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trials with large group sizes and prolonged trial durations to detect statistically sig-nificant effects. The expense and requi-site delay in such trials has pushed much of the pharma ceutical industry to redirect efforts away from OA structural progression and towards pain palliation, which is per-ceived as hav ing greater short-term yield. Concomi tantly, the US NIH has focused most of its OA resources on observational longitudinal and epidemiological studies, leaving few resources for efforts at discovery of novel disease-modifying therapeutics.

Although it is heartening that there is consensus among our major organizations regarding the rational approach to OA care today, the fact that agreement exists does not mitigate the paucity of effective therapy for this common and increasingly preva-lent disease. The past decades have seen the failure of several promising approaches; hopefully, the next decades will bring sub-stantive advances to treat pain and protect structure in OA, and will enable patients with OA to benefit from the revolutionary advances currently enjoyed by patients with inflammatory arthritis.

Division of Rheumatology, Rush University Medical Center, 1611 West Harrison Street, Suite 510, Chicago, IL 60612, USA. jblock@rush.edu

Competing interestsJ.A.B. is Associate Editor of Osteoarthritis & Cartilage, which is owned by OARSI, and Chair of the ACR Committee on Education.

1. Hochberg, M. C. et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 64, 465–474 (2012).

2. American Academy of Orthopaedic Surgeons. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd ed. [online], http://www.aaos.org/research/guidelines/TreatmentofOsteoarthritisoftheKneeGuideline.pdf (2014).

3. McAlindon, T. E. et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 22, 363–388 (2014).

4. National Institute for Health and Care Excellence (UK). Osteoarthritis: care and management in adults (CG177) [online], http://guidance.nice.org.uk/CG177 (2014).

5. Zhang, W., Robertson, J., Jones, A. C., Dieppe, P. A. & Doherty, M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann. Rheum. Dis. 67, 1716–1723 (2008).

6. Sawitzke, A. D. et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann. Rheum. Dis. 69, 1459–1464 (2010).

7. Block, J. A. & Shakoor, N. Lower limb osteoarthritis: biomechanical alterations and implications for therapy. Curr. Opin. Rheumatol. 22, 544–550 (2010).

8. Lawrence, R. C.et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58, 26–35, (2008).

9. Weinstein, A. M. et al. Estimating the burden of total knee replacement in the United States. J. Bone Joint Surg. Am. 95, 385–392 (2013).

10. Bedson, J. & Croft, P. R. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet. Disord. 9, 116 (2008).

RHEUMATOID ARTHRITIS

Is imaging needed to define remission in rheumatoid arthritis?Mikkel Østergaard and Signe Møller-Bisgaard

New research reports that ultrasonography predicts absence of clinical flare following discontinuation of biologic therapy in patients with rheumatoid arthritis in clinical remission. Other studies also support the inclusion of ultrasonography and MRI in future remission criteria. Ongoing studies to clarify clinical and structural damage benefits of imaging-based treat-to-target strategies are awaited.Østergaard, M. & Møller-Bisgaard, S. Nat. Rev. Rheumatol. 10, 326–328 (2014); published online 22 April 2014; doi:10.1038/nrrheum.2014.63

As treatment with biologic agents is associ-ated with an increased risk of adverse events and is costly, the identification of patients in whom biologic therapy can be tapered or stopped without compromising disease control is highly relevant. Unfortunately, no techniques with sufficient sensitivity and specificity for this identification have so far been available. Potentially ultra sono-graphy or the other modern and sensitive imag ing technique, MRI, could be the solu-tion. In a recent study of 40 patients with rheuma toid arthritis (RA) in clinical remis-sion, Iwamoto et al.1 investigated whether power Doppler ultrasono graphy (PDUS) and greyscale ultrasonography (GSUS) of 40 joints could predict relapse within 6 months of discontinuation of biologic therapy (31 patients had been treated with a TNF inhibitor and 9 with the IL-6 inhibitor tocilizumab)1. Optimal cut-off points were calculated from receiver-operator charac-teristics (ROC) curve analysis and, using these selected cut-offs, both PDUS and GSUS could predict flare with a moderate sensitivity (both 50%) and a high specificity (96% and 92%, respectively).

