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Abstract
Objective To evaluate the efficacy and safety of golimumab to induce clinical remission in patients with very early, active peripheral spondyloarthritis (pSpA).
Methods Clinical REmission in peripheral SPondyloArthritis is a monocentric study of golimumab treatment in patients with pSpA. All patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria for pSpA, with a symptom duration ≤12 weeks. Patients were randomised 2:1 to receive golimumab 50 mg every 4 weeks or matching placebo for 24 weeks. The primary end point was the percentage of patients achieving clinical remission at week 24, defined as absence of arthritis, enthesitis and dactylitis. Secondary end points included joint and enthesis counts, patient-reported outcomes, erythrocyte sedimentation rate and C reactive protein. From week 12, non-responders were allowed to receive rescue medication with golimumab. Adverse events were recorded.
Results 60 patients were randomised with similar baseline characteristics. At week 24, a significantly higher percentage of patients receiving golimumab achieved clinical remission compared with placebo (75% (30/40) vs 20% (4/20); p<0.001). At week 12, similar results were observed (70% (28/40) vs 15% (3/20); p<0.001). All secondary end points were met at week 24. Rescue medication was necessary in 50% in the placebo group opposed to only 10% in the golimumab arm. Rates of adverse events were low and similar in both groups.
Conclusions Markedly high remission induction rates were noted with golimumab in very early pSpA. Of interest, in placebo-treated patients, very low spontaneous remission rates were observed.
Trial registration number NCT01426815; Results.
- Spondyloarthritis
- Anti-TNF
- Psoriatic Arthritis
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Introduction
The spondyloarthritis (SpA) concept is split depending on the predominant clinical manifestation into axial and peripheral disease, the latter including psoriatic arthritis (PsA) and non-psoriatic peripheral SpA (pSpA). The natural evolution of pSpA is poorly understood, especially in early forms. However, there are some reports suggesting a benign course with a high rate of spontaneous remission.1 ,2 At present, it is unclear if early pSpA demands intensive therapy similar to early rheumatoid arthritis (RA) and axial SpA (axSpA).
The therapeutic landscape has profoundly changed with the introduction of targeted (anti)cytokine treatments, particularly anti-tumour necrosis factor (TNF)-α.3 TNF inhibitors have been successfully tested in numerous phase III studies in ankylosing spondylitis (AS) and PsA, the two major diseases belonging to the SpA concept, leading to worldwide approval.4–11 TNF blockade also has a proven beneficial effect on the peripheral manifestations of AS.12 Several small studies suggest a good efficacy of anti-TNF therapy in non-AS and non-PsA pSpA.13–18 Recently, two randomised controlled trials (RCTs) in longstanding pSpA confirmed these findings.19 ,20
In RA, there is accumulating evidence for a so-called ‘window of opportunity’ referring to the existence of a transient time frame in which the disease is more susceptible to treatment.21 In axSpA, anti-TNF agents are effective across the full spectrum from non-radiographic axSpA22–25 to AS.
It was shown that response to treatment was markedly higher in early forms of axial disease with high rates of clinical remission.26 This suggests there could also be a ‘window of opportunity’ for drug-free remission in axSpA. This is currently explored in ongoing clinical trials in axSpA. To date, there are no data exploring this concept in pSpA. We tested this in a proof-of-concept placebo-controlled study, exploring the efficacy and safety of an induction therapy with the TNF-blocking agent golimumab in very early pSpA. The placebo-controlled design permitted to estimate the spontaneous remission rate in this population. Our data highlight a markedly high clinical remission rate in anti-TNF-treated patients as opposed to only low spontaneous remission in the placebo group.
Methods
Study design
Overall, 60 patients with pSpA were randomised in a single-centre, double-blind clinical trial to receive golimumab 50 mg or placebo subcutaneously every 4 weeks through week 24. Patients were randomised in a 2:1 ratio (2 golimumab:1 placebo). There was an option to start rescue medication with golimumab 50 mg subcutaneously starting at week 12 if all 3 of the following criteria were met: (1) no improvement of patient-reported outcomes (PROs) of disease activity compared with baseline (Bath AS Disease Activity Index (BASDAI), Patient Global Assessment (PGA) of disease activity (0–100 mm Visual Analogue Scale (VAS)), Patient Global Pain Assessment(0–100 mm VAS); (2) severe disability defined as Bath AS Functional Index (BASFI) >6 on a 10-scale numerical rating scale (NRS) and (3) no improvement of peripheral arthritis, enthesitis and/or dactylitis compared with baseline. The study drug was provided in prefilled syringes containing golimumab 50 mg or matching placebo (Janssen Pharmaceutica NV). The study was approved by the Medical Ethics Committee of the Ghent University Hospital and written informed consent was obtained from each patient before study-related procedures were performed. The study was conducted in compliance with International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki.
