Patients
In total, 686 patients were treated in OPAL Balance (363 patients from OPAL Broaden, 323 from OPAL Beyond). At the data cut-off for this interim analysis (31 August 2017), 468 (68.2%) patients remained in the study, 190 (27.7%) patients had discontinued, and 28 (4.1%) patients had completed 36 months of treatment (ESM Fig. S3); the mean (range) duration of tofacitinib treatment for the all tofacitinib group was 614 (1–1032) days. The total duration of tofacitinib treatment was 1153.2 PY for the all tofacitinib group (Table 1). Six patients did not receive tofacitinib 5 mg BID at study entry due to protocol deviations; therefore, 680 patients were included in the constant tofacitinib 5 mg BID group, and the total duration of tofacitinib treatment (constant tofacitinib 5 mg BID) was 686.9 PY in this group. Overall, the most common reasons for patients discontinuing from the study included that they were no longer willing to participate (58/190 patients [30.5%]), had insufficient clinical response (37/190 patients [19.5%]), had an AE related to the study drug (33/190 patients [17.4%]), or had an AE not related to the study drug (21/190 [11.1%]). Additional reasons for discontinuation included patients that were lost to follow-up (9/190 [4.7%]), had protocol violations (8/190 [4.2%]), died (4/190 [2.1%]), withdrew due to pregnancy (4/190 [2.1%]), no longer met eligibility criteria (2/190 [1.1%]), had a medication error without associated AE (1/190 [0.5%]), or discontinued due to ‘other’ reasons (13/190 [6.8%]).
Table 1 Patient demographics and baseline disease characteristics Patient demographics and baseline disease characteristics (from the qualifying studies) are shown in Table 1. In the all tofacitinib group, the mean duration of PsA was 7.6 years. A slightly lower proportion of patients in the average tofacitinib 10 mg BID group (15.8%) received oral corticosteroids on day 1 of OPAL Balance, compared with the average tofacitinib 5 mg BID (21.6%) and constant tofacitinib 5 mg BID groups (19.1%). Most patients (675 [98.4%]) were receiving concomitant csDMARDs on day 1 of OPAL Balance (most commonly MTX); 86 (12.7%) later discontinued and did not restart csDMARD treatment. Mean doses of concomitant oral corticosteroids and MTX were 6.4 mg/day and 18.5 mg/week, respectively, for the all tofacitinib group; doses were similar across all treatment groups. Of the 686 patients in OPAL Balance, 21 (3.1%) enrolled > 14 days after the end of study visit of the qualifying study; therefore, baseline values for safety endpoints for these patients were taken from the LTE screening visit.
Safety
Treatment-Emergent AEs and SAEs
In the all tofacitinib group, 2189 all-causality AEs were reported in 546 (79.6%) patients up to month 36; 95 (13.8%) patients reported SAEs, 73 (10.6%) experienced severe AEs, 59 (8.6%) discontinued due to AEs, and 212 (30.9%) reduced their dose or temporarily discontinued tofacitinib due to AEs. The IR (95% CI) for SAEs occurring within the risk period was 7.8 (6.2–9.6) per 100 PY for the all tofacitinib group (Table 2); IRs were generally similar across the other treatment groups, with overlapping 95% CIs. The IR (95% CI) for discontinuations due to AEs during the risk period was 3.8 (2.7–5.1) per 100 PY for the all tofacitinib group; IRs (95% CI) per 100 PY were numerically lower in the average tofacitinib 10 mg BID group (2.0 [1.0–3.7]) than in the average tofacitinib 5 mg BID group (5.1 [3.5–7.1]), with 95% CIs marginally overlapping (Table 2). AEs that occurred in ≥ 5% of all tofacitinib patients included upper respiratory tract infection, nasopharyngitis, urinary tract infection, bronchitis, and hypertension (ESM Table S1).
