Lengthening the time intervals between doses of biological agents in psoriatic arthritis patients: A single-center retrospective study

Abstract

Anti-tumor necrosis factor (TNF) alpha therapy has changed the course of psoriatic arthritis (PsA), but clinical experience about lengthening of time intervals between drug administrations is still limited. The aims of the study were to evaluate: (1) the long-term efficacy (over a 4-year period) of etanercept/adalimumab in a subset of PsA patients who did not require switches; and (2) the progressive lengthening of time intervals between treatments in patients who achieved minimal disease activity (MDA). PsA outpatients attending the Rheumatology Clinic-University of Padova who took a single anti-TNF agent (etanercept/adalimumab) for a 4-year period were studied. Therapy efficacy was assessed using clinical, biochemical, and disease activity (DA) indexes. The intervals between treatments were empirically and progressively lengthened after MDA was reached and maintained. One hundred and forty-one patients (mean age, 51.22 ± 12.34 years; mean disease duration, 12.1 ± 8.42 years) treated with etanercept/adalimumab (47.5% and 52.5%, respectively) were studied. DA indexes showed a marked, persistent improvement in all the patients throughout 4 years. The interval between injections could be extended in 46.1% of the patients (35% for adalimumab, 58% for etanercept) without provoking relapses. The mean therapy interval at the end of the study period was 3.12 weeks for adalimumab 40 mg (with respect to 2 weeks) and 2.75 weeks for etanercept 25 mg (with respect to 0.5 weeks). The new therapy timetable also led to cost savings. In conclusion, lengthening the time intervals between injections of anti-TNF agents in PsA patients who reach MDA is safe, effective, cost-effective, and facilitates patient compliance.

Keywords

adalimumab anti-TNFα agents etanercept minimal disease activity psoriatic arthritis spondyloarthritis

Introduction

Psoriatic arthritis (PsA) is a progressive inflammatory arthropathy¹ affecting both the axial and peripheral joints and is often accompanied by enthesitis, dactylitis, psoriatic lesions, and systemic involvement.^2,3 PsA can lead to major anatomical and functional impairment, and the health-related quality of life (QOL) of patients may be impaired if therapy is inappropriate or inadequate. The use of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids is not always sufficient to adequately control disease activity (DA) and therefore to prevent radiological damage.^3–5 Causing an improvement in functional status and in QOL, the introduction of anti-tumor necrosis factor α (TNFα) agents has changed the disease’s natural history both in terms of DA and disease severity.^6–9 The therapeutic efficacy of anti-TNFα agents as well as their long-term safety have been demonstrated in PsA patients by numerous randomized controlled double blind studies.^10–14 There are, nevertheless, only limited data available on the actual therapy survival rate in clinical practice, and, in particular, on the timing of drug administration in the event a patient demonstrates a satisfactory clinical response. Even less is known about the percentage of patients whose injection intervals can be prolonged once they have reached a minimal disease activity (MDA) according to Coates et al.’s criteria.¹⁵

While PsA patients are initially treated with doses recommended by phase III clinical trials for product registration and approval by the competent authorities, there is no consensus on the action to take when remission is reached and sustained. Some observational studies^16–18 and management guidelines for other types of inflammatory arthritis^19–21 recommend that biological therapy should be reduced to the lowest effective dose in the event of an optimal clinical response, confirmed by a MDA state.^22,23 Until now, dose reduction has been implemented empirically in patients to reduce drug costs.

Our observational study aimed, first of all, to assess the clinical efficacy of the same anti-TNFα agent over a 4-year period. The percentage of patients in whom therapy intervals could be lengthened while maintaining good disease control, and the actual cost savings linked to this strategy were also evaluated.

Materials and methods

One hundred and forty-one outpatients attending the spondyloartrhritis clinic of the University of Padova Medical Center (2005–2013) and diagnosed with PsA in accordance with the Classification criteria for Psoriatic Arthritis (CASPAR)²⁴ who consistently took either etanercept or adalimumab for a 4-year period were studied retrospectively. The study protocol was approved by the local Ethics Committee and carried out in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from the patients permitting us to analyze their data, and we have made every effort to protect their anonymity.

All the patients studied showed axial and/or peripheral involvement, very limited skin involvement, and presented occasional episodes of dactylitis (2%) or enthesitis (10%). Only those patients who started biological therapy in accordance with EULAR international guidelines and who consistently took the same TNF-alpha inhibitor throughout the 4- year period were included. Patients with signs or symptoms of latent or active tuberculosis, chronic infection, severe clinical disease, cancer, or congestive heart failure were excluded.