Patients
Adult patients, newly diagnosed with active pSpA and fulfilling the Assessment of SpondyloArthritis international Society (ASAS) criteria for pSpA, were included. This was defined as presence of arthritis, enthesitis or dactylitis at screening visit with at least one of the following SpA features: anterior uveitis, Crohn's disease, evidence of a preceding infection (acute diarrhoea or non-gonococcal urethritis or cervicitis 1 month before arthritis), psoriasis, HLA B27 positivity or sacroiliitis by imaging defined as bilateral grade 2–4 or unilateral grade 3–4 sacroiliitis on plain radiographs, according to the modified New York criteria or active sacroiliitis on MRI according to the ASAS consensus definition. All subjects had to have onset of pSpA symptoms (arthritis, enthesitis, dactylitis) ≤12 weeks prior to the screening visit. Active disease was defined as the persistent presence of arthritis, enthesitis and/or dactylitis and by PGA of disease activity VAS ≥40 mm and PGA of pain VAS ≥40 mm at both screening and baseline visits. In patients with concurrent axSpA symptoms, the pSpA symptoms had to be the predominant symptoms at study entry based on the investigator's clinical judgement. In all patients, an MRI of the sacroiliac joints (SI) was performed at screening. Sacroiliitis on imaging was defined as active sacroiliitis on MRI according to the ASAS consensus definition.
Women of childbearing potential or men capable of fathering children had to be using adequate birth control measures during the study and for 6 months after receiving the last administration of study agent. Female patients of childbearing potential had to test negative for pregnancy. Exclusion criteria included serious infections in the previous 4 weeks, history of malignancy in the past 10 years, significant history of other severe diseases or uncontrolled concomitant disease. All patients were screened for latent tuberculosis with a purified protein derivative test and chest radiography. If screening was positive, adequate chemoprophylaxis according to local guidelines was started. Patients with positive rheumatoid factor or anticyclic citrullinated peptide antibody at screening and subjects with diagnosis and current symptoms of fibromyalgia were excluded.
Concurrent and prior medication
Patients were allowed to be treated with non-steroidal anti-inflammatory drugs (NSAIDs) provided that the dose at baseline was stable for 2 weeks. During the trial, tapering of NSAIDs guided by clinical signs and symptoms was allowed and reported. No concomitant disease-modifying antirheumatic drug (DMARD) therapy or corticosteroid therapy was allowed with the exception of patients already treated for established psoriasis or inflammatory bowel disease and provided that the dose was stable 4 weeks before baseline that developed SpA signs and symptoms for the first time. Local corticosteroid treatments for skin psoriasis and local treatments for uveitis were allowed. Treatment with intra-articular corticosteroid injection(s) for pSpA symptoms in the preceding 12 weeks were not allowed.
Efficacy assessments
Primary efficacy end point
The primary end point for this study was the proportion of patients achieving a status of clinical remission at week 24, defined as complete absence of peripheral arthritis, enthesitis and dactylitis on clinical examination.
Secondary efficacy end points
Several secondary efficacy variables were analysed.
As PROs, we evaluated at baseline and every 4 weeks the PGA of disease activity (0–100 mm VAS), the BASDAI (0–10), the BASFI (0–10) and the 36-item Short-Form Health Survey with the Physical Component Summary and the Mental Component Summary scales.
Clinically, we evaluated at baseline and every 4 weeks the 76/78 tender and swollen joint count (TJC, SJC), dactylitis count (0–20) and enthesitis count included the Maastricht AS Enthesitis Score (0–13) with the addition of the plantar fascia insertion to the calcaneus, quadriceps tendon insertion into the superior pool of the patella and patellar ligament insertion into the inferior pool of the patella, which accounts for a total of 19 entheseal locations. Also the Bath AS Metrology Index and scores for psoriasis including the Psoriasis Area and Severity Index and body surface area were evaluated every 4 weeks.
