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Clinical therapeutics: Edited by Gerd Burmester and Thomas Dörner

Drug-free remission: is it already possible?

van den Broek, Mariannea; Huizinga, Tom WJa; Dijkmans, Ben ACb,c; Allaart, Cornelia Fa

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Current Opinion in Rheumatology: May 2011 - Volume 23 - Issue 3 - p 266-272
doi: 10.1097/BOR.0b013e32834563e3
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Abstract

Introduction

Remission is the current treatment goal in rheumatoid arthritis (RA) [1]. An increasing number of patients in clinical trials achieve this goal [2]. This raises the question whether patients who have been in remission for a prolonged period still need medication. Although old studies have observed different remission rates in population-based RA and hospital-based RA [3], the current review has focused on hospital-based RA. Several small studies [4–8] conducted in the 1970s and 1980s show high relapse rates after cessation of disease-modifying antirheumatic drugs (DMARDs), with the exception of one trial [9] in patients treated with high doses of gold. In 1996, ten Wolde et al.[10] published a double-blind placebo-controlled study on 285 patients with longstanding RA in remission, who were randomized to continuing their DMARDs or to switch to placebo. The sustained drug-free rate was 62% in 1 year in the drug-free (placebo) group. The BeSt study [11] was the first large treatment strategy trial to show that in 65% of patients in remission, medication could be stopped without losing remission during median 11 months. In this review, we discuss the most recent trials covering drug-free remission, radiological damage progression in drug-free patients, response after retreatment and predictors of sustained drug-free remission.

Recent trials investigating drug-free remission

Predictors of sustained drug-free remission were studied [12•] in the Leiden Early Arthritis Clinic (EAC) and the British Early Rheumatoid Arthritis Study (ERAS) (Table 1) [12•,13•,14,15•,16•]. The follow-up duration of patients from these cohorts varied, with a maximum of 10 years. For the purpose of this study, drug-free remission in the EAC and ERAS was defined as having no swollen joints and drug-free remission according to the treating rheumatologist. The 454 patients from the Leiden EAC had RA according to the 1987 American Rheumatism Association [ARA, now American College of Rheumatology (ACR)] diagnostic criteria at or within 1 year after diagnosis. They were included between 1993 and 2002, and their mean symptom duration at inclusion was 6.4 months. Patients were treated either with analgesics, followed by hydroxychloroquine (HCQ) or sulfasalazine (SSA) in case of an insufficient response, or with initial HCQ, SSA or methotrexate (MTX), depending on their inclusion period. Sustained drug-free remission, defined as drug-free remission for at least 1 year consecutively, was achieved in 68 out of 454 patients (15%). The 895 patients from the ERAS with recent onset RA according to the 1987 ARA criteria were diagnosed slightly earlier, between 1986 and 1996. Their mean symptom duration at inclusion was 8.3 months. Patients were treated according to their rheumatologist's preference. Most patients were first treated with analgesics, followed by sequential monotherapy or combination therapy with synthetic DMARDs in severe RA, in case of an insufficient response. Drug-free remission during at least 1 year was achieved in 84 out of 895 patients (9.4%).

T1-9
Table 1:
Studies covering drug-free remission published between June 2009 and December 2010

Drug-free remission and retreatment were studied in 70 Finnish early rheumatoid arthritis (ERA) patients [13•], in a prospective cohort study started in 1986 with a follow-up of 15 years. Median disease duration at inclusion was 8 months. Patients were treated according to the ‘sawtooth treatment strategy’. Most patients used conventional DMARD monotherapy and combination therapy in case of insufficient response; 4% used biologicals. DMARDs were discontinued if remission according to the 1981 ACR criteria [14] was achieved for at least 1 year or in case of a prolonged symptom-free phase with minor disease activity. Nine (45%) out of the 20 patients who had been drug-free restarted treatment after a disease flare, after a median duration of 50 months. Of the 11 patients who had not restarted medication, 64% were in remission and the other 36% had low disease activity.

In the 5-year follow-up of the double-blind Ciclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial, Hetland et al.[15•] reported on the drug-free remission rate of 139 patients with recent onset RA, included between 1999 and 2002. Patients were treated according to a dynamic treatment protocol. Initially, patients were randomized to receive either MTX + cyclosporin (CSA) or MTX + placebo. Both groups received 2 weekly and then monthly intraarticular betamethasone injections in the first 52 weeks. HCQ was added after 68 weeks. After 2 years, MTX + CSA + HCQ triple therapy and then biologicals were started in case of insufficient response. The mean symptom duration at inclusion was 3.2 months in the combination therapy group and 3.9 months in the MTX + placebo group. After achieving remission according to the 1981 ACR criteria for at least 1 year, DMARDs were tapered and finally stopped. Drug-free remission at year 5 was achieved in 17% with no differences between the two initial treatment groups: 14% in the MTX + placebo group and 19% in the combination therapy group (P value 0.68).

