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Ankylosing Spondylitis (AS) is a chronic, immune-mediated systemic inflammatory disease of the axial skeleton.
Approximately one-third of tofacitinib-treated
AS patients experienced clinically meaningful reductions in spinal MRI
inflammation at week 12. Patients achieving MIC for MRI inflammation had
greater clinical response.
Ankylosing Spondylitis (AS) is a chronic, immune-mediated
systemic inflammatory disease of the axial skeleton. MRI is the most widely
used diagnostic tool to assess the inflammation in the SI joint and spine in
patients with AS. MRI provides objective measure of inflammation and disease
activity. Although MRI evaluations have been shown to be highly biased between
treatments in studies of TNF inhibitors (TNFi) vs placebo, the association
between changes in MRI and clinical outcomes is less well-defined. Minimally
important change (MIC) can be a valuable concept to understand the number of
patients showing meaningful change and can be applied to both clinical and
imaging parameters so that associations in treatment responses can be evaluated
more readily by clinicians.
A previous RCT study of adalimumab established the MICs for
SPARCC SI joint and spine scores in patients with AS, with a global evaluation
of change based on expert radiologist opinion as for the external anchor.
Receiver-operating characteristic curves were used to define the MIC as ⩾2.5-point
change for SI joint scores, and ⩾five-point change for spine
scores.
Tofacitinib is an oral Janus kinase (JAK) inhibitor. It
inhibits the signalling via JAK3 and JAK1 with functional selectivity over
JAK2. As such, tofacitinib affects signalling via IL-17, IL-21 and IL-23,
thereby reduce the inflammation. A previous study demonstrates the efficacy and
safety of tofacitinib 5 and 10 mg in biologic-naïve patients with active AS.
This study showed that tofacitinib 5 and 10 mg are twice daily (BID) provided
greater efficacy vs placebo in reducing signs and symptoms of active AS over 12
weeks. MRI estimates showed significantly greater improvements from baseline in
SPARCC SI joint and spine scores at week 12 with tofacitinib compared with
placebo.
Rationale behind research:
Minimally important changes (MICs)
for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ⩾2.5 for SI joint and ⩾5 for spine. This post hoc analysis
assessed achievement of MIC in SPARCC scores in biologic-naïve patients with AS
treated with tofacitinib or placebo, and correlation with clinical responses.
Objective:
Study outcomes:
Time period: Baseline, week 12, week 16
Of the 207 patients who participated in the phase 2 study, 164 patients had MRI data at baseline and follow-up (week 12 or study withdrawal) and were included in this analysis. Follow-up MRI data were not available for 43 patients (16 patients had no baseline MRI; data for five patients were not available due to technical issues; two patients withdrew prior to MRI completion; two patients had a visit deviation for MRI; no reason for missing MRI was provided for 18 patients).
Patients with MRI data at baseline and follow-up, after 12 weeks of treatment, greater proportions of patients achieved reduction in MRI inflammation according to the MIC in SPARCC SI joint scores with tofacitinib 2 mg BID (28.6%), 5 mg BID (38.6%) and 10 mg BID (29.5%) compared with placebo (11.8%) (Fig.1A). Similarly, greater proportions of patients achieved reduction in MRI inflammation according to the MIC in SPARCC spine scores with tofacitinib 2 mg BID (29.3%), 5 mg BID (36.4%) and 10 mg BID (40.9%) compared with placebo (11.8%) (Fig.1B). No placebo-treated patients achieved the MIC for both SPARCC SI joint and spine scores, compared with 7.3% of patients treated with tofacitinib 2 mg BID, 18.2% with 5 mg BID and 6.8% with 10 mg BID (Fig.1C).
Greater proportion of patients who achieved the MIC in SPARCC SI joint
or spine scores also achieved ASAS20 and ASAS40 responses compared with those
patients who did not achieve the MIC in SPARCC SI jointor spine scores. A
greater proportion of patients treated with tofacitinib who achieved the MIC in
SPARCC SI joint or spine scores also achieved ASDAS MI and ASDAS CII compared
with those patients who did not achieve MIC. However, the results were less
clear for ASDAS ID and ASDAS moderate disease activity; clinical response was
greater in patients achieving MIC in SI joint and spine scores in some, but not
all, tofacitinib dose groups.
MRI and the SPARCC scoring system provide an objective
diagnosis of inflammation and disease activity in AS patients. A previous
12-week phase 2 study showed significantly greater improvements from baseline
in SPARCC SI joint and spine scores with tofacitinib 5 and 10 mg BID compared
with placebo. The present study showed that a higher proportion of
tofacitinib-treated patients achieved the MIC in both SPARCC SI joint and spine
scores compared with placebo. Clinically about 30% of patients showed a
reduction in spinal and SI joint inflammation with tofacitinib compared with
12% of placebo-treated patients.
In conclusion, The current
analysis revealed that ∼30% of AS patients treated
with tofacitinib 2, 5 or 10 mg BID for 12 weeks showed significant reductions
in axial MRI inflammation, and achieved MIC in SPARCC SI joint and spine scores
compared with placebo. There was a trend for greater clinical responses among
tofacitinib-treated patients who achieved MIC for MRI inflammation compared
with those not completing MIC across all doses, although findings were limited
by the small patient numbers in each group and differences between groups were
small for some endpoints. Therefore, further evaluations are required in larger
study populations and over a longer time-course to confirm if the MIC for
SPARCC assessments is related to clinical outcomes and thus can be viewed as a
true minimum clinically relevant difference in patients with AS in general, and
those treated with tofacitinib especially.
At week 12, approximately one-third tofacitinib-treated AS patients
experienced clinically meaningful spinal MRI inflammation reductions.
Tofacitinib-treated AS patients gained the minimally significant change in MRI
inflammation as compared to placebo. The excellent clinical response was
observed in AS patients obtaining the minimally considerable change for MRI
inflammation.
Rheumatology (Oxford). 2018 Aug; 57(8): 1390–1399.
Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients
Walter P Maksymowych et al.
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