The following response criteria were evaluated at weeks 12 and 24: clinical remission status at week 12, peripheral spondyloarthritis remission criteria (pSpARC) 40%, 50% and 70% response at week 12 and 24 defined as ≥40%, 50% or 70% improvement from baseline (≥20 or ≥30 mm absolute improvement), respectively in the VAS scores for PGA of disease activity and PGA of pain on a 100 mm VAS, and ≥40%, ≥50% and ≥70% improvement in at least one of the following scores: (1) 76 SJC and 78 TJC; (2) total enthesitis count or (3) dactylitis count.19 The ASAS 20 and 40 response, the BASDAI 50% response and the ankylosing spondylitis disease activity score (ASDAS) improvement criteria were evaluated at weeks 12 and 24. Also the Physician Global Assessment (PhGA) was recorded every 4 weeks.
At baseline, weeks 12 and 24 laboratory tests were performed including C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At baseline, the NSAID intake was calculated using the ASAS NSAID index based on the last 2 weeks of NSAID intake; during the study time frame of every 4 weeks, the NSAID index was calculated based on the last 4 weeks of NSAID intake.27
Safety assessments
The safety was assessed by recording adverse events (AEs) and serious AEs (SAE) that began or worsened after the first dose of study medication during study time. Routine laboratory investigations were performed on the screening visit and on weeks 12 and 24 for safety evaluations to explore AEs.
Statistical analysis
The intent-to-treat population analysed for efficacy and safety included all randomised patients who received at least one dose of blinded study medication. A sample size of 60 patients (20 placebo and 40 golimumab) was calculated based on previous anti-TNF trials, which included pSpA to provide 80% statistical power and α level of 0.05.12 ,28 For categorical improvement and response variables, patients with missing data at week 24 were considered to be non-responders using non-responder imputation. For all other variables, last observation carried forward was applied to impute missing values at week 24. At each time-point, differences between placebo and golimumab were tested using a Fisher's exact test for the categorical outcome variables and a Mann-Whitney U test for the continuous outcome variables. All statistical tests were two-sided and p values of <0.05 were considered to be statistically significant.
Results
Baseline characteristics
Sixty patients were enrolled in the study and subsequently randomised to treatment with golimumab (n=40) or placebo (n=20) from March 2012 to July 2015. All patients completed the 24-week double-blind placebo-controlled period (supplementary file). The demographic features and disease characteristics of the patients were comparable across both treatment arms and summarised in table 1. The mean symptom duration was 4.4 and 5.2 weeks in the placebo and golimumab arm, respectively. Presence of peripheral arthritis, enthesitis and dactylitis was observed in 59, 25 and 24 patients out of the 60, respectively. There was only one patient with dactylitis as the unique peripheral manifestation. In all other patients with dactylitis and/or enthesitis, there was also concomitant arthritis. There was no difference in concomitant NSAID use at baseline between the two treatment groups. None of the included patients was on DMARD therapy except for one patient who was on a stable dose of sulfasalazine for an established inflammatory bowel disease. No patients received glucocorticoids at screening. The most frequent extra-articular manifestation was skin and/or nail psoriasis in 25 out of the 60 patients with an overall median disease duration of 4.3 years. Only 7 out of 60 patients reported having experienced inflammatory back pain in their past medical history; nevertheless 35% of patients (21/60) exhibited bone marrow oedema of the SI joints on MRI and fulfilled the ASAS definition of a positive MRI. The median TJC, SJC and proportion of patients with dactylitis and enthesitis at baseline were comparable in both groups. Most patients were on NSAIDs at baseline with a comparable median NSAID index.
Demographic features and baseline disease characteristics of the study patients by treatment group
Clinical efficacy at weeks 12 and 24
The primary end point of the study was met. At week 24, 75% (30/40) of golimumab-treated patients reached a status of complete absence of arthritis, enthesitis and dactylitis compared with only 20% (4/20) in the placebo group (p<0.001) (figure 1). The status was already achieved as early as week 12 (70% (28/40) vs 15% (3/20); p<0.001). At week 12, a pSpARC 40%, 50% and 70% response was observed in respectively 57.5%, 55% and 50% of patients treated with golimumab versus 20%, 20% and 15% in the placebo group. In table 2, the individual components of the pSpARC response criteria, as well as ESR and CRP, are described at baseline, weeks 12 and 24. All assessments demonstrated a statistical significant improvement at weeks 12 and 24 with golimumab treatment compared with placebo. The evolution over time of the mean TJC, SJC, enthesitis (0–19) and dactylitis count, and PGA and PhGA is visualised in figure 2. A statistically significant improvement in TJC, SJC, PGA and PhGA was already achieved after 4 weeks of treatment and was sustained up to week 24. Of note, the intake of NSAIDs also decreased significantly in the golimumab-treated patients, compared with a stable NSAID index over time in the placebo group.