Table 2 Incidence rates for all-causality serious adverse events, discontinuations due to adverse events, deaths, and select adverse events of special interest occurring within the risk period up to month 36 Deaths
There were five deaths reported up to month 36 in the all tofacitinib group (Table 2); four of the five deaths occurred after the 28-day risk period (one death due to chronic obstructive pulmonary disease [COPD] occurred within the risk period). The IR (95% CI) for deaths occurring within the risk period in the all tofacitinib group was 0.1 (0.0–0.5) per 100 PY (Table 2). The causes of death were acute cardiac failure secondary to hypertensive heart disease, cardiovascular insufficiency leading to sudden cardiac death, COPD, pancreatic adenocarcinoma, and PE (all n = 1; ESM Table S2). The patients who died from acute cardiac failure and cardiovascular insufficiency both had a history of hypercholesterolemia and hypertension; the patient with cardiovascular insufficiency also had diabetes mellitus. The patient who died from COPD discontinued tofacitinib upon exacerbation of COPD. Of the patients who died outside the 28-day risk period, only one patient discontinued tofacitinib because of the condition that caused their death (pancreatic adenocarcinoma). The patient who died from acute cardiac failure (following post-elective surgery for myocardial infarction) had discontinued tofacitinib due to an infection, while the patient with a PE was reported to have discontinued tofacitinib due to non-serious AEs of viral upper respiratory tract infection and lower respiratory tract infection. The reason for discontinuation of tofacitinib for the patient who died from cardiovascular insufficiency is unknown.
AEs of Special Interest
The IRs for select AEs of special interest occurring within the risk period up to month 36 are reported in Table 2.
The IR (95% CI) for all (non-serious and serious) herpes zoster was 1.7 (1.0–2.6) per 100 PY for the all tofacitinib group, which was generally similar across the other treatment groups (overlapping 95% CI). Of the 19 patients in the all tofacitinib group who reported herpes zoster within the risk period, one case of facial herpes zoster was an SAE. This event occurred on day 83 in a 67-year-old white male patient who had previously completed 11 months of treatment with tofacitinib 5 mg BID in OPAL Broaden and was receiving the same dose in OPAL Balance; tofacitinib treatment was permanently discontinued, and the event subsequently resolved. One severe event of herpes zoster occurred in a 61-year-old white female patient who had previously completed 5 months of treatment with tofacitinib 5 mg BID in OPAL Beyond and was receiving the same dose in OPAL Balance at the onset of the event on day 43; tofacitinib was temporarily discontinued, and the event resolved. Four patients with herpes zoster, including three patients with multi-dermatomal herpes zoster and one with disseminated herpes zoster, were adjudicated as having opportunistic infections (IR 0.3, 95% CI 0.1–0.9); these were the only opportunistic infections reported in the study. Five patients with herpes zoster were receiving concomitant glucocorticoids; none of these patients had adjudicated opportunistic infections. In the all tofacitinib group, 11 patients reported serious infections within the risk period, with an IR (95% CI) of 0.9 (0.5–1.7) per 100 PY; this was generally similar across the other treatment groups (overlapping 95% CI). Four patients (one of whom was living in Russia, a country with a high burden of TB [13]), reported AEs of latent TB where a previously negative QuantiFERON response became positive; no cases of active TB were reported.
In the all tofacitinib group, the IR (95% CI) for adjudicated malignancies (excluding NMSC) was 0.8 (0.4–1.5) per 100 PY, and the IR (95% CI) for NMSC was 1.0 (0.5–1.7) per 100 PY. These were generally similar across the other treatment groups (95% CI overlapping), with the exception that the IR (95% CI) per 100 PY for malignancies (excluding NMSC) for the average tofacitinib 10 mg BID group (0.2 [0.0–1.1]) was numerically lower than that for the average tofacitinib 5 mg BID group (1.2 [0.5–2.3]), with 95% CI marginally overlapping. These malignancies (20 in total, including NMSC, in the all tofacitinib group within the risk period) included one case of pancreatic adenocarcinoma (diagnosed on day 85 of tofacitinib treatment in OPAL Balance, after 12 months of adalimumab treatment in the OPAL Broaden qualifying study; the patient received concomitant MTX during OPAL Balance) and one case of non-Hodgkin’s B-cell lymphoma (day 585 of treatment in OPAL Balance, after 11 months of tofacitinib 5 mg BID treatment in OPAL Broaden; the patient also received MTX in OPAL Broaden but switched to sulfasalazine due to lack of efficacy, and the patient later discontinued sulfasalazine in OPAL Broaden due to improvement).