The potential importance of ultrasono-graphy and MRI in defining and monitor-ing remission have attracted much interest in recent years, as described in detail in a 2012 review.2 Key steps in the establish ment of an evidence base for this are des cribed in the following: Brown et al. demonstrated

in 2006 that MRI and/or ultrasonographic findings of inflammation are common in patients in clinical remission,3 and in 2008 that these findings are related to subsequent progression of structural joint damage.4 Sub sequent papers confirmed that sub-clini cal inflammation detected by MRI and ultrasono graphy independently predict progression of structural joint damage5,6 and reported that ultrasono graphy find-ings can predict flare during continu ed DMARD therapy.7

These encouraging results have already been acknowledged in international recom-mendations. The 2013 EULAR recommen-dations for the use of imaging of the joints in the clinical management of RA8 state: “MRI bone oedema is a strong independ-ent predictor of subsequent radiographic progression in early RA and should be con-sidered for use as a prognostic indicator. Joint inflammation (synovitis) detected by MRI or ultrasound as well as joint damage detected by conventional radiographs, MRI or ultrasound can also be considered for the prediction of further joint damage.” Specifically related to patients in clinical remission, the recommendations add: “MRI and ultrasound can detect inflammation that predicts subsequent joint damage, even when clinical remission is present.”8

Iwamoto et  al.1 contribute to these research advances by indicating that flare or, even more importantly, absence of flare after

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Box 1 | Evidence-based incorporation of imaging into future treat-to-target goals in RA

Step 1: Establish that subclinical inflammation can be detected by MRI and/or ultrasonography ■ Document that MRI and/or ultrasonography demonstrate subclinical inflammation in patients

with RA in clinical remission

Step 2: Establish that subclinical inflammation detected by MRI or ultrasonography is clinically important ■ Document that MRI and/or ultrasonography findings of subclinical inflammation predict any

or all of: subsequent structural damage progression; clinical flares during continued therapy; and clinical flares in patients who taper or discontinue therapy

■ Document that absence of MRI and/or ultrasonography findings of subclinical inflammation predict any or all of: absence of subsequent structural damage progression; absence of clinical flares during continued therapy; and absence of clinical flares in patients who taper or discontinue therapy

Step 3: Demonstrate that subclinical MRI or ultrasonography-detected inflammation can be improved by treatment and that the use of this improves key end points ■ Document that an imaging-guided treatment strategy (involving therapeutic adjustments in

case of certain imaging findings) will improve patient outcome over and above a treatment strategy based on conventional clinical and biochemical assessments

Abbreviation: RA, rheumatoid arthritis.

discontinuation of anti-TNF therapy can be predicted by ultrasono graphy. Further studies need to confirm this finding, par-ticularly because a previous paper by Saleem et al.9 did not find ultrasono graphy to have predictive value.

If the results by Iwamoto et al.1 should be transferred into clinical practice, how would this be done? Each of the 40 joints evalu-ated was graded 0–3 for synovitis severity, and the suggested cut-off for scores pre-dictive of relapse was ≥3 for PDUS (range 0–120) and ≥14 for GSUS (range 0–120). The GSUS cut-off was fairly far from 0, and it seems likely that the clinical importance of 15 joints with subtle (grade 1) synovi-tis is not identical to that of 5 joints with maximal (grade 3) synovitis. Thus, the GSUS cut-off of exactly 14 could seem arbitrary, and its predictive value would probably not be reproducible in subsequent verification studies, which might have dif-ferent joint distributions. By contrast, the low PDUS cut-off suggests that absent or very low-scoring synovitis on PDUS of 40 joints means that a patient can be taken off biologic therapy with a high certainty that they will not experience a clinical flare, at least within the subsequent 6 months. The specificity of the PDUS cut-off in this study (96%) is very impressive. Future studies are needed to verify this finding in other settings.

Performing ultrasonography of 40 joints in all patients who are in remission is time consuming, and assessment of fewer joints would increase the feasibility for clinical practice. The widespread distribution of inflammatory findings by Iwamoto et al.1 gives no immediate solution as to how to

reduce the number of scanned joints. In the future, whole-body MRI, a technique that enables evaluation of all joints in a single examination and which has recently been introduced for use in RA,10 could be an alternative, but further validation of this technique is needed.

The available data indicate that imaging should be part of future remission criteria. It is relevant, however, to consider how com plete the evidence-base is for incor-porat ing modern imaging into future treat-to-target goals in RA (Box 1). That sub clinical inflammation detectable by MRI and/or ultrasonography exists (step 1) is, beyond any doubt, documented by several studies. The clinical importance of this subclinical inflammation is also fully or partly documented (step 2) by at least one study. Specifically, on the basis of the study by Iwamoto et al.,1 it seems possible to identify which patients will not (or at least are unlikely to) flare following dose-reduction of biologic agents, and a study by Gandjbakhch et al.6 indicates that it might be possible to identify which patients will not (or at least who are unlikely to) show radiographic progression.

By contrast, no studies have yet addressed whether subclinical inflammation detected by imaging can be improved by treatment and whether an imaging-guided treat-ment strategy (where treatment is intensi-fied in the presence of certain subclini cal ultra sonographic or MRI-detected signs of inflammation) improves key out comes over and above what is achieved by a treat-to-target therapy based on conventional clinical and biochemical examina tions (step 3). However, randomized controlled

trials addressing this question are currently ongoing in Scotland (TaSER study, using an ultrasonography-based target and clini-cal and MRI-defined primary endpoints), Norway (ARCTIC study, in which the tar get is no PDUS signal and the primary endpoint is clinical remission), Denmark (IMAGINE-RA study, in which the target is no MRI-detected bone oedema and clini-cal remission and no radiographic progres-sion are the primary endpoints) and Europe (TURA study, using a PDUS-based target and primary endpoint); see Supplementary Table 1 online for further details of these studies. These studies will contribute immensely to our knowledge on the value of applying MRI and ultra sonography in clinical practice to patients with RA in clinical remission.

In conclusion, a steeply increasing amount of data support the use of ultra-sonography and MRI in the assessment in clinical practice of patients with RA who are in clinical remission, to identify those who will show clinical flare and/or progression of structural joint damage. Ongoing studies will provide evidence concerning the value of an imaging-based treat-to-target strategy.

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spinal Diseases, Copenhagen University Hospital Glostrup, Nordre Ringvej 57, DK-2600 Glostrup, Denmark (M.O.). Department of Rheumatology, Copenhagen University Hospital Slagelse, Ingemannsvej 18, DK-4200 Slagelse, Denmark (S.M.-B.). Correspondence to: M.O. mo@dadlnet.dk

Competing interestsThe authors declare no competing interests.

1. Iwamoto, T. et al. Ultrasonographic assessment predicts relapse after discontinuation of biological agents in patients with rheumatoid arthritis in clinical remission. Arthritis Care Res. (Hoboken) http://dx.doi.org/10.1002/acr.22303.

2. Haavardsholm, E. A., Lie, E. & Lillegraven, S. Should modern imaging be part of remission criteria in rheumatoid arthritis? Best Pract. Res. Clin. Rheumatol. 26, 767–785 (2012).

3. Brown, A. K. et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum. 54, 3761–3773 (2006).

4. Brown, A. K. et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum. 58, 2958–2967 (2008).

5. Foltz, V. et al. Power Doppler ultrasound, but not low-field magnetic resonance imaging, predicts relapse and radiographic disease progression in rheumatoid arthritis patients with low levels of disease activity. Arthritis Rheum. 64, 67–76 (2012).

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6. Gandjbakhch, F. et al. Determining a magnetic resonance imaging inflammatory activity acceptable state without subsequent radiographic progression in rheumatoid arthritis: results from a followup MRI study of 254 patients in clinical remission or low disease activity. J. Rheumatol. 41, 398–406 (2014).

7. Scirè, C. A. et al. Ultrasonographic evaluation of joint involvement in early rheumatoid arthritis in

clinical remission: power Doppler signal predicts short-term relapse. Rheumatology (Oxford) 48, 1092–1097 (2009).

8. Colebatch, A. N. et al. EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis. Ann Rheum. Dis. 72, 804–814 (2013).

9. Saleem, B. et al. Patients with RA in remission on TNF blockers: when and in whom can TNF

blocker therapy be stopped? Ann. Rheum. Dis. 69, 1636–1642 (2010).

10. Axelsen, M. B. et al. Whole-body MRI assessment of disease activity and structural damage in rheumatoid arthritis: first step towards an MRI joint count. Rheumatology (Oxford) http:// dx.doi.org/10.1093/rheumatology/ket425.

Supplementary information is linked to the online version of the paper at www.nature.com/nrrheum.

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