Disease activity and response criteria at baseline, week 12 and week 24
Primary outcome: percentage of patients in clinical remission after 12 and 24 weeks in the placebo and golimumab group, respectively. Non-response imputation was applied at week 24.
Changes in the clinical disease activity parameters during treatment with golimumab and placebo from week 0 till week 24. The panels represent the tender and swollen joint count, dactylitis and enthesitis count, non-steroidal anti-inflammatory drug (NSAID) index and Patient Global Assessment of disease activity on a 100 mm visual analogue scale. Data are presented as median with corresponding 95% CI. *Statistically significant result based on the Mann-Whitney U test.
supplementary table
supplementary flowchart
We additionally evaluated more conventional axSpA response criteria. At week 24, golimumab-treated patients reached ASAS 20 and 40 response and BASDAI 50% response in respectively 67.5%, 65% and 72.5% as opposed to only 30%, 15% and 20% in the placebo group (p<0.05 for all parameters). Comparable efficacy was observed using the ASDAS improvement criteria: at week 24, in golimumab-treated patients a clinically important or major improvement of ASDAS was observed in respectively 77.5% and 45% of patients versus in 20% and 20% in the placebo group (p<0.05). Similar results were observed at week 12 (supplementary file).
As expected, physical function and health-related quality of life also improved significantly in the active treatment group compared with placebo (p<0.05 for all parameters).
Dropouts and safety analysis
All patients completed the 24-week placebo-controlled phase. The safety analysis is summarised in table 3. Overall, there were no unexpected safety signals. The overall incidence of any AE in the golimumab group was similar to that in the placebo group. The most common events (MedDRA preferred terms) were nasopharyngitis and upper respiratory tract infection in both groups. There were no SAE observed in the placebo group compared with four events in golimumab-treated patients (p=0.29), all of which were considered to be not related to study drug by the investigator: elective prostatectomy because of known benign prostatic hypertrophy, acute calculous cholecystitis, food poisoning and worsening of arthritis. No local injection reactions were observed. No deaths or malignancies were noted during the study period. No tuberculosis reactivation was observed.
Incidence and types of AEs during the 24-week double-blind period
Need for rescue and efficacy in subgroups
From week 12 onwards, there was an option to start rescue medication with open-label golimumab if patients were not responding. In the placebo group, 10 out of 20 patients (50%) entered the rescue arm compared with only 4 out of 40 (10%) patients in the golimumab arm.
We analysed whether treatment effect was different in patients with or without elevated CRP at baseline: no interaction could be demonstrated with regard to the major outcome parameters. We also assessed whether response to treatment was comparable in patients with PsA (n=25) versus non-psoriatic (undifferentiated peripheral) SpA (n=35). The overall median disease duration of skin and/or nail psoriasis was 4.3 years: again there were no statistically significant differences for all primary and secondary end points between these two groups.
Discussion
The results from this study provide several novel and clinically relevant findings with important implications for management of patients with pSpA. First, very early recognition of disease and initiation of biological treatment leads to a substantially higher response compared with published reports in patients with more established disease.19 ,20 Second and of equal importance, the results from the placebo arm do not support the hypothesis that a substantial proportion of patients with early pSpA goes into spontaneous clinical remission.
Our study was the first to explore the therapeutic potential of an anti-TNF agent, golimumab, in patients with very early (<12 weeks symptom duration) pSpA, classified according to the ASAS criteria. Our main results show improvement in all clinical and laboratory assessments and PROs, as well as validated measures of quality of life. We especially observed high remission rates, defined in a very stringent way as the complete absence of arthritis, enthesitis and dactylitis. Given the paucity of large clinical trials conducted in patients with pSpA at this moment, no efficacy end point has been specifically developed and validated for a patient population with predominant pauciarticular joint and enthesis involvement. It seems logical that classic response criteria based on the decrease in the number of active joints/entheses are probably not the best evaluation method to assess efficacy. Therefore, we chose as our primary end point an outcome based on the actual disease activity status and not on a percentage of improvement.