Some of the patients were taking 40 mg adalimumab, which was initially administered subcutaneously once every 2 weeks; others were taking 25 mg etanercept, which was originally administered subcutaneously twice weekly.¹³ Patients who achieved a stable remission/MDA lasting at least 6 months were considered eligible for drug reduction, which can be obtained by lowering the drug dosage or increasing the time intervals between injections. The latter method was the one that was used in this study. The increase of the time intervals between injections was carried out progressively and empirically, depending on DA; in particular we used the MDA criteria developed by Coates et al.¹⁵ Patients were prescribed increased time intervals after a thorough examination including a careful assessment of all clinical, biochemical, and clinimetric parameters by two rheumatologists (ML and AO). Since there are no established guidelines for practitioners on this matter, the decision to lengthen time intervals was at the discretion of the rheumatologists: whenever possible, the interval was progressively extended from 1 to 4 weeks for adalimumab and from 3 to 30 days for etanercept.

Clinical, biochemical, and clinimetric evaluations were carried out at baseline (t0), at 3 months (t3), at 6 months (t6) and once a year thereafter (t12, t24, t36, t48). Therapy efficacy was determined using the Peripheral Joint Assessment (68 tender and 66 swollen joint count), the DA Score 28 (DAS28–CRP), the Bath Ankylosing Spondylitis Activity Score (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Health Assessment Questionnaire (HAQ), the visual analogue scale of pain (VAS), the visual analogue scale of global disease activity (VASg), the erythrocyte sedimentation rate (ESR) expressed in mm/h, and C-reactive protein (CRP) expressed in mg/L. The PsA Response Criteria (PsARC)²⁵ is considered an index of optimal response to treatment which is defined as an amelioration in at least two of the following four criteria: (1) 20% or more improvement in physician global assessment of DA; (2) 20% or more improvement in patient global assessment of DA; (3) 30% or more improvement in tender joint count; (4) 30% or more improvement in swollen joint count.

When patients achieved MDA (15), which is based on five of the following seven criteria: (1) tender joint count ⩽1; (2) swollen joint count ⩽1; (3) PASI ⩽1 or BSA ⩽3; (4) VAS ⩽15; (5) VASg ⩽20; (6) HAQ ⩽0.5; (7) tender entheseal points ⩽1, they were considered eligible for dose reduction.

Statistical analysis: Baseline descriptive analyses were conducted to estimate means and standards deviations for the continuous variables. The Mann-Whitney test was used to compare DA indexes (TJ, SJ, DAS28, BASDAI, BASFI, HAQ, VAS, VASg, ESR, CRP) in the patients being treated with adalimumab or etanercept at t0 and at t48; Friedman’s test with Dunn’s Multiple Comparison test was carried out to evaluate the DA indexes at each of the study’s time points (t0, t6, t12, t24, t36, t48) in both groups. A value ofP <0.05 was considered significant.

Results

One hundred and forty-one patients with axial and /or peripheral involvement (79 men, 56.02%; median age, 51.22 ± 12.34 years; mean disease duration, 12.1 ± 8.42 years) were treated continuously with etanercept or adalimumab (47.5% and 52.5%, respectively). Clinical, demographic, and anamnestic data including age, gender, disease onset and disease duration times, type of involvement, use of DMARDS and/or prednisone at t0, in both groups (those in whom the dose interval could be lengthened and those in whom the original treatment timing needed to be maintained) are outlined in Table 1. These parameters were found to be similar in both the patients treated with adalimumab and in those with etanercept (Table 1). As regards DMARDS therapy, it was progressively reduced during the study period until interruption. This occurred within 6 months of clinical remission. There was a statistically significant improvement in clinical, biochemical, and functional indexes over the study period in all the patients (Table 2). There was a positive response to treatment already at t6 that was reflected in a reduction in: DA scores (DAS28-CRP and BASDAI), functional index scores (BASFI, HAQ, VAS, and VASg), and inflammatory indexes (ESR and CRP). All of these values were clearly significant at t12 (Table 2). The t0 and t48 values, expressed using median and interquartile range (IQR) were: BASDAI 52.50 (31.45) vs. 22.00 (29.75) (0–100) (P <0.0001); BASFI 32.10 (37.95) vs. 11.90 (19.50) (0–100) (P <0.0001); HAQ 0.50 (0.82) vs. 0.25 (0.63) (0–2.4) (P <0.0001); DAS 28 3.60 (1.53) vs. 2.11 (1.31) (0–5.1) (P <0.0001); VASg 40 (30) vs. 20 (30) (0–100) (P <0.0001); VAS 50 (30) vs. 20 (30) (0–100) (P <0.0001); ESR 21 (27) mm/L^h vs. 11 (13) mm/L^h (P <0.0001); CRP 7 (10.40) mg/L vs. 2.5 (2.59) mg/L (P <0.0001) (Table 2).

