Characteristics of the participants and study completion
During the study period, 170 patients were enrolled in the study, including 100 patients treated with tofacitinib and 70 treated with bDMARDs (Etanercept (39.7%), rituximab (16.2%), tocilizumab (16.2%), infliximab (13.2%), golimumab (8.8%), abatacept (2.9%), adalimumab (1.1%), and certolizumab (1.1%)). Eighty-six patients were from Colombia, and 83 patients were from Peru. At the 6-month follow-up, 92.9% (158) of enrolled patients completed the study, including 90 in the tofacitinib group and 68 in the bDMARDs group. Nine patients withdrew due to a loss to follow-up (tofacitinib (n = 8) and bDMARDs (n = 1)) for administrative reasons, however it was not possible to stablish if patients continued with the treatment; 2 patients treated with tofacitinib discontinued for other reasons. Only 1 patient from the bDMARDs group discontinued the study due to AEs. Although the mean time to supply at the start of the treatment was similar in both groups, more dispersion was observed in patients who received tofacitinib.
The mean age was 53.53 years (SD 13.77); 88% were women, and 97% were living in urban areas. The mean disease duration was 6.31 (SD 7.02) years. Methotrexate (58.82%), leflunomide (19.41%), or any chloroquine (11.76%) were the most frequent csDMARDs previously used. Corticosteroids were used previously in 82.94% of patients.
When comparing baseline data, the main differences were found in insurance characteristics and previous treatments. Patients had mainly private health insurance (n = 91), followed by public health insurance (n = 53). More patients with tofacitinib had coverage through private health insurance (67%), while the majority of the bDMARDs group had coverage through public health insurance (59%). The group that received tofacitinib reported more access barriers than patients with bDMARDs (29% vs 14%). Another observed difference in both studied groups was in the proportions of patients with concomitant treatment with leflunomide, previous use of methotrexate, and previous use of prednisolone. Although the mean time to supply to start the treatment was similar in both groups, more dispersion was reported in patients who received tofacitinib (Table 1).
Table 1
Demographic and clinical characteristics of patients by groups
|
bDMARDs group
|
Tofacitinib group
|
p-value
|
Number of subjects
|
70
|
100
|
|
Age mean (SD)
|
51 (13)
|
55 (14)
|
0.072
|
Female - No. of patients
|
65 (93%)
|
85 (85%)
|
0.11
|
Country - No. of patients
|
|
|
|
Peru
|
45 (64%)
|
39 (39%)
|
0.002
|
Colombia
|
25 (36%)
|
61 (61%)
|
|
Area - No. of patients
|
|
|
|
Rural
|
1 (1.4%)
|
5(5%)
|
0.41
|
Urban
|
69 (99%)
|
95 (95%)
|
|
Access information
|
|
|
|
Health insurance - No. of patients
|
|
|
|
Complementary
|
1 (1.4%)
|
2 (2%)
|
< 0.001
|
Patient
|
1 (1.4%)
|
10 (10%)
|
|
Private
|
24 (34%)
|
67 (67%)
|
|
Public
|
41 (59%)
|
12 (12%)
|
|
No report
|
3 (4.3%)
|
9 (9%)
|
|
Access barriers - No. of patients
|
10 (14%)
|
29 (29%)
|
0.024
|
No report
|
3 (4.3%)
|
9 (9%)
|
|
Time to supply (days) mean (SD)
|
24 (31)
|
22 (45)
|
0.0017
|
Disease year mean (SD)
|
6 (6.8)
|
6.5 (7.2)
|