Contrary to most phase III clinical trials in PsA, our patient population consisted of mainly oligoarticular and very early, DMARD-naïve disease. Recently, two other RCTs in established pSpA were performed.19 ,20 In both trials, the mean symptom duration was around 7 years compared with only 5 weeks in our study. Paramarta et al 20 evaluated the efficacy of adalimumab in 40 patients with active pSpA fulfilling the European Spondyloarthropathy Study Group or Amor criteria but not the criteria for AS or PsA. As primary end point they used the PGA at week 12 and found a strong improvement at week 12 compared with baseline in the adalimumab group (−31.0±SD 23.3 mm), while the placebo group showed almost no improvement (−5.9±SD 21.4 mm). In our study population, we found a numerically even larger decrease regarding the PGA at week 12 in the golimumab-treated patients (−37.8±SD 33.2 mm). In the ABILITY-2 study, the efficacy and safety of adalimumab was evaluated in 165 patients with active non-psoriatic pSpA fulfilling the peripheral ASAS classification criteria.19 In this trial, efficacy was evaluated with newly designed peripheral SpA Remission Criteria (pSpARC), with as a primary endpoint a 40% improvement. At week 12, a greater proportion of patients receiving adalimumab achieved this pSpARC40 response compared with patients receiving placebo (39% vs 20%; p=0.006). In our study, the pSpARC40 response was achieved in 57.5% of patients treated with golimumab vs 20% in the placebo group (p=0.0069). Despite the fact that the included study populations in both trials were not exactly identical compared with ours, we observed at least a trend that efficacy was better in patients with short symptom duration, compared with more longstanding disease. This concept is already established in axSpA, but our data are the first to also demonstrate this in pSpA.
Interestingly, more conventional axSpA response criteria, such as ASAS 20 and 40 response, BASDAI 50% response and ASAS improvement criteria, also showed good discriminatory capacity in our patients, with our results indicating again a higher response rate compared with patients with longer symptom duration.
An obvious strength of our study is the inclusion of a placebo group. In pSpA, one might consider that there is a danger of overtreatment in a very early phase of the disease, because a fraction of these patients might go spontaneously into remission, a phenomenon regularly observed in reactive arthritis. The rationale for including a placebo group in this 24-week study design was indeed to estimate the spontaneous remission rate. We observed that only 20% of the patients in the placebo group reached our definition of clinical remission. This number should however be interpreted with caution, because these patients had a higher intake of NSAIDs, which makes it impossible to exclude remission induced by continuous NSAID use. Starting at week 12, there was an option to start rescue medication with open-label golimumab. In the placebo group, 10 out of 20 patients (50%) entered the rescue arm compared with only 4 out of 40 (10%) patients in the golimumab arm. This finding, together with the difference in NSAID intake over time in both groups and the clinical evolution (persistence of increased TJC and SJC, enthesitis and dactylitis in up to 80% of the placebo patients at weeks 12 and 24), indicates that our patient population with pSpA do not have self-limiting disease.
We also examined whether distinct different treatment effects were present in patients with psoriasis or elevated CRP at baseline, but could not demonstrate any significant interaction. Of note, in our study 65% of patients had an elevated CRP at baseline compared with only 38% in the trial by Paramarta et al and 44% in the ABILITY-2 trial. This suggests that the overall inflammatory burden in this group of very early pSpA is higher than in more longstanding disease.
The data of our proof-of-concept study will need to be confirmed in larger multicentre studies. In any case, the data reiterate the importance of early recognition and referral strategies from primary care to rheumatologists, in order to install adequate treatment and consequently achieve better outcomes. Future strategy trials should also include other relevant treatment arms, such as sulfasalazine since this is the current standard of treatment for peripheral symptoms according to the ASAS/European League Against Rheumatism recommendations.3 Our Clinical REmission in peripheral SPondyloArthritis cohort provides unique opportunities to study potential biomarkers of remission, as well as the possibility to achieve drug-free remission.
Conclusion
Our findings indicate that a large majority of patients with early pSpA does not go into spontaneous remission, and benefits from intensive treatment. In this study, initiation of TNF blockade in pSpA with short symptom duration leads to high rates of clinical remission and significant improvement in all secondary efficacy outcomes.
References
Footnotes
Handling editor Tore K Kvien
DE and FVdB contributed equally.
Contributors PC, DE and FVdB: study concept and design. PC, GV, HC, LVP, DE and FVdB: data acquisition. PC, GV, DE and FVdB: analysis and interpretation of data. PC, DE and FVdB: manuscript preparation. PC, DE and FVdB: manuscript revision.
Ackowledgements We thank all referring rheumatologist for the help in recruiting patients.
Funding This research was carried out as an Investigator Initiated Study with support from Janssen Pharmaceutica NV, who also provided the study medication.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Medical Ethics Committee of the Ghent University Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.