FBU1-9
Box. 1

The most recent study on drug-free remission is the 5-year analysis of the 508 patients with recent onset RA from the double-blind BeSt trial [16•], who were included between 2000 and 2002. Median symptom duration at inclusion was 23 weeks (5.8 months). Patients were randomized to four treatment groups: sequential monotherapy, step-up combination therapy, initial combination therapy with prednisolone or initial combination therapy with a tumor necrosis factor (TNF) blocker (infliximab). Treatment was adjusted 3 monthly in case of an insufficient response, differently for each treatment group. In groups 1–3, combination therapy with a TNF blocker was started after patients had failed on three previous treatment steps with synthetic DMARDs, including at some time prednisolone in groups 2 and 3. After a Disease Activity Score (DAS; 53 tender, 44 swollen joint count) less than 1.6 on monotherapy was achieved for at least 6 months, medication was stopped. Drug-free remission was achieved in 115 out of 508 patients (23%), with no significant differences between the four treatment groups. In 46%, DMARDs had to be restarted due to a rise in disease activity to a DAS at least 1.6. The 51% in sustained drug-free remission had a median follow-up of 23 months after cessation of DMARDs.

Response after retreatment

Clinical and radiological response in restarters was studied in two of the trials (Table 2). In the Finnish ERA study [13•], restarters had a significantly higher mean DAS28 at t equal to 15 years than patients in sustained drug-free remission: 3.68 (SD 1.23) versus 2.08 (SD 1.01), with a P value of 0.0018. The mean DAS28 in continued DMARD users was also slightly lower: 3.37 (SD 1.01). The mean scores on the Health Assessment Questionnaire (HAQ) of the three groups were not significantly different. Radiological damage after 15 years in restarters was also comparable to the other two groups. Restarters had a mean Larsen score of 25 (SD 30). There was a significant difference between continued DMARD users and patients in sustained drug-free remission. Their mean Larsen scores were 54 (SD 36) and 12 (SD 18), respectively (P < 0.001).

T2-9
Table 2:
Response after retreatment and predictors of sustained drug-free remission

In the BeSt study [16•], retreatment was successful in 96%: 25 out of 53 patients achieved remission again within 3 months, 14 out of 53 patients within 6 months and 11 out of 53 achieved low disease activity. Two patients (4%) were lost to follow-up and one patient did not achieve low disease activity. The median HAQ scores of patients in drug-free remission and restarters were comparable to the scores of the general population. Significant radiological damage progression was not seen in the majority of drug-free patients in the first year after discontinuation of DMARDs. Radiological damage progression in the first year of increase of disease activity in patients who needed retreatment was not different when compared to radiological damage progression in the first year after discontinuation of medication in patients in sustained drug-free remission. Median Sharp–van der Heijde progression scores were 0 [interquartile range (IQR) 0–1] and 0 (IQR 0–0), respectively (P value 0.44).

Predictors

Although cessation of medication appears to be relatively safe with, in general, good response after retreatment and no increase in radiological damage progression, some patients do not achieve remission again after retreatment. Therefore, predictors of sustained drug-free remission are needed.

Van der Woude et al.[12•] studied independent predictors of sustained drug-free remission, defined as drug-free remission for at least 1 year consecutively, in the Leiden EAC cohort and tried to replicate these results in the British ERAS cohort. The strongest predictor for sustained drug-free remission in the Leiden EAC cohort was anticitrullinated protein antibody (ACPA) negativity, but ACPA status was not known for patients from the ERAS cohort. Rheumatoid factor negativity, shared epitope negativity and short symptom duration at baseline were found to be independent predictors in both cohorts (Table 2).

A separate analysis of predictors of sustained drug-free remission was not described by Tiippana-Kinnunen et al.[13•] in their Finnish ERA study. They did find an association with rheumatoid factor negativity and nonerosiveness at baseline and sustained drug-free remission.

ACPA negativity was also found to be the strongest predictor of sustained remission in the BeSt study [16•], followed by low DAS until remission, a higher baseline HAQ and SSA as last DMARD when compared with MTX. Rheumatoid factor negativity was associated with sustained drug-free remission in the univariable analyses.