The IR (95% CI) of adjudicated MACE was 0.3 (0.1–0.8) per 100 PY in the all tofacitinib group, which was generally similar across the other treatment groups (overlapping 95% CI). In the all tofacitinib group, three non-fatal MACE occurred within the risk period; these were myocardial infarction, ischemic stroke, and stress cardiomyopathy. Two fatal cases of MACE occurred outside the risk period; these were acute cardiac failure and cardiovascular insufficiency.
In the all tofacitinib group, the IR (95% CI) of PE was 0.1 (0.0–0.5) per 100 PY, with one patient experiencing a non-fatal PE within the risk period. This patient, a 66-year-old white male, was also included in the average tofacitinib 5 mg BID and constant tofacitinib 5 mg BID groups. The patient had previously received tofacitinib 10 mg BID in OPAL Broaden. He experienced a PE on day 439, was hospitalized, and temporarily discontinued tofacitinib 5 mg BID; once he had recovered (day 448), the patient was discharged from the hospital and resumed tofacitinib treatment. It was noted that two of the patient’s brothers had died from PE, but investigations for coagulopathy disorders had not been carried out in either the patient or his brothers. One fatal PE occurred outside the risk period in a 45-year-old female patient in the average tofacitinib 5 mg BID and constant tofacitinib 5 mg BID groups. The patient had previously received tofacitinib 5 mg BID in OPAL Beyond. The patient had developed non-serious AEs of viral upper respiratory tract infection and lower respiratory tract infection, which reportedly led to the temporary discontinuation of tofacitinib 5 mg BID on day 170; 29 days after discontinuing tofacitinib, the patient experienced the PE (considered to be the result of deep vein embolism) and died. The IR (95% CI) for ATE events was 0.4 (0.1–1.0) for the all tofacitinib group; of the total of five patients with ATE events, two were in the average tofacitinib 5 mg BID group and three in the average tofacitinib 10 mg BID group.
Finally, there were no reports of DVT, gastrointestinal perforations, interstitial lung disease, or inflammatory bowel disease.
Laboratory Parameters
In the all tofacitinib, average tofacitinib 5 mg BID, average tofacitinib 10 mg BID, and constant tofacitinib 5 mg BID groups, ALT was elevated ≥ 3-fold the ULN in 27 (4.0%), 19 (4.7%), 8 (2.9%), and 14 (2.4%) patients, respectively, while AST was elevated ≥ 3-fold the ULN in 15 (2.2%), 10 (2.5%), 5 (1.8%), and 9 (1.5%) patients, respectively (ESM Table S3).
Up to month 36, in the all tofacitinib group, seven (1.0%) patients met any protocol criteria for discontinuing the study due to changes in laboratory parameters: one patient due to two sequential hemoglobin values of < 8.0 g/dL or decreases of > 30% from baseline value; one patient due to two sequential platelet counts < 75 × 103/mm3; one patient due to two sequential increases in serum creatinine > 50% and an increase > 0.5 mg/dL over the average of screening and baseline; one patient due to two sequential ALT or AST elevations ≥ 5-fold the ULN regardless of total bilirubin or accompanying signs or symptoms; two patients due to a confirmed positive urine pregnancy test; and one patient due to multiple criteria, including two sequential ALT or AST elevations ≥ 5-fold the ULN regardless of total bilirubin or accompanying signs or symptoms, two sequential ALT or AST elevations ≥ 3-fold the ULN with at least one total bilirubin value > 2-fold the ULN, and two sequential ALT or AST elevations ≥ 3-fold the ULN, accompanied by signs or symptoms consistent with hepatic injury. Additionally, 17 (2.5%) patients met the monitoring criterion of a creatine kinase elevation > 5-fold the ULN; however, no patients met the discontinuation criterion of two sequential creatine kinase elevations > 10-fold the ULN. Furthermore, no patients met the criteria for Hy’s law.
ALT and AST showed a slight increase from baseline through month 27 in all treatment groups, with values decreasing slightly at month 30 (Fig. 1a, b). Changes from baseline in hemoglobin remained generally stable through month 24, then increased up to month 30, in patients in the all tofacitinib group. A similar trend was observed in patients in the average tofacitinib 5 mg BID and constant tofacitinib 5 mg BID groups, whereas in the average tofacitinib 10 mg BID group, hemoglobin declined slightly up to month 21 and then increased and returned to baseline by month 30 (Fig. 1c). In all treatment groups, ALC declined from baseline and stabilized by month 24 (Fig. 1d), while ANC appeared relatively stable up to month 30 after an initial decline at month 1 (Fig. 1e). Up to month 36, no patient in the all tofacitinib group met the discontinuation criterion of confirmed (i.e., two or more consecutive measurements) ALC < 0.5 × 103/mm3, and ANC < 0.5 × 103/mm3. In all treatment groups, changes from baseline in creatinine remained relatively stable until month 24 (Fig. 1f). Changes from baseline in creatine kinase showed an increase until month 9 in the all tofacitinib group, after which the values remained generally stable until month 30 (Fig. 1g). The trend was similar in the average tofacitinib 5 mg BID and constant tofacitinib 5 mg BID groups, whereas values continued to increase slightly to month 21 in the average tofacitinib 10 mg BID group, after which levels decreased to be similar to those in the other treatment groups. Levels of CD16+56 cells appeared to fluctuate throughout the study (Fig. 1h). HDL-cholesterol, LDL-cholesterol, total cholesterol, and triglyceride levels increased at month 3, then appeared to be generally stable up to month 30 (Fig. 1i–l). Absolute mean values for these laboratory parameters are reported in ESM Fig. S2.
Efficacy
Rheumatologic and Dermatologic Outcomes
Across all treatment groups, the proportions of patients who had an ACR20, ACR50, ACR70, and PsARC response were maintained up to month 30 (Fig. 2a–d). These proportions were generally higher in the average tofacitinib 5 mg BID and constant tofacitinib 5 mg BID groups versus the average tofacitinib 10 mg BID group up to month 21; however, it must be noted that patient numbers were smaller in the latter group. Improvements in skin outcomes (i.e., PASI75 response rates and changes from baseline in PGA-PsO; Fig. 2e, f) were also maintained over time, as were improvements from baseline in LEI and DSS (Fig. 2g, h).
Composite Outcomes
The proportions of patients who achieved MDA were maintained up to month 30; these were also generally higher in the average tofacitinib 5 mg BID and constant tofacitinib 5 mg BID groups versus the average tofacitinib 10 mg BID group (Fig. 3a). Improvements from baseline in DAPSA were also generally maintained up to month 30 (Fig. 3b), while improvements in CPDAI and PASDAS continued over time (Fig. 3c, d).
Patient-Reported Outcomes
The proportions of patients who achieved HAQ-DI response (decrease from baseline in HAQ-DI ≥ 0.35) were generally constant up to month 30 (Fig. 4a), and improvements from baseline were maintained over time in HAQ-DI, Pain, FACIT-F total score, and DLQI (Fig. 4b–e). Improvements from baseline in SF-36v2 PCS, MCS (Fig. 4f, g), and eight norm-based domain scores (ESM Fig. S4), as well as all EQ-5D-3L dimensions and EQ-VAS (ESM Fig. S5), were also generally maintained over time.