Long-term follow-up of patients in the TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) trial

Abstract

Objectives

The TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) study was the first strategy trial in psoriatic arthritis using an early treat-to-target strategy to improve clinical outcomes. The current study aimed to review a cohort of patients who had completed TICOPA to judge if the clinical advantage gained by participants in the tight control (TC) arm was sustained, and to explore subsequent therapy.

Methods

A case note review was conducted for a cohort of patients who had participated in TICOPA. Current drug use and clinical status were obtained, with low disease activity judged as no tender or swollen joints, no dactylitis and enthesitis, and no change in treatment required.

Results

Approximately five years after completion of the TICOPA study, notes were reviewed for 110 patients [TC, n = 54; standard care (StdC), n = 56]. Disease activity was found to be similar in both groups (current low disease activity: TC 69%, StdC 76%). Biologic use at the end of the study was higher in the TC arm (TC 33%, StdC 9%), but at review a similar percentage in both groups were taking biologic drugs (TC 54%, StdC 52%), whereas MTX use diminished.

Conclusion

After several years, clinical outcomes and therapeutic drug use were similarly good for patients in both arms of the TICOPA study, with no obvious clinical advantage after TC ended. Notably, TC did not result in greater biological use long term, and MTX use decreased in both arms of the study.

Rheumatology key messages

• In TICOPA study a treat-to-target strategy improved clinical outcomes over 48 weeks.

• Five years later there were no clinical advantages for the T2T group.

• The optimal time to start bDMARDs in PsA remains to be determined.

Introduction

The concept of treat to target is well established in rheumatoid arthritis, and early treatment leads to better long-term outcomes both clinically and radiographically [1]. The TIght COntrol of inflammation in early Psoriatic Arthritis (TICOPA) study was the first strategy trial in PsA to demonstrate that a treat-to-target strategy in early disease improves clinical outcomes over a 48-week period [2]. In the TICOPA study almost 40% of patients in the tight control, treat-to-target arm were in minimal disease activity (MDA) at 48 weeks, compared with 25% in the standard care arm. Following exit from this study, we hypothesized that this advantage would translate to a clinical advantage in the medium term.

Methods

The full trial protocol and clinical results of the TICOPA study have been previously reported [2, 3]. In brief, this randomized, controlled, parallel group, open label, multicentre clinical trial recruited people with early (<2 years symptom duration), treatment-naïve PsA. The primary objective of the main trial was to compare tight control (TC) with standard care (StdC), using MDA [4] as the treatment target. Participants received either TC or StdC for a period of 48 weeks.

Two hundred and six patients were recruited into TICOPA, 101 in the TC arm and 105 in the StdC arm. In 2018, ∼5 years after the end of the study, the notes of all the available patients who participated in the TICOPA study at St Luke’s Hospital, Bradford and Chapel Allerton Hospital, Leeds were reviewed. From the case notes, information was obtained on current treatment, treatment since the end of the study and current clinical state. A patient was judged to be in low disease activity (LDA) if there were no swollen or tender joints, no record of active enthesitis and dactylitis, and no escalation or change of treatment (unless the patient changed therapy because of adverse events). If the psoriasis was recorded as requiring further treatment, then the patient was judged not to be in LDA. Unfortunately, not enough participants had current radiographs of the hands and feet to make meaningful comparisons with radiographs and radiographic scores at the end of the study.

Results

Across the two sites, 77 patients were randomized to the TC arm and 81 to StdC (Table 1). There had been four deaths in the TC arm, none of whom had been on biologics (causes of death: multi-organ failure, non-HIV Kaposi’s sarcoma, recurrent glioblastoma and septicaemia/diabetes). Data were available for 54 patients from the TC arm and 56 patients from the StdC arm of the study. Methotrexate use at the end of the study was similar between the groups (93% in TC, 80% in StdC). Methotrexate use at review was similar between groups but reduced overall (44% in TC, 54% in StdC). Biologic use at the end of the study was, as previously reported, higher in the TC arm (33% in TC, 9% in StdC) but at review, a similar percentage in both groups were taking biologic drugs (54% in TC, 52% in StdC). The treatment algorithm in TICOPA included the use of combination conventional synthetic DMARDs (csDMARDs) and this was reflected in the percentage of patients taking combination csDMARDs (30% in TC, 15% in StdC). At review, these figures had decreased with just one patient (2%) in the TC arm and four patients (7%) in the StdC arm on combination csDMARDs. In terms of disease activity at the end of the study, more patients were in MDA in the TC arm (50%) than in the StdC arm (32%) but at follow-up the percentage of patients considered to be in LDA was similar across the two arms (69% in TC; 76% in StdC). Although no formal statistics have been performed, it is clear that there are no differences between the outcomes for PsA patients in the different arms of the study, in terms of treatment and assessed disease activity, some 5 years after study completion.

Table 1.