In summary, all trials found rheumatoid factor negativity to be associated with sustained drug-free remission. ACPA negativity was found to be an even stronger predictor in those cohorts that measured ACPA status. Short symptom duration before treatment initiation and shared epitope negativity predicted sustained drug-free remission in two cohorts.

Translation to clinical practice and consequences for further research

The four recent studies on drug-free remission cover a heterogeneous patient population treated according to different strategies. Different remission definitions and criteria for retreatment were used. The available sets of remission criteria vary in components used and in stringency (Table 3[17]).

T3-9
Table 3:
Comparison of remission criteria

It is, therefore, hard to draw general conclusions. These recent studies and previous publications do show that drug-free remission is indeed possible in 17–29% of patients. Sustained (>1 year) remission was reported in an even smaller group: 9–16% of all patients. Retreatment was needed in 44–45% of all drug-free patients in recent studies [13•,16•] and in 11–100% of all drug-free patients in older publications [4–6,18]. More research on sustainable drug-free remission is necessary with longer follow-up. Preferably, these studies would use a uniform set of remission criteria. Recently, new criteria have been proposed by the ACR/European League Against Rheumatism Commission to Redefine Remission in RA [19]. In contrast to the ACR 1981 criteria, these criteria allow for one swollen and one tender joint. This does raise the concern that patients in remission might still have active synovitis, causing joint damage [2]. Only two of the 115 patients in DAS remission [which shows similarities with the new criteria (Table 3)] from the BeSt study showed clinically relevant joint damage progression in the first year after cessation. Unfortunately, long-term radiologic follow-up of patients in drug-free remission is not yet available. This underlines the importance of monitoring of disease activity and joint damage progression in patients in drug-free remission. Future research should also focus on radiological joint damage progression in drug-free patients with longer follow-up duration. Moreover, one wonders whether patients who have discontinued all antirheumatic drugs can taper or need to intensify other therapies such as NSAIDs or physical therapy, but none of the papers offers information on that.

Furthermore, only few studies report on the effect of retreatment: do patients respond well to therapy again? The positive results from the BeSt study, which included 508 patients and had a dynamic treatment protocol in which treatment effect was evaluated every 3 months, suggest that this is indeed the case. Retreatment was successful in 96%. DMARDs were stopped when patients were in DAS remission for at least 6 months and restarted when remission was lost. These results are in line with some smaller studies conducted between 1976 and 1987 investigating cessation of and retreatment with synthetic DMARDs [4,5,7] and a more recent trial [20] that studied cessation of and retreatment with biologicals, which all report a good response after retreatment in all patients. However, in the study of ten Wolde et al.[21], only 78% had a good response to retreatment and in the Finnish ERA trial, the majority of patients did not achieve low disease activity during follow-up after retreatment. A possible explanation for these differences is that in these studies, treatment was restarted when disease flared to moderate or high disease activity, whereas in the BeSt study, patients were retreated when an increase in DAS to at least 1.6 occurred. Moreover, not all patients in the Finnish trial were in clinical remission when medication was stopped. These results suggest that DMARDs should only be stopped in patients in sustained clinical remission. Treatment should be restarted as soon as remission is lost, without delay.

Conclusion

There are few studies that report on drug-free remission in RA and even fewer that report on restart of treatment. From four recent studies in patients with recent onset RA with a follow-up duration up to 15 years, the following conclusions can be drawn:

  1. Drug-free remission is achieved in 17–29% of patients and sustained in 9–16% during 1–4 years.
  2. Joint damage progression in drug-free patients is not different from DMARD users and does not increase in the first year(s) of drug-free remission, regardless of flare.
  3. Low disease activity is achieved again in the majority of patients who have to restart treatment.
  4. Auto antibody negativity (rheumatoid factor, ACPA), shared epitope negativity and short symptom duration before treatment initiation are predictors of sustained drug-free remission.

The low rates of drug-free remission are possibly due to the fact that the treatment of these patients was aimed at achieving low disease activity, at best. With new treatment options, more patients can now be treated to achieve remission and potentially this will lead to more drug-free remission in the future. Clinical research should focus on the consequences of drug-free remission and retreatment after longer follow-up and on identifying predictors of sustained drug-free remission.

Acknowledgements

The authors would like to thank J.W. Schoones from the Walaeus Library of the Leiden University Medical Center for his assistance in the literature search.

None of the authors or professional colleagues has any conflict of interest.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 322–323).

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Keywords:

drug-free; predictors; remission; rheumatoid arthritis; treatment

© 2011 Lippincott Williams & Wilkins, Inc.