Table 1.

Baseline characteristics of PsA patients receiving anti-TNFα agents (adalimumab or etanercept).

Parameters	PTS with lengthened interval	PTS without lengthened interval	ADA	ETN
Patients (n)	65 (46.1%)	76 (53.9%)	74 (52.5%)	67 (47.5%)
Gender (M) (n, %)	42 (29.8%)	37 (26.2%)	45 (32.2%)	42 (29.9%)
Mean age (years)	51.11± 11.57	49.40±12.02	50.98±11.45	51.39±12.25
DMA (years)	12.78±7.35	11.26±9.04	12.76±9.14	11.25±7.44
Peripheral involvement (%)	53.6%	54.1%	41.3%	65.4%
Peripheral and axial involvement (%)	42.2%	41.3%	48.2%	32.5%
Axial involvement (%)	5.3%	4.2%	10.5%	2.1%
DMARDS (%)	8.5%	15.6%	23.4%	27.2%
Prednisone intake (%)	3.1%	10.7%	5.3%	7.9%
DMARDS+ prednisone intake (%)	1.3%	4.2%	1.8%	4.1%

Percentages are calculated on the total number of patients studied.

ADA, adalimumab; DMA (years), duration mean arthritis (years); DMARDs (%), disease-modifying antirheumatic drugs (%); ETN, etanercept.

Table 2.

Clinical, functional, and serological indexes during the 4-year study period.

	Variable median (IQR)	SJ	TJ	DAS28	BASDAI	BASFI	HAQ	VAS	VASg	ESR	CRP
ADALIMUMAB	t0	3 (2)	5 (5)	3.63 (1.58)	55.00 (35.70)	32.10 (37.90)	0.63 (0.75)	50 (40)	45 (30)	20 (26)	6.00 (6.60)
	t6	2 (1)	3 (2)	2.89 (1.33)	41.50 (34.50)*	24.20 (31.00)*	0.50 (0.88)	40 (30)*	40 (25)	15 (17)*	4.10 (4.10)
	t12	1 (1)**	2 (1)***	2.56 (1.19)**	39.50 (31.40)**	18.10 (30.00)**	0.50 (0.63)**	35 (30)*	30 (30)***	13 (15)***	3.19 (3.57)**
	t24	0 (1)***	2 (1)***	2.25 (1.22)***	33.80 (29.00)*	15.20 (23.00)**	0.38 (0.63)**	30 (30)**	30 (20)**	12 (13)*	2.45 (2.43)*
	t36	0 (0)**	2 (0)**	2.15 (1.30)*	29.50 (27.30)**	13.50 (25.50)***	0.38 (0.38)***	25 (29)**	25 (15)***	11 (16)**	2.34 (2.43)**
	t48	0 (0)**	1 (1)**	2.10 (1.35)*	24.00 (28.40)**	13.00 (19.50)*	0.38 (0.63)*	20 (25)*	25 (25)*	11 (15)*	2.10 (2.20)*
	P°	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001
ETANERCEPT	t0	3 (3)	6 (3)	3.59 (1.52)	52.05 (26.80)	32.11 (34.56)	0.55 (0.84)	50 (30)	40 (28)	22 (32)	9.40 (11.03)
	t6	2 (1)**	4 (2)**	2.93 (1.11)**	44.25 (30.00)*	25.00 (28.50)	0.50 (0.94)	35 (25)*	35 (25)	18 (14)*	5.60 (3.83)*
	t12	1 (1)***	2 (1)***	2.62 (1.12)*	34.50 (27.75)*	19.75 (21.38)*	0.25 (0.72)**	30 (24)***	30 (24)**	15 (12)*	4.70 (2.35)*
	t24	0 (1)***	2 (1)**	2.45 (1.05)***	31.00 (26.30)**	16.50 (18.75)**	0.19 (0.63)**	30 (24)**	28 (30)**	13 (12)**	4.24 (2.25)**
	t36	0 (1)**	1 (1)***	2.26 (1.28)*	26.25 (27.38)**	12.75 (16.63)***	0.25 (0.63)***	25 (24)**	23 (30)***	12 (9)**	3.94 (2.66)***
	t48	0 (1)**	1 (1)**	2.22 (1.26)*	20.75 (30.73)*	9.05 (19.50)*	0.19 (0.63)*	20 (26)*	20 (31)**	11 (13)*	3.00 (2.70)*
	P°°	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001
TOTAL (141 patients)	t0	3 (3)	5 (4)	3.60 (1.53)	52.50 (31.45)	32.10 (37.95)	0.50 (0.82)	50 (30)	40 (30)	21 (27)	7.00 (10.40)
TOTAL (141 patients)	t48	0 (0)	1 (1)	2.11 (1.31)	22.00 (29.75)	11.90 (19.50)	0.25 (0.63)	20 (30)	20 (30)	11 (13)	2.50 (2.59)
	P§	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001	P <0.0001