Treatments and outcome

	Tight control arm	Standard care arm
n at completion of TICOPA	77	81
n reviewed	54	56
MTX therapy at end of study	50 (93)	45 (80)
MTX therapy now	24 (44)	30 (54)
Biologic treatment at end of study	18 (33)	5 (9)
Biologic treatment now	29 (54)	29 (52)
Combination csDMARD at end of study	16 (30)	8 (15)
Combination csDMARD now	1 (2)	4 (7)
No DMARD currently	8 (15)	7 (13)
In MDA at end of study	27 (50)	18 (32)
In LDA now	37 (69)	41 (76)

Data are shown as n (%) except where otherwise indicated. csDMARD: conventional systemic DMARD; LDA: low disease activity; MDA: minimal disease activity.

To explore predictors of people being on biologic drugs in the moderate term, logistic regression was performed with current biologic use as the dependent variable and baseline age, gender, arthritis classification (oligoarthritis vs polyarthritis), patient global visual analogue scale and Psoriatic Arthritis Disease Activity Score (PASDAS) as independent variables. In this analysis, where all variables were entered simultaneously, only age was a predictor of future biologic use, with younger patients more likely to be taking biologic drugs (odds ratio 0.95; 95% CI: 0.92, 0.99).

Discussion

The TICOPA study confirmed the benefit of a treat-to-target strategy in PsA, but as the patients completed the study, they returned to routine rheumatology care. There were equivalent numbers of patients judged to be in LDA at the review period suggesting that the added benefit of treat to target does not continue beyond the use of this strategy. There were also significant changes in prescribing patterns after the study ended. In TICOPA the majority of patients were on methotrexate at the end of the study but this reduced to around 50% at follow-up, demonstrating a substantial reduction in MTX use in both arms of the study over time. Although considerably more patients in the TC arm had escalated to biologics at 48 weeks, the number of patients on biologics at this 5-year review was similar between groups due to more patients in the SC being started on biologics. Very few patients in either arm were on combination csDMARDS.

What useful information can be gleaned from this review? Despite an early intervention at the time of diagnosis with a treat-to-target strategy for 1 year, the additional benefit identified in TICOPA at 48 weeks does not extend to a longer term advantage in disease activity once patients return to routine care. Although patients in the TC arm continue to do well, patients in the StdC arm improved proportionally more, thus negating the end-of-study differences between the two arms. This may have occurred with the greater use of biologics in the StdC arm in follow-up.

In the TICOPA study, treatment costs were higher in the TC arm, due mainly to two factors: the higher use of biologic drugs and the more frequent appointments over the 48 week study period. However, at the follow-up review, equivalent numbers in both treatment arms were on biologic drugs. Thus, the use of biologics in the StdC arm was later in the course of the disease, but eventually became equivalent to the TC arm. In both arms, at 50%, use of biologic drugs at the review was comparable to other published cohorts [5]. Given that a number of biologic studies have shown higher response rates when used in patients with shorter disease duration [6, 7], this may justify the earlier use of biologics in those failing DMARD therapy despite the slight increase in cost over the patient’s lifetime. There is also the benefit of improved quality of life (and benefit for work) during the year of TC, which was not quantified. In this study, the only significant predictor of future biologic use was younger age: disease sub-group, disease activity and gender were not predictors, but the numbers were small in this analysis.

Methotrexate use, on the other hand, decreased over the 5 years after the end of the study, at a rate of just under 10% per year, consistent with other reports in this disease [8]. Combination csDMARDs was relatively high in the TC cohort, reflecting the treatment algorithm used in TICOPA, but their use at review was much less. There is extremely limited data supporting the use of combination DMARDs in PsA, but in the UK, failure of at least two csDMARDs is required prior to the use of biologics. As previously reported, combination csDMARDs were used in ∼50% of those in MDA at 48 weeks in TICOPA, but this benefit either did not continue or there were unacceptable adverse events—there was insufficient detail during the notes review of the current study to answer this point. Of interest, 50% of patients on combination csDMARDS at the end of the study were on biologics at the review, so not all patients made the transition to biologic drugs.

The study has several limitations. When evaluating these results, it must be noted that there was no formal intention to continue the treatment strategy, nor to continue detailed clinical and radiographic observations beyond the end of the TICOPA study. Other studies are needed to answer the question of the long-term benefits, including benefits on function and quality of life, of an early continuous treat-to-target strategy. Secondly, the current status of the patients was based on notes review only and formal assessments, such as MDA, were rarely found in these routine clinic appointments. Disease status data are therefore uncertain, although this uncertainty applies equally to both treatment groups. Thirdly, an objective measure of disease status, such as structural damage, would have provided more tangible evidence of the medium-term benefit, or otherwise, of an early treat-to-target strategy in PsA but insufficient radiographs were available.

In summary, 5 years after study end, clinical outcomes and therapeutic drug use were similar but with considerable changes in patients who had been in the TICOPA study, with no obvious long-term clinical advantage to the 48-week TC intervention. Without a formal intention to continue a treat-to-target strategy, this result reflects clinical practice in routine rheumatology care. No data were available on disease status to reflect a benefit of early tight control of disease activity.