0.81
|
Time previous treatment mean (SD)
|
34 (37)
|
26 (31)
|
0.091
|
Concomitant therapy - No. of patients (%)
|
|
|
|
Leflunomide - No. of patients
|
20 (29%)
|
15 (15%)
|
0.05
|
Methotrexate - No. of patients
|
30 (56%)
|
52 (52%)
|
0.75
|
Aminoquinolines - No. of patients
|
7 (10%)
|
16 (16%)
|
0.37
|
Corticosteroids - No. of patients
|
60 (86%)
|
77 (77%)
|
0.22
|
Clinical characteristics
|
|
|
|
Lymphocytes/mm3 mean (SD)
|
2,200 (865)
|
2,600 (1,800)
|
0.71
|
Neutrophils/mm3 mean (SD)
|
4,400 (2,500)
|
4,600 (2,200)
|
0.58
|
Swollen joins mean (SD)
|
6.9 (4.2)
|
8.7 (7.2)
|
0.18
|
Tender joints mean (SD)
|
10 (4.4)
|
11 (7.3)
|
0.57
|
Medical condition
|
1.4% (1)
|
7 (7%)
|
0.18
|
DAS28-ESR mean (SD)
|
5.9 (4.5)
|
5.2 (1)
|
0.28
|
Previous treatment - No. of patients (%)
|
|
|
|
Deflazacort - No. of patients
|
9 (13%)
|
22 (22%)
|
0.19
|
Leflunomide - No. of patients
|
11 (16%)
|
13 (13%)
|
0.78
|
Methotrexate
|
18 (26%)
|
48 (48%)
|
0.0055
|
Prednisolone - No. of patients
|
40 (57%)
|
37 (37%)
|
0.015
|
Folic acid - No. of patients
|
0 (0%)
|
1 (1%)
|
1
|
Chloroquine - No. of patients
|
4 (5.7%)
|
8 (8%)
|
0.79
|
Hydroxychloroquine - No. of patients
|
2 (2.9%)
|
2 (3%)
|
1
|
Sulfasalazine
|
2 (2.9%)
|
0 (0%)
|
0.33
|
Methylprednisolone
|
1 (1.4%)
|
1 (1%)
|
1
|
bDMARDs: biological disease-modifying anti-rheumatic drugs; SD: standard deviation |
The patients had severe disease activity according to the DAS28-ESR reported at baseline, 5.9 (SD 4.5) for bDMARDs and 5.2 (SD 1) for tofacitinib. Seven percent of patients prescribed tofacitinib had any comorbidity, whereas this value was 1.4% for the bDMARDs group. Lymphocyte counts, neutrophil counts, and the numbers of swollen joints and tender joints were similar between the study groups.
PRO results
The measurement of outcomes (RAPID3, adapted HAQ-DI, EQ5D) was conducted at baseline in 100 patients in the tofacitinib group and in 70 patients in the bDMARDs group. Ninety and sixty-eighty patients in the tofacitinib and bDMARDs groups, respectively, completed the study and had RAPID3, adapted HAQ-DI and EQ5D scores recorded at the last visit. The DAS28-ESR is another response measure of disease activity, and the availability of data depends on its use in clinical practice. DAS28-ESR data were available for all patients at baseline; however, at the second visit, DAS28-ESR data were reported in only 86 patients treated with tofacitinib and 61 treated with bDMARDs.
Regarding the primary outcome of this study, reduction of RAPID3 scores from baseline to month 6 was observed in both studied treatments with statistical difference between visits (p value > 0.001) (Fig. 1). At the end of follow-up, a similar proportion of patients treated with tofacitinib and bDMARDs achieved remission, while 18% more patients from the bDMARDs group than the tofacitinib group achieved low disease activity (Fig. 2). The reduction in RAPID3 score during the follow-up between the bDMARDs and tofacitinib groups was not statistically significant different (p value 0.154) (Table 2). The multivariable analysis composed by significant variables (Supplemental material Table 1S) has the same tendency remained.