Data are expressed as median and interquartile range (IQR).

The Friedman’s test with corresponding post-hoc tests (P° and P°°) and Dunn’s multiple Comparison test were used.

P <0.0001 vs. t0, **P <0.001 vs. t0, ***P <0.01 vs. t0.

The Mann-Whitney test (P§) was performed to compare all the variables at t0 and t48.

BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; CRP, C-reactive protein; DAS28, Disease Activity Score; ESR, erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; SJ, swollen joint; TJ, tender joint; VAS, Visual Analogue Scale of pain; VASg, Visual Analogue Scale global disease activity.

DA indexes at t0 and at the other study time points (t6, t12, t24, t36, t48) in all the patients receiving adalimumab or etanercept are outlined in Table 2. There was a progressive improvement in all DA indexes, both in the patients whose time intervals could be prolonged, as well as in those in whom it could not. Although not statistically significant, the tendency towards improvement in all indexes was more pronounced in those patients whose intervals could be lengthened (Figure 1). Forty-six (32.6%) of the 141 patients showed a satisfactory clinical response already at t3, 111 (79%) at t6, 135 (96%) at t12, and 100% at t24. The interval between injections was lengthened in 65 patients (46.1%) who fulfilled the criteria for dose reduction after a mean treatment period of 12.85 ± 6.49 months for those taking etanercept and 10.05 ± 3.39 months for those taking adalimumab. Twenty-six of the 74 patients (35%) treated with adalimumab and 39 of the 67 patients (58%) treated with etanercept were prescribed longer therapy intervals in view of their optimal drug response (Table 3). We decided against lengthening the treatment interval for one patient who reached MDA after 6 months for fear of provoking a flare-up because of his history of recurrent uveitis. None of the other patients suffered from inflammatory eye disease.

Figure 1.

Serological, clinical, and functional parameters during the 4-year study period.

Table 3.

A comparison of the two groups (adalimumab vs. etanercept) of patients whose time intervals between injections could be lengthened.

	ADA	ETN
n (%) of patients whose intervals between injections could be lengthened	26/74 (35%)	39/67(58%)
Mean period (months) it took for patients to meet the criteria for drug reduction	10.05±3.39	12.85±6.49
Mean interval (weeks) between injections at the 48-month time point	3.12±0.22	2.75±0.68
Overall lengthening of treatment (%)	35.89 %	81.80%
Cost saving / year / patient	8,230 Euro	17,019 Euro

ADA, adalimumab; ETN, etanercept.

The mean treatment interval at the end of the study period was 3.12 (±0.22) weeks for adalimumab and 2.75 (±6.49) weeks for etanercept (Table 3). The average reduction of drug dosage thus obtained, in terms of percentage with respect to the standard dose administrated according to the regular time intervals, was 35.9% for the 26 patients treated with adalimumab and 81.8% for the 39 patients treated with etanercept. The patients who did not achieve MDA were kept on the initial therapy timetable (40 mg adalimumab subcutaneously once every 2 weeks, 25 mg etanercept subcutaneously twice weekly). The cost savings per year for those patients whose treatment intervals could be prolonged, calculated for the mean administration interval was 35.9% for adalimumab and 81.8% for etanercept with respect to full dose regimens. In monetary terms, the cost of providing the drug to those patients fell from 22,926.15 to 14,696 Euros/year for adalimumab and from 20,800.52 to 3781.91 Euros/year for etanercept.

