoglobin, n (%)^†	n = 4095	n = 1419	n = 2676	n = 2741	n = 1354
Decrease ≥ 1 g/dl to ≤ 2 g/dl	521 (12.7)	187 (13.2)	334 (12.5)	339 (12.4)	182 (13.4)
Decrease > 2 g/dl to < 3 g/dl or hemoglobin > 7 g/dl, but < 8 g/dl	109 (2.7)	49 (3.5)	60 (2.2)	64 (2.3)	45 (3.3)
Decrease of ≥ 3 g/dl or hemoglobin ≤ 7 g/dl	41 (1.0)	24 (1.7)	17 (< 1.0)	21 (< 1.0)	20 (1.5)
Neutropenia, n (%)^†	n = 4095	n = 1419	n = 2676	n = 2741	n = 1354
1500–1999 cells/mm³	158 (3.9)	78 (5.5)	80 (3.0)	91 (3.3)	67 (4.9)
500–1499 cells/mm³	30 (< 1.0)	15 (1.1)	15 (< 1.0)	20 (< 1.0)	10 (< 1.0)
< 500 cells/mm³	0	0	0	0	0
Lymphopenia, n (%)^†	n = 4095	n = 1419	n = 2676	n = 2741	n = 1354
1500–1999 cells/mm³	966 (23.6)	280 (19.7)	686 (25.6)	631 (23.0)	335 (24.7)
500–1499 cells/mm³	2197 (53.7)	950 (66.9)	1247 (46.6)	1495 (54.5)	702 (51.8)
< 500 cells/mm³	17 (< 1.0)	9 (< 1.0)	8 (< 1.0)	12 (< 1.0)	5 (< 1.0)
Aminotransferases, n (%)	n = 4054	n = 1413	n = 2641	n = 2721	n = 1333
AST ≥ 1 × ULN with normal baseline	1205 (29.7)	471 (33.3)	734 (27.8)	832 (30.6)	373 (28.0)
AST ≥ 2 × ULN with normal baseline	152 (3.8)	69 (4.9)	83 (3.1)	106 (3.9)	46 (3.5)
AST ≥ 3 × ULN with normal baseline	50 (1.2)	25 (1.8)	25 (1.0)	37 (1.4)	13 (1.0)
AST ≥ 1 × ULN without regard to baseline abnormality	1516 (37.4)	545 (38.6)	971 (36.8)	1097 (40.3)	419 (31.4)
AST ≥ 2 × ULN without regard to baseline abnormality	202 (5.0)	90 (6.4)	112 (4.2)	147 (5.4)	55 (4.1)
AST ≥ 3 × ULN without regard to baseline abnormality	63 (1.6)	31 (2.2)	32 (1.2)	45 (1.7)	18 (1.4)
ALT ≥1 × ULN with normal baseline	1134 (28.0)	451 (31.9)	683 (25.9)	774 (28.5)	360 (27.0)
ALT ≥2 × ULN with normal baseline	244 (6.0)	109 (7.7)	135 (5.1)	173 (6.4)	71 (5.3)
ALT ≥3 × ULN with normal baseline	90 (2.2)	43 (3.0)	47 (1.8)	61 (2.2)	29 (2.2)
ALT ≥1 × ULN without regard to baseline abnormality	1513 (37.3)	553 (39.1)	960 (36.4)	1089 (40.0)	424 (31.8)
ALT ≥ 2 × ULN without regard to baseline abnormality	355 (8.8)	154 (10.9)	201 (7.6)	258 (9.5)	97 (7.3)
ALT ≥ 3 × ULN without regard to baseline abnormality	133 (3.3)	64 (4.5)	69 (2.6)	95 (3.5)	38 (2.9)
Serum creatinine, n (%)^†	n = 4102	n = 1421	n = 2681	n = 2742	n = 1360
> 50% from baseline	136 (3.3)	49 (3.4)	87 (3.2)	82 (3.0)	54 (4.0)

↵* Total patient-years of exposure are based on the safety population; some individual rates have been calculated using exposures based on specific databases for that variable/group.
↵† Two consecutive values.
↵‡ Some events may have occurred post end of treatment.
↵§ All cardiac deaths, i.e., coronary heart disease, cardiac death [sudden and other]; non-cardiac vascular death, i.e., pulmonary embolism cerebrovascular and other; non-fatal cardiovascular event, i.e., myocardial infarction (MI), procedural MI, cerebrovascular event. AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BID: twice daily: DMARD: disease-modifying antirheumatic drug; MedDRA: Medical Dictionary for Regulatory Activities; NMSC, non melanoma skin cancer; NR: not reported; ULN: upper limit of normal.

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Table 3.

Definite or probable cases of gastrointestinal perforations in the tofacitinib program.

Patient Age/sex	Tofacitinib Dose	Event	Location of Perforation/surgery	Concomitant Medications	Onset Study Day/outcome	Related Factors
52/female	3 mg twice daily + MTX	Gastric ulcer perforation	Upper GI/simple gastrectomy	Prednisolone, methotrexate, diclofenac, rabeprazole	Day 19/recovered	Peritonitis was also presented, had prior recurrent gastric ulcer, smoking for 17 years, and NSAID/low-dose steroid use.
58/female	5 mg twice daily + MTX	Diverticulitis and diverticular perforation	Lower GI/hemicolectomy	Prednisone, methotrexate, acetylsalicylic acid, diclofenac, omeprazole	Day 815/recovered	Diverticulitis was also presented. Perforation confirmed by pathology report.
46/male	5 mg twice daily + MTX	Appendicitis	Lower GI/retrocecal appendectomy	Prednisone, methotrexate	Day 664/death	Ascending colon necrosis was also presented. Fourteen days delayed treatment for appendicitis and subsequently developed septicemia and cardiac and respiratory arrest.
55/female	5 mg twice daily + MTX	Diverticulitis and intestinal perforation	Lower GI/resection of sigmoid	Methylpresnisolone, methotrexate, nimesulide, omeprazole	Day 551/recovered
59/female	5 mg twice daily + MTX	Abdominal abscess	Lower GI/laparatomy omentectomy, transversectomy	Methylprednisolone, aceclofenac (previous medication)	Day 447/recovered	Peritoneal infection was also presented.
59/male	10 mg twice daily + MTX	Diverticular perforation	Lower GI/sigmoid colon resection	Prednisone, methotrexate, aspirin	Day 362/recovered	History of severe diverticulosis. Abscess intestinal was also presented.
52/female	10 mg twise daily + MTX	Peritonitis and appendicitis	Lower GI/appendectomy	Methylprednisolone, methotrexate, omeprazole	Day 45/recovered	History of diverticulum. Abscess was also presented.
62/female	10 mg twice daily + MTX	Diverticular perforation	Lower GI/colostomy	Methylprednisolone, methotrexate	Day 128/recovering
62/female	10 mg twice daily + MTX	Peridiverticular abscess	Upper GI/sigmoid resection	Prednisone, meloxicam, methotrexate, cortisone injection, pantoprazole, omeprazole	Day 950/recovered	Possibly secondary to the previous event of sigmoid colitis with Clostridium difficile infection; aspiration of abscesses was carried out.
61/female	10 mg twice daily + MTX	Peritonitis	Lower GI/unspecified surgery	Prednisone, hydroxychloroquine, methotrexate, ketoprofen, deflazacort	Day 357/recovered	Classic symptoms of acute appendicitis. CT and surgery reports described in the narrative confirmed perforation.
66/female	10 mg twice daily + MTX	Diverticular perforation	Lower GI/laparoscopy	Methotrexate, celecoxib	Day 63/recovered	Confirmed by surgical report and pathology report.