Table 2
PRO mean changes from baseline to month 6 in bivariable analyses and multivariable by groups
|
bDMARDs
group
|
Tofacitinib group
|
Difference bivariate analysis
|
Difference by multivariable
analysis
|
p-value
|
RAPID3
|
-3.28 ± 0.30
|
-2.71 ± 0.26
|
-0.57 ± 0.40
|
-0.04 ± 0.38
|
0.93
|
Adapted HAQ-DI
|
-0.68 ± 0.08
|
-0.66 ± 0.07
|
-0.02 ± 0.10
|
-0.06 ± 0.10
|
0.57
|
EQ-5D-3L
|
0.43 ± 0.05
|
0.35 ± 0.04
|
0.09 ± 0.06
|
-0.01 ± 0.06
|
0.83
|
DAS28-ESR
|
-3.03 ± 0.42
|
-2.13 ± 0.35
|
-0.91 ± 0.55
|
-0.40 ± 0.23
|
0.09
|
Values are the mean ± SE. bDMARDs: biological disease-modifying anti-rheumatic drugs DAS28-ESR: Disease Activity Score 28-joint count assessment-erythrocyte sedimentation rate; HAQ-DI: Health Assessment Questionnaire – Disability Index; EQ-5D-3L: EuroQoL 5-Dimension 3-Level; PRO: patient-reported outcomes; RAPID3: Routine Assessment of Patient Index Data 3; SE: standard error. |
Pain and health status are other dimensions included in the RAPID3. Patients who received tofacitinib reported a mean reduction in pain of 3.94 ± 0.89, while bDMARDs patients reported a mean reduction of 3.28 ± 0.77. In the health status dimension, the tofacitinib group presented an improvement of 3.79 ± 0.47, whereas the bDMARDs group presented an improvement of 2.78 ± 0.47. Differences in both groups for these outcomes were not found (p value 0.577 and 0.104). The RAPID score obtained at month 6 compared to baseline for both groups (bDMARD and tofacitinib) were minor with difference statistically significant being steady results in the bivariate and multivariable analysis (Supplement material table 5S).
Likewise, the reduction in the disease activity as measured using the DAS28-ESR for both groups was statistically significant comparing the score at baseline and month 6 (p value < 0.001) (Fig. 1). During the 6 months, the difference of score in DAS28-ESR in both visits were similar between treatments both bivariable and multivariate analyses (p value 0.985 and 0.521, respectively) (Supplement material table 4S). The proportion of patients who achieved remission at month 6 was almost twice that observed with the RAPID3 and similar in both studied groups. For low disease activity, 11% more bDMARDs patients than tofacitinib patients reported low disease activity (Fig. 2). Comparing the score of DAS28-ESR between baseline and month 6 visit, a reduction of the activity was found in both treatment groups with consistency of the results with bivariate and multivariable analysis (Supplement material table 8S).
Regarding other secondary PROs, patients who received tofacitinib or bDMARDs reported an improvement in their functional status and quality of life, with no statistically significant difference between groups in the mean change during 6 months (p value: 0.57 and 0.83, respectively) (Table 2). Comparable results were obtained for adjusted and unadjusted model (Table 2).
The results of the bivariate analysis, multivariable analysis with all variables, and reduced model comparing the score for all PROs by treatment and by visits were consistent (Supplementary material Table 1S – 8S).
Safety
Twenty patients treated with tofacitinib and sixteen treated with bDMARDs reported any AEs. The most frequent events (over 2%) in patients treated with bDMARDs were diarrhea, pharyngitis, falls, headache, urinary tract infection, and nasopharyngitis, while those for tofacitinib group were headache, influenza, and pharyngotonsillitis. Herpes simplex and herpes zoster were reported in 2 patients treated with tofacitinib (Table 3). Cardiovascular, malignancies or thromboembolism AEs were not reported. Two serious AEs were reported by one patient treated with tofacitinib (appendicitis and peritonitis that were reported as not related to the treatment)
Table 3
Adverse events reported by groups
|
Tofacitinib group
|
bDMARDs group
|
|
n
|
(%)
|
n
|
(%)
|
Patients evaluable for adverse events
|
100
|
|
70
|
|
Number of subjects with serious adverse events
|
1
|
(1.00)
|
0
|
(0.00)
|
Number of subjects with non-serious adverse events
|
20
|
(20.00)
|
16
|
(22.86)
|
Number of non-serious adverse events
|
30
|
(30.00)
|
20
|
(28.57)
|
Number (%) of subjects with one (1) adverse event
|
12
|
(60.00)
|
12
|
(75.14)
|
Number (%) of subjects with two (2) adverse events:
|
6
|
(30.00)
|
4
|
(5.71)
|
Number of subjects with three (3) adverse events
|
2
|
(10.00)
|
0
|
(0.00)
|
Non serious adverse events according to System Organ Classes (SOC)
|
|
|
|
|
Blood and lymphatic system disorders
|
2
|
(2.00)
|
1
|
(1.43)
|
Bicytopenia
|
1
|
(1.00)
|
0
|
(0.00)
|
Neutropenia
|
0
|
(0.00)
|
1
|
(1.43)
|
Purpura
|
1
|
(1.00)
|
0
|
(0.00)
|
Endocrine disorders
|
1
|
(1.00)
|
0
|
(0.00)
|
Oligomenorrhea
|
1
|
(1.00)
|
0
|
(0.00)
|
Eye disorders
|
2
|
(2.00)
|
0
|
(0.00)
|
Photophobia
|
1
|
(1.00)
|
0
|
(0.00)
|
Vision blurred
|
1
|
(1.00)
|
0
|
(0.00)
|
Gastrointestinal disorders
|
1
|
(1.00)
|
4
|
(5.71)
|
Abdominal pain
|
0
|
(0.00)
|
1
|
(1.43)
|
Diarrhea
|
1
|
(1.00)
|
3
|
(4.29)
|
General disorders and administration site conditions
|
1
|
(1.00)
|
0
|
(0.00)
|
Malaise
|
1
|
(1.00)
|
0
|
(0.00)
|
Infections and infestations
|
2
|
(2.00)
|
0
|
(0.00)
|
Herpes simplex
|
1
|
(1.00)
|
0
|
(0.00)
|
Herpes zoster
|
1
|
(1.00)
|
0
|
(0.00)
|
Injury, poisoning and procedural complications
|
0
|
(0.00)
|
2
|
(2.86)
|
Fall
|
0
|
(0.00)
|
2
|
(2.86)
|
Musculoskeletal and connective tissue disorders
|
3
|
(3.00)
|
2
|
(2.86)
|
Arthralgia
|
1
|
(1.00)
|
0
|
(0.00)
|
Coccydynia
|
0
|
(0.00)
|
1
|
(1.43)
|
Lumbar vertebral fracture
|
1
|
(1.00)
|
0
|
(0.00)
|
Musculoskeletal pain
|
0
|
(0.00)
|
1
|
(1.43)
|
Myalgia
|
1
|
(1.00)
|
0
|
(0.00)
|
Nervous system disorders
|
4
|
(4.00)
|
2
|
(2.86)
|
Headache
|
3
|
(3.00)
|
2
|
(2.86)
|
Spinal pain
|
1
|
(1.00)
|
0
|
(0.00)
|
Renal and urinary disorders
|
3
|
(3.00)
|
2
|
(2.86)
|
Cystitis
|
1
|
(1.00)
|
0
|
(0.00)
|
Pollakiuria
|
1
|
(1.00)
|
0
|
(0.00)
|
Urinary tract infection
|
1
|
(1.00)
|
2
|
(2.86)
|
Reproductive system and breast disorders
|
1
|
(1.00)
|
0
|
(0.00)
|
Vulvovaginitis
|
1
|
(1.00)
|
0
|
(0.00)
|
Respiratory, thoracic and mediastinal disorders
|
8
|
(8.00)
|
7
|
(10,0)
|
Cough
|
1
|
(1.00)
|
0
|
(0.00)
|
Influenza
|
3
|
(3.00)
|
1
|
(1.43)
|
Nasopharyngitis
|
0
|
(0.00)
|
2
|
(2.86)
|
Pharyngitis
|
1
|
(1.00)
|
3
|
(4.29)
|
Pharyngitis bacterial
|
1
|
(1.00)
|
0
|
(0.00)
|
Pharyngotonsillitis
|
2
|
(2.00)
|
0
|
(0.00)
|
Rhinorrhea
|
0
|
(0.00)
|
1
|
(1.43)
|
Skin and subcutaneous tissue disorders
|
2
|
(2.00)
|
0
|
(0.00)
|
Alopecia
|
1
|
(1.00)
|
0
|
(0.00)
|
Ecchymosis
|
1
|
(1.00)
|
0
|
(0.00)
|