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Abstract
Undifferentiated arthritis (UA) is defined as an inflammatory oligoarthritis or polyarthritis in which no definitive diagnosis can be made. We performed a literature review to assess the efficacy of various drug therapies in patients with UA. The literature search was conducted using electronic databases Pubmed, EMBASE and MEDLINE in adults with UA or early arthritis (not fulfilling the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis). Drug therapy consisted of disease modifying antirheumatic drugs (DMARDs), biological agents and oral, intramuscular or intra-articular corticosteroids. Nine publications on eight randomised controlled trials (RCTs), two publications on two uncontrolled open-label trials and seven publications on three cohort studies were included. Temporary treatment with methotrexate (MTX), abatacept and intramuscular corticosteroids were demonstrated in RCTs with 12 months to 5 years follow-up to be more effective than placebo in suppressing disease activity or radiological progression. One study suggests that DMARD combination therapy is, at least after 4 months, superior to MTX monotherapy in patients with UA at high risk of developing persistent arthritis. The open-label uncontrolled trials and cohort studies also suggested that early treatment may provide immediate suppression of inflammation. The long-term benefit of early treatment in UA remains unclear. In conclusion, patients with UA benefit from early treatment with MTX. Combining multiple DMARDs or DMARDs with corticosteroids and biological agents may be even more beneficial. However, which treatment may provide the best results or may alter the disease course has still to be determined. More RCTs with longer follow-up time are needed.
- Early Rheumatoid Arthritis
- Treatment
- DMARDs (synthetic)
- DMARDs (biologic)
- Corticosteroids
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Introduction
Undifferentiated arthritis (UA) is defined as an inflammatory oligoarthritis or polyarthritis in which no definitive diagnosis can be made, and which over time may naturally evolve into a chronic inflammatory disease or into remission. Several observational cohorts of patients with early arthritis have shown that, depending on the inclusion criteria, 17–32% of the patients progress to rheumatoid arthritis (RA),1 while 40–55% achieve spontaneous remission.2 ,3
Since many studies have proven that early treatment of RA improves clinical, functional and radiological outcomes,4–6 the question has risen if treatment in the stage of UA may be even more beneficial. The so-called ‘window of opportunity theory’ hypothesises that in an early stage of RA, possibly in the stage of UA, a period may exist in which the disease course can be altered by the appropriate treatment, preventing it from becoming a chronic and disabling disease.7 In 2010, new classification criteria have been published to enable earlier diagnosis and treatment of patients with RA.8 Recent data have shown that patients indeed are diagnosed earlier,9 but the benefit of the new criteria in terms of long-term disease outcome still needs to be elucidated. Furthermore, also with these new criteria part of the patients with inflammatory oligoarthritis or polyarthritis cannot (yet) be classified as RA.
To investigate whether early initiation of disease modifying antirheumatic drugs (DMARDs) is beneficial for patients with UA, we performed a systematic literature review to identify all articles on disease outcomes of drug treatment in patients with UA, and aimed to assess the efficacy of the different drug therapies.
Methods
The systematic literature search was conducted using electronic databases Pubmed, EMBASE and MEDLINE and restricted to adults with UA or early arthritis (not fulfilling the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 classification criteria for RA). The following definitions were searched for up to February 2012: undifferentiated or early or unclassified or probable (inflammatory) arthritis or oligoarthritis or polyarthritis. Drug treatment was restricted to glucocorticosteroids (GCs), DMARDs and biological agents. Articles were only included if they concerned disease outcomes of drug therapy. All types of publications were included and no language restrictions were used.
Using predefined inclusion criteria, titles and abstracts were screened by one researcher and checked up by a second researcher. Disagreements were solved by discussion. Of the selected articles, full texts were screened for final selection in the review. Reference lists of included review articles were hand searched for additional relevant articles. Data extraction was performed by one researcher. Methodological quality of included randomised controlled trials (RCTs) was assessed by two independent researchers following the Guidelines for Cochrane Musculoskeletal Group Systematic Reviews, using the Cochrane Collaboration's tool for assessing risk of bias.10 For each study, the risk of several types of bias (selection, performance, detection, attrition and reporting bias and ‘other sources of bias’) was judged and summarised in an overall risk as low, high or unclear. Also, the Jadad score was performed, a quality score assessing randomisation, blinding, withdrawals and dropouts.11 Scores ranged from 0 to 5 with higher scores indicating better methodological quality.
Because of the large heterogeneity in types of patients, drug therapies and outcome measures, no meta-analysis was performed.
Results
After screening 3608 titles and abstracts, 67 articles were screened full text.
In total 30 articles were selected: 11 on 10 clinical trials of which eight were RCTs and five placebo controlled, seven on three cohort studies, and 10 review/opinion articles and two recommendations which were disregarded for this analysis. (figure 1)
Flow diagram of systematic literature search for publications on drug treatment of patients with undifferentiated arthritis (UA).
(A) Remission percentages after 1 year20 ,23 ,24 and 30 months16 follow-up of the four completed placebo controlled trials on temporary treatment of patients with UA. (B) Percentages of patients who progressed to rheumatoid arthritis after 1 year20 ,23 ,24 and 30 months16 follow-up of the four completed placebo controlled trials on temporary treatment of patients with UA * p=0.048; CS, corticosteroids; IM, intra-muscular; RA, rheumatoid arthritis.
Characteristics of clinical trials are shown in table 1. Three trials included patients with UA and RA.12–14 Drug therapies studied were intramuscular (IM) or intra-articular corticosteroids (three RCTs, two placebo controlled, one open-label trial), DMARDs with or without oral GCs (two RCTs, one placebo controlled, one open-label trial), biological agents (two placebo controlled RCTs) and one RCT comparing tight control (TC) with ‘routine DMARD’ treatment. On one placebo controlled RCT two articles with different follow-up duration were published.
Characteristics of clinical trials on drug treatment in patients with early or undifferentiated arthritis (UA)
Characteristics of observational studies are shown in table 2. Five of seven publications were based on the Norfolk Arthritis Register (NOAR), a primary care-based cohort in adults with ≥two swollen joints for at least 4 weeks, of which 46% at baseline fulfilled the 1987 criteria for RA.15 Four studies compared treated and untreated patients and/or early versus delayed start of treatment. Adjustments for differences in disease severity or time dependent confounders between groups were made using propensity scores or marginal structural models. One publication comparing anticitrullinated protein antibodies positive and negative patients and two publications without comparisons between treated and/or untreated patients are not mentioned further.
Characteristics of observational cohort studies in patients with early inflammatory polyarthritis
Main outcomes of all included clinical trials are shown in table 3. Seven clinical trials investigated temporary treatment and three trials continuous tight controlled treatment. Follow-up varied between 3 months and 5 years. Many different outcome measures were used for assessing response to treatment in terms of disease activity state, achieving remission, joint damage or progression to RA.
Main outcomes of clinical trials included in the systematic review
Results of synthetic DMARDs
Van Dongen et al16 and van Aken et al17 compared a 12 months course of methotrexate (MTX) with placebo after 30 months and 5 years follow-up. After 30 months 22 (40%) in the MTX group and 29 (53%) in the placebo group had progressed to RA (1987 criteria) (p value not published), after 5 years 25 (45%) and 29 (53%) did (p=0.45). Remission was achieved in comparable numbers after 30 months and 5 years (after 30 months 15 (27%) and 13 (24%) and after 5 years 20 (36%) and 15 (27%) in the MTX and placebo groups, respectively (p values not published)). All patients in the placebo group who progressed to RA did so within 1 year compared with half of the patients in the MTX group (p=0.04), suggesting that progression to RA was at least postponed by 1 year of MTX treatment. After 30 months, more patients showed radiological progression in the placebo group (14 vs 6, p=0.046), but after 5 years median Sharp- van der Heijde (SHS) progression did not differ between groups (p=0.78). Up to 30 months, fewer adverse events (AEs) were reported in the placebo group, serious AEs (SAEs) were reported similarly in both groups.
de Jong et al14 compared MTX monotherapy with MTX+sulphasalazine (SSZ)+hydroxychloroquine (HCQ) in patients with early arthritis at high risk for developing persistent arthritis according to the prediction model of Visser et al18 All patients received GC bridging therapy (either a tapering scheme or IM injection). After 3 months, the combination therapy group had a lower mean disease activity score (DAS) than the monotherapy group (difference (95% CI) 0.39 (0.67 to 0.11)). No significant difference was seen between oral and IM GC bridging therapy. AE and SAE were reported in 67 (75%) and 50 (56%) in the combination therapy and the monotherapy groups. Fewer medication changes were made in the monotherapy group (14 (16%) vs 18 (20%), p=0.006).
In an open-label trial in patients with UA or recent onset RA (2010 criteria)13 MTX was combined with a tapered high dose of prednisone for 4 months. Remission after 4 months was achieved in 79 (65%) patients with UA and 291 (61%) patients with RA (p=0.5). Median (IQR) SHS progression was 0 (0–0) in patients with UA and RA (p=0.9). AEs were reported in 341 (56%) and SAEs in 16 (3%) of all patients.
These studies indicate that synthetic DMARDs suppress disease activity in patients with UA. MTX monotherapy may postpone but not prevent the development of RA and may slow down radiological progression. It appears that initial combination therapy with MTX and multiple DMARDs or corticosteroids (oral or parenteral) results in better short-term clinical outcomes. No long-term data are available.
Results of biological DMARDs
Two trials have investigated biological agents in patients with UA. Saleem et al19 compared a 14 week course of infliximab with placebo in patients with UA who had relapsed after a single corticosteroid injection. If clinical inflammation was persistent after week 14, MTX was started. Independent safety monitors halted recruitment ‘because of poor outcomes in all subjects’ before inclusion was completed, after inclusion of 17 patients (10 randomised to infliximab, 7 to placebo). Clinical remission at 26 weeks was achieved in one patient and two patients in the placebo and infliximab groups, respectively. After 1 year, all patients in the infliximab group had progressed to RA (1987 criteria) compared with 5/7 in the placebo group, in which this occurred earlier (after a median of 14 weeks compared with 26 weeks, respectively). Data on (S)AE were not reported.
Emery et al20 compared a 6 months course of abatacept with placebo. After 1 year, respectively 12 (46%) and 16 (67%) of the abatacept and placebo groups progressed to RA (1987 criteria) (difference (95% CI) −21% (−47% to 8%)). Radiological progression (Genant-modified Sharp score) after 1 year was significantly less in the abatacept group (difference in total score −1.10 (95% CI −2.05 to −0.15)). Remission (DAS28 definition) after 1 year was achieved in nine (47%) and five (39%) patients in the abatacept and placebo groups, respectively. Numbers of reported AEs and SAEs were similar.
These trials suggest that a biological agent may slow down progression to RA in patients with UA. Early treatment with abatacept appears to suppress radiological damage progression. Long-term benefits remain uncertain.
Results of corticosteroid injections
Green et al21 performed an open-label pilot with intra-articular GC injections in all arthritic joints in 51 patients. Clinical synovitis was absent in 23 (45%) and 26 (51%) after 12 weeks 1 year, respectively.
Marzo-Ortega et al22 injected all inflamed joints with GC (early intervention (EI) group) and compared this with ‘conservative treatment’ (CT group) with non-steroidal anti-inflammatory drugs. In case of progression to polyarthritis SSZ was started. Clinical synovitis was absent in 25 (81%) and 16 (57%) patients after 52 weeks in the EI and CT groups, respectively (p=0.05), but more patients in the EI group started DMARD treatment (14 (45%) versus 4 (14%), p=0.012). The EI group reported a significantly lower mean visual analogue scale pain after 4 weeks than the CT group, but not after 12 weeks and 52 weeks. Data on (S)AE were not reported.
Machold et al23 compared a single IM injection of GC with placebo. Respectively, 32 (16%) and 33 (18%) in the GC and placebo groups achieved persistent remission without additional treatment after 1 year (p=0.68). Initiation of a DMARD and core set variables were comparable. AEs generally were mild and comparable between groups.
Verstappen et al24 compared a 3-week course of IM GC injections with placebo. When patients met ≥two of four predefined criteria (≥three swollen joints, ≥six painful joints, morning stiffness ≥45 min or erythrocyte sedimentation rate (ESR) ≥28 mm/h), they were referred for DMARD treatment. After 6 months, patients in the placebo group were more often referred for DMARD treatment than the GC group (96 (76%) vs 77 (61%), adjusted OR (95% CI) 2.11 (1.16 to 3.85), p=0.015). After 1 year, remission without DMARD use was less often achieved in the placebo group (11 (10%) vs 22 (20%), adjusted OR (95% CI) 0.42 (0.18 to 0.99), p=0.048). Sixty-seven (60%) and 54 (49%) in the placebo and GC groups were classified as RA (1987 criteria) (adjusted OR (95% CI) 1.58 (0.85 to 2.93), p=0.15). AEs were comparable between groups.
These studies indicate that a single corticosteroid injection probably has no long-term benefit. Repeated IM corticosteroid injections may postpone the need to start DMARDs but not prevent progression to RA, and in one study possibly encourage remission. No long term follow-up data exist.
Results of tight control and treat-to-target strategies
van Eijk et al12 compared TC treatment (TC group) with conventional care (CC group) in patients with early arthritis. The TC group (n=42) started with MTX monotherapy, medication was intensified in case of no remission (19 patients changed to adalimumab, 15 increased adalimumab, 11 switched to multiple DMARDs, 3 added prednisone and 1 switched to leflunomide). The CC group (n=40) used conventional DMARDs without treatment target (24, 14 and 2 patients started HCQ MTX and SSZ, respectively). No prednisone or biologicals were allowed. After 2 years, respectively 66% and 49% in the TC and CC groups were in remission (numbers and p values not published). Median SHS progression was 0 (0–1.0) and 0.25 (0–2.5) in the TC and CC groups (p=0.17). Over 2 years, no significant differences in DAS and Health Assessment Questionnaire (HAQ) levels were seen. The number of reported AEs was higher in the TC group (62 vs 35, p=0.03). The number of SAEs was comparable.
In conclusion, this trial shows no benefit to patients with UA of TC treatment over CC in terms of radiological and clinical outcomes and achieving remission.
Early versus delayed treatment
No RCTs compared early versus delayed start of treatment in patients with UA. In an open label study13 no difference in proportions remission was found between patients with UA and RA (2010 criteria) after 4 months of MTX and a tapered high dose of prednisone. But although patients with UA had a lower baseline DAS, baseline symptom duration was similar between patients with UA and RA.
In an observational study in the ESPOIR cohort, Lukas et al25 compared early versus delayed treatment, adjusting for selection bias using propensity scores. The estimated marginal mean (SE) SHS progression was 0.8 (0.37) and 1.7 (0.19) in patients who respectively started DMARD therapy within and after 3 months (p=0.03). Stratification in propensity quintiles showed that only patients with high baseline disease activity starting DMARD therapy after 3 months showed more progression than patients starting within 3 months.
Bukhari et al26 found a similar result in the NOAR cohort, also using propensity scores. Starting treatment within 6 months after symptom onset was associated with less radiological damage after 5 years than starting after 6–12 months and >12 months (OR (95% CI) 1.5 (0.9 to 2.3) vs 2.3 (1.4 to 3.9) and 2.2 (1.4 to 3.5), respectively, with untreated patients as reference (1.0)).
Wiles et al27 compared early versus delayed treatment in the NOAR cohort using propensity scores, with functional ability after 5 years as outcome. Starting treatment early (within 6 months of symptom onset) was not associated with a HAQ score ≥1.0 (OR 0.71 (0.34 to 1.44), but starting treatment after 6–12 months and >12 months was (OR (95% CI) 1.98 (0.86 to 4.54) and 2.03 (1.10 to 3.75), respectively, with untreated patients as reference (1.0)). Farragher et al15 used functional ability after 10 years as outcome and adjusted for time-dependent confounders using marginal structural models. Patients treated within 6 months after symptom onset improved more in functional ability than untreated patients, although not significantly (difference (95% CI) in change from baseline HAQ −0.24 (−0.58 to 0.09)). In patients treated after 6–12 months and >12 months functional ability improved less than in untreated patients (difference (95% CI) in change from baseline of respectively 0.12 (−0.13 to 0.37) and 0.18 (−0.06 to 0.41)). For each month that treatment was started earlier within 6 months, a significant additional benefit was found (difference (95% CI) in change from baseline HAQ −0.10 (−0.19 to −0.02) per month).
In conclusion, results from these observational cohort studies may indicate that disease outcomes improve if treatment is started within at the most 6 months after symptom onset, and starting sooner may even be better.
Discussion
This systematic literature review shows that to date, few placebo-controlled RCTs have been done to answer the question if early treatment in patients with UA is beneficial and which treatment might be the best. To compare results is difficult because of inconsistent outcome measures. Five clinical trials, two open-label studies and four observational studies suggest that starting treatment early may provide symptom relief, improve functional ability and suppress radiological progression. It may also postpone progression to classifiable RA or the need for other therapies. The strongest evidence of a potential benefit is present on early treatment with MTX, possibly in combination with other DMARDs or corticosteroids. Observational studies, which by using propensity scoring and minimal structural models try to partially compensate for indication bias, suggest that other DMARDs than MTX may be used. Data from these cohorts also suggest that starting treatment in UA may be a case of ‘the earlier the better’. The benefit of earlier treatment has been previously demonstrated for patients with RA.4 ,5 ,28 ,29 But contrary to what is recognised and recommended for patients with classifiable RA,30 ,31 one study suggests that patients with UA may not gain additional benefit from tight controlled targeted treatment.12
The ultimate goals in the treatment of UA would be to prevent progression to destructive RA or even induce permanent remission. Achieving these goals would mean that the so-called ‘window of opportunity’, in which appropriate treatment can alter the disease course, does exist. The closest evidence for the presence of the window of opportunity possibly comes from a study in 253 patients with UA24 where after a 3 week course of IM corticosteroid injections more patients achieved remission (20% vs 10%), fewer required initiation of DMARDs (61% vs 76%) and possibly fewer progressed to classifiable RA than in the placebo group (49% vs 60%). Also 6 months abatacept appears to suppress progression to RA, at least over 1 year follow-up, although no statistically significant difference was found possibly due to small numbers.20 Similarly, a 1 year course of MTX suppressed progression to RA and radiological progression, but after discontinuation of MTX the disease appeared to rerun its course.16 ,17 None of the articles included data on sustained drug-free remission.
Overdiagnosis as ‘early RA’ followed by overtreatment is a serious concern when treating patients with UA, or even patients who according to the new 2010 criteria would now be classified as RA. Patients may have another illness that may go into spontaneous remission. The solution may lay in predicting disease outcome, such as persistent arthritis or radiological progression, or response to treatment. Prediction models for disease outcome have been developed.18 ,32 However, to predict disease outcome and response to treatment in individual patients is not yet possible.
In conclusion, there are limited trials and observational studies exploring the possibility of inducing remission and/or permanently altering the disease course in patients with UA. Long-term follow-up data are mostly not available. During treatment with MTX monotherapy, combination therapy with multiple DMARDs or corticosteroids, biological agents and IM corticosteroid injections, active inflammation and ensuing radiographic damage may be suppressed. Early initiation of treatment may be better than delayed initiation, in particular if disease activity appears to be high. Thus, we should optimise strategies for early referral and early identification of patients with arthritis. In addition, any new randomised clinical trials in patients with UA should include a short-term placebo arm to investigate if early treatment can induce (drug-free) remission and a long-term follow-up period to demonstrate if early treatment can alter the disease course.
References
Footnotes
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Handling editor Tore K Kvien
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Contributors We declare that all authors included on this paper fulfil the criteria of authorship and no one who fulfils the criteria is not included as an author.
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Competing interests : None.
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Provenance and peer review Not commissioned; externally peer reviewed.