The main confounders (age, gender, steroid and DMARDs intake, axial and/or peripheral involvement) could be excluded since the distribution variables at study entry were not significant.

Discussion

A good response to treatment in PsA patients means alleviating their physical and psychological distress. While non-steroidal anti-inflammatory drugs or local intra-articular injections of corticosteroids can be used successfully in patients with monoarticular and/or enthesitis PsA, systemic therapies such as DMARDs or anti-TNFα agents, or a combination of these, are considered first-line treatments for patients with moderate to severe active disease forms.^11,24 According to data from short-term studies, anti-TNFα agents are, in fact, more efficacious than DMARDs in delaying joint disease progression and in improving patient’s functional status and QOL.^11–14 A systematic literature review of treatments available for PsA¹³ carried out by two working groups instituted to provide data to be used to develop treatment recommendations for the EULAR taskforce confirmed the efficacy of anti-TNFα agents in improving joint symptoms, skin and functional status.^26–28

The present study’s findings confirmed the efficacy of adalimumab and etanercept treatment in PsA patients who showed a protracted, long-lasting response even when injection intervals were extended. The amelioration was, in fact, persistent and enduring throughout the 4-year study. The good response to adalimumab or etanercept, which was already detectable at t6, reached its peak at t12. The PsARC response, which was already significant at t12, was confirmed in all of the patients with a stable disease state throughout the study period.

Only limited data are available on the success of lengthening treatment intervals in the event of a satisfactory clinical response, but it is known that stopping treatment often leads to relapse.²⁹ Our findings show that it was possible to lengthen the treatment interval in almost 50% of our patients after t12. All of the patients whose treatment intervals could be lengthened maintained the regimen throughout the 4-year study period and all of the patients studied were characterized by a progressive improvement in all DA indexes (both those with longer therapy intervals and those receiving therapy on the original timetable, with a better improvement pattern in the former).

The cost of therapy was greatly reduced in the patients whose treatment interval could be lengthened. The cost savings per year for those patients, calculated for the mean administration interval, was 35.9% for adalimumab and 81.8% for etanercept with respect to full dose regimens. An important saving was observed in both groups of anti-TNF-alpha treatment. The mean period it took for the two groups to fulfill the lengthening criteria was comparable, which probably implies that the two drugs have the same power to induce MDA. Although the mean treatment interval at the end of the 4-year period seemed to be longer in the adalimumab group with respect to the etanercept one, the lengthening of interval in the latter group was actually more relevant since it is usually administered more frequently (twice a week for etanercept versus once every 2 weeks for adalimumab). In fact, despite the different half-lives of the drugs (average half-life 70 h for etanercept, 12 days for adalimumab), it was possible to lengthen etanercept dose interval more for the former. This observation appears particularly interesting taking into account the short half-life of etanercept and highlights an additional impact of anti-TNF treatment efficacy beyond its pharmacokinetics. Further studies are of course warranted to clarify this point.

Lengthening the treatment interval may, in any case, be a better strategy than reducing the drug dose in patients who have achieved MDA because the drug’s half-life is respected, the dose is consistently maintained, and only the treatment interval is modified. In accordance with our results, other studies have described anti-TNF drug dose reduction in other forms of inflammatory arthritis, such as rheumatoid arthritis.^30,31 Clinical remission and arrest of radiographic progression persisted in a substantial percentage of patients with rheumatoid arthritis even after standard etanercept doses were reduced.

There are some limitations to the present study: first, the decision and the time to reduce drug dosage was entirely at the discretion of the attending rheumatologists. Second, the decision to lengthen treatment intervals was made empirically and progressively, depending on the DA. In addition, the study design itself implies some biases as only PsA patients who were able to continue biological treatment over a 4-year period were included. The study, in fact, focuses on patients with a prolonged, stable response to anti-TNF alpha therapy and excludes patients who needed to switch to a second agent because of non-response or loss of efficacy.

In conclusion, lengthening treatment intervals of anti-TNF agents in PsA patients who reached and maintained MDA is not only safe, effective, and cost-effective, but also facilitates patient compliance. Further investigations are warranted to maximize the strategy’s therapeutic effects and to reduce toxicity without losing therapeutic effectiveness.

Footnotes

Acknowledgements

The authors would like to express their appreciation to Linda Inverso Moretti for her help in preparing the English version of this manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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