With large enthusiasm I read the paper on the 2010 ACR/EULAR RA classification criteria,[1,2] which in the interest of our patients allow earlier diagnosis of rheumatoid arthritis (RA). I congratulate the authors
for their hard and successfull work, which I am sure will benefit our patients.
Being interested in imaging methods and the way they can assist rheumatologists in improving the care of patient...
With large enthusiasm I read the paper on the 2010 ACR/EULAR RA classification criteria,[1,2] which in the interest of our patients allow earlier diagnosis of rheumatoid arthritis (RA). I congratulate the authors
for their hard and successfull work, which I am sure will benefit our patients.
Being interested in imaging methods and the way they can assist rheumatologists in improving the care of patients with RA, I have attended several presentations and/or discussions by various authors of the manuscript, incl. Professors Aletaha and Smolen. From these presentations/discussions the roles of imaging in the new criteria were clear and unambiguous. However, the published manuscript is less explicit on some areas, and the roles of imaging may seem more limited than the authors explained orally, eventhough it seems unlikely that the criteria
have been changed. This has led to some confusion in the imaging field, which needs to be resolved.
To recapitulate, classification as definite RA is based on presence of definite clinical synovitis (swelling at clinical examination) in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score at least 6(of a possible
10) from the individual scores in 4 domains: number/site of involved joints(score range:0-5), serologic abnormality (range 0-3), elevated acute-phase response(range:0-1), and symptom-duration(range:0-1).[1,2]
It was very clear from the above-mentioned presentations/discussions (but not from the paper) that joint involvement by detection of joint inflammation(synovitis) by MRI or US counted in the scoring in the "joint involvement domain". For example, this means that a patient with 2 clinically swollen small joints, in which MRI or US confirms the 2 swollen small joints but also detects 3 additional small joints with obvious
synovitis (as assessed by MRI/US), will have a total of 5 involved joints and a resulting score of 3 in the "joint involvement domain".
It should be emphasized that the initial requirement of "presence of synovitis in at least 1 joint", which allows the patient to enter the score-based algorithm, can only be achieved by detection of swelling by clinical (not imaging) examination.
Concerning radiography, the above-mentioned presentations included an illustration describing that patients with "typical RA erosion on conventional radiographs" on top of fulfilling the 2 initial criteria
(synovitis in at least 1 joint and absence of an alternative diagnosis better explaining synovitis), sufficed for fulfilling the RA criteria. The paper does not include a such figure but states "patients with erosive
disease typical of RA with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA".
A role of MRI and US in the diagnosis of RA is supported by the fact that MRI/US are much more sensitive for detection of synovitis than clinical examination, that MRI/US can detect subclinical inflammation in patients in clinical remission,[3,4] and that such findings are predictors of subsequent radiographic erosive progression in early RA,[5-9] and of development of RA in undifferentiated arthritis.[10] However, the purpose
of this letter is not to argue for the virtues of MRI and US, but solely to make sure that the roles of imaging in th new RA criteria are made totally clear.
References
1. Aletaha D, Neogi T, Silman AJ et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69:1580-8.
2. Aletaha D, Neogi T, Silman AJ et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
3. Brown AK, Quinn MA, Karim Z 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 2006;54:3761-73.
4. Gandjbakhch F, Conaghan PG, Ejbjerg B et al. Synovitis and osteitis are very frequent in rheumatoid arthritis clinical remission: Results from an MRI study of 294 patients in clinical remission or low disease activity state. J Rheumatol 2010;(In Press).
5. Brown AK, Conaghan PG, Karim Z et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008;58:2958-67.
6. Haavardsholm EA, Boyesen P, Ostergaard M et al. Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: bone marrow oedema predicts erosive progression. Ann Rheum Dis 2008;67:794-800.
7. Hetland ML, Ejbjerg B, Horslev-Petersen K et al. MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis 2009;68:384-90.
8. Hetland ML, Stengaard-Pedersen K, Junker P et al. Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial. Ann Rheum Dis 2010;69:1789-95.
9. Boyesen P, Haavardsholm EA, Ostergaard M et al. MRI in early rheumatoid arthritis: synovitis and bone marrow oedema are independent predictors of subsequent radiographic progression. Ann Rheum Dis 2010; Online First, published on August 31, 2010 as 10.1136/ard.2009.123950.
10. Duer-Jensen A, Horslev-Petersen K, Hetland ML et al. MRI bone edema is an independent predictor of development of rheumatoid arthritis in patients with early undifferentiated arthritis. Arthritis Rheum 2010;62:S55-S56.
We thank Dr. Smolen for commenting our criticism. As Dr. Smolen correctly states we did not pay attention to the fact that the EULAR recommendations (1) are based on 5 different systematic reviews. However, we assumed that
the authors of the recommendations would attempt to reach an unambiguous position on the basis of the different reviews. Comparing the 15 recommendations in Table 1 with the treatment al...
We thank Dr. Smolen for commenting our criticism. As Dr. Smolen correctly states we did not pay attention to the fact that the EULAR recommendations (1) are based on 5 different systematic reviews. However, we assumed that
the authors of the recommendations would attempt to reach an unambiguous position on the basis of the different reviews. Comparing the 15 recommendations in Table 1 with the treatment algorithm in Figure 1 we agree that there is not full accordance between the two. This is in itself
a problem, especially as the object for the conflicting recommendations, the combination DMARD therapy, potentially could save a significant proportion of biologic treatment. Still, for the reader, the more obvious of the two conflicting recommendations is the one given in Table 1, which has the headline "Final set of 15 recommendations for the management of RA".
We are not ignoring recommendation no. 6, in which we agree. We do not object to the combination of DMARDs with glucocorticoids, but to the lack of recommendation of two or more DMARDs.
Dr. Smolen indicates that our meta-analysis (2) is less complete, because we only include one outcome measure. However, the outcome measures of RA are not mutually independent, on the contrary. If a study shows a
difference in ACR 50, it will almost invariably also show a difference in ACR 20, ACR 70, ESR, CRP, number of swollen joints, DAS28 etc.
Consequently, one measure would generally be enough to decide whether there is a difference between treatments in randomised trials. Although most rheumatologists probably may recall exceptional patient cases where inflammation and joint destruction may run separately, several studies
have shown that on the average there is a very high association between integrated measures of inflammatory variables (i.e. CRP, swollen joint count etc.) and the radiographic score. Therefore, the radiographic score
has the advantage that it not only shows the present status of the patient, but also reflects the preceding disease course including joint swelling, pain and fatigue. Furthermore, we were able to standardize the
radiographic outcome measure to the same scale, which made it possible to make comparisons across all 70 studies. This is in contrast to the Cochrane analysis by Katchamart et al (3), which include 19 combination studies of methotrexate + DMARD vs. methotrexate. They were not able to find one single common outcome variable, and therefore this analysis
consists of many small meta-analyses each investigating a separate outcome and each including very few studies with a low statistical power. In spite of this and in spite of the fact that the majority of studies included in this meta-analysis are short-term studies, almost all efficacy variables are in favour of combination treatment, many of them statistically significant. Dr. Smolen states the conclusion of the Cochrane review to be "no statistically significant advantage of the MTX combination versus
monotherapy". However, the full conclusion of the authors is as follows:
"When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy." Accordingly, the conclusion is that the increased toxicity
in the combination group outbalances the increased efficacy. In their analysis (3) the withdrawal rate due to adverse reactions in the combination group was 14% and in the methotrexate group it was 9%. In DMARD naive patients, the ACR 50 response in the combination group was 51%
(similar to biologic + methotrexate in biologic studies) and in the methotrexate group 29% (similar to methotrexate single therapy in biologic studies). This clinically significant difference was not statistically significant because only 127 patients were included in the analysis.
The problem with the many analyses of this Cochrane review is that they are of small size with no power. However one might pose the question: Does an extra withdrawal of 5% (14%-9%) outbalance an extra effect on ACR 50 of 22% (51%-29%)? This is a matter of opinion, but if we had made this meta-analysis we would have concluded that the fact that 15 % of the patients had to leave the treatment because of side effects should not stop the
remaining 85% of patients from getting the benefit from the better combination treatment. We think that the weak signal in this underpowered meta-analysis is in accordance with the results of our meta-analysis of studies of DMARD combinations, which has a very significant power, including 1384 patients (2).
It is correct that we mislabelled one of our studies in the online version of our meta-analysis. We did, however, discover this mistake, and it has been changed in the final published version (2). It is also correct that 8 of 12 DMARD combination studies are not statistically significant.
However, 11 of 12 studies have a trend towards a reducing effect on radiographic progression. Furthermore, these studies are in general much smaller than studies of biologic drugs, which may reflect that DMARDs are less profitable than biologic agents. The idea of a meta-analysis is to increase the power of the conclusion by integrating many small studies into one large study. Doing this we find that the average effect of DMARD combination studies is highly significant (p = 0.001) and almost as good as the one of studies combining a biologic agent with methotrexate.
We still think that the authors of the EULAR guidelines should consider a quick revision of the guidelines and give combination DMARD treatment a definite place in the treatment algorithm.
References
(1) Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid
arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69(6): 964-975.
(2) Graudal N, Jurgens G. Similar effects of disease modifying anti rheumatic drugs, glucocorticoids and biologics on radiographic progression in rheumatoid
arthritis: meta-analysis of 70 randomised placebo or drug controlled studies including 112 comparisons. Arthritis Rheum 2010;62:2852-2863.
(3) Katchamart W, Trudeau J, Phumethum V, et al. Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2010;4:CD008495.
The article describing '2010 Rheumatoid Arthritis Classification Criteria' is very informative and contains much useful practical guidance. However there are factual errors regarding the measurement of ACPA/CCP
which ought to be corrected.
With a high specificity anti CCP is very useful for early diagnosis of rheumatoid arthritis. [1, 2, 3] While the definition of positivity is understandably va...
The article describing '2010 Rheumatoid Arthritis Classification Criteria' is very informative and contains much useful practical guidance. However there are factual errors regarding the measurement of ACPA/CCP
which ought to be corrected.
With a high specificity anti CCP is very useful for early diagnosis of rheumatoid arthritis. [1, 2, 3] While the definition of positivity is understandably vague given the lack of correlation and standardization of
assays, the discussion of the reporting of CCP in 'IU' is an error which will lead clinicians to believe that there is meaningful standardisation of testing.
Although Rheumatoid factor (RF) assay standardization is still suboptimal, it can be reported in 'IU' when using assays such as nephelometry, turbidimetry, EIA (enzyme linked immunoassay) since IRP is
available to calibrate against (WHO, NIBSC code- W1066). [4, 5]
In contrast, at least (11) assays are available for detecting anti CCP in the UK yet currently there is no current IRP for anti-CCP nor is there consistency in reporting of units. Stating that there are 'IU' for anti
CCP measurement can unintentionally lead to the assumption that one CCP result is equivalent, and comparable with another. How could a clinician be assured that what is "high-titre" in one assay is not "low-titre" in another?
Some manufacturers report in arbitrary U/ml. [6, 7, 8, 9, 10]. Some calibrations are heterologous and made against an immunoglobulin standard lyophilized human immunoglobulin G, A, and M (WHO, NIBSC code-67/086) [4,
5]. The units are not truly anti-CCP IU; they are essentially still arbitrary units and do not prove equivalence between assays or imply standardisation.
Guidelines often require clinical management decisions on the basis of diagnostic tests. This article has rightly pointed out that pathogenetic and prognostic perspective of RA is found to be different depending upon the positivity of ACPA. Therefore input from experts in
laboratory testing is essential to ensure the recommendations are robust and achievable in real-life testing and in the knowledge of the true performance characteristics of a "test". [4] Since anti-CCP is an
important assay, future development of IRP is required to enable standardised decision making on the basis of test equivalence across centres and methods. Furthermore, if such tests are to be used, there should be a recommendation for appropriate quality assurance such as participation in 'External Quality Assurance' programmes to ensure
equivalence of testing across geographical networks and time.
References
1. Bas S, Perneger T V, Seitz M, et al. Diagnostic tests for rheumatoid arthritis: Comparison of anti-cyclic
citrullinated peptide antibodies, anti-keratin antibodies and IgM rheumatoid factors. Rheumatology 2002;41:809-814.
2. Forslind K, Ahlm?n M, Eberhardt K, et al. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis
2004;63:1090-1095.
3. Zendman A J W, Venrooij W J van, Pruijn G J M. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology. 2006; 45:20-25.
In the paper "EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis" [1] it is stated that microscopic polyangiitis (MPA) was described in 1948 [2]. In fact, the first description of MPA I know of is considerably older than
that, dating back to 1923 [3].
References
[1] Basu N, Watts R, Bajema I et al. EULAR points to consi...
In the paper "EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis" [1] it is stated that microscopic polyangiitis (MPA) was described in 1948 [2]. In fact, the first description of MPA I know of is considerably older than
that, dating back to 1923 [3].
References
[1] Basu N, Watts R, Bajema I et al. EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis 2010;69:1744-1750.
[2] Davson J, Ball J, Platt R. The kidney in periarteritis nodosa. Q J Med 1948;17:175-202.
[3] Wohlwill F. Ueber die nur mikroskopisch erkennbare Form der Periarteritis nodosa [About the purely microscopic form of polyarteritis nodosa]. Virchows Arch Pathol Anat Physiol 1923;246:377-411.
We read with interest the above publication which we found to be very informative.
The article presents the results of a systemic literature review of patients with established rheumatoid arthritis (RA) (>2 years disease duration) treated with stable
and effective disease modifying anti-rheumatic drug (DMARD) therapy, with a metaanalysis to determine the effect of therapy withdrawal...
We read with interest the above publication which we found to be very informative.
The article presents the results of a systemic literature review of patients with established rheumatoid arthritis (RA) (>2 years disease duration) treated with stable
and effective disease modifying anti-rheumatic drug (DMARD) therapy, with a metaanalysis to determine the effect of therapy withdrawal vs. continuation on disease flare. We note that the authors mention 'withdrawing biological drugs
after patients have achieved sustained remission is a burning question......
Unfortunately there is a lack of primary research in this area, and as a consequence we were unable to address the question in the current systematic review. It is an area in which more primary research is needed.'
We would, however, like to bring to the attention of the readers data published by ourselves in 2004 [1] and in last month's ARD [2], and by Brocq et al [3] and Tanaka et al [4].
In 2004 Buch et al published long-term data from patients completing the ATTRACT study [5] in our unit. In patients with established RA on methotrexate, 100% (17/17)
flared after infliximab therapy was stopped after 2 years of therapy [1].
Our more recent data, in patients with both early and established disease (median disease duration of the established group was 10 years), demonstrated high (85%, 17
/20) flare rates in patients with established RA when tumour necrosis factor (TNF)-inhibitor therapy was stopped despite continuation of methotrexate [2].
Prior to stopping TNF inhibitor therapy, there were no differences in neither DAS28 scores nor duration of remission; but HAQ and RAQoL scores were lower and
patients had shorter disease duration in those who maintained remission. We also observed that sustained remission was associated with lower inflammation-related T cell, higher naïve T cell, and higher CD62L+ Treg frequencies when compared to patients that flared [2].
Our flare rates post discontinuation of TNF inhibitor therapy have been confirmed by Brocq et al [3]. Patients with an average duration of RA of 11 years were withdrawn
from TNF inhibitor therapy after being in DAS28-defined remission for at least 6 months. Seventy-five percent (15/20) of patients flared 12 months after the withdrawal of TNF inhibitor therapy.
A Japanese study in which infliximab was discontinued in patients who were in sustained low disease activity (>6 months), 57% of the patients had lared 1 year after
stopping therapy [4]. This better outcome may be due to the genetically different population, lower DAS28 requirement to receive infliximab and different methotrexate dosing regimes.
We agree that more research is required but believe that there are already some useful data available for rheumatologists who may be considering withdrawing or
stopping TNF inhibitor therapy. Cautious therapy reduction maybe considered [6] in patients with short disease duration and low levels of functional impairment.
References
[1] Buch MH, Marzo-Ortega H, Bingham SJ, et al. Long-term treatment of rheumatoid arthritis with tumour necrosis factor alpha blockade: outcome of ceasing and restarting biologicals. Rheumatology (Oxford) 2004;43(2):243-4.
[2] Saleem B, Keen H, Goeb V et al. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 2010;69(9):1636-42.
[3] Brocq O, Millasseau E, Albert C, et al. Effect of discontinuing TNF-alpha antagonist therapy in patients with remission of rheumatoid arthritis. Joint Bone Spine
2009 Apr 9.
[4] Tanaka Y, Takeuchi T, Mimori T, et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR
(remission induction by Remicade in RA) study. Ann Rheum Dis 2009;69(7):1286-91.
[5] Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis
patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354(9194):1932-9.
Sawitzke et al (1) reported on the results from the GAIT study assessing the long term effects of 2-year treatment on knee osteoarthritis (OA) symptoms. The findings indicate that the effects of glucosamine hydrochloride (GHCl), chondroitin sulfate (CS), and celecoxib treatment were not better than placebo, although safe and well tolerated.
The study results are not surprising in view of the original G...
Sawitzke et al (1) reported on the results from the GAIT study assessing the long term effects of 2-year treatment on knee osteoarthritis (OA) symptoms. The findings indicate that the effects of glucosamine hydrochloride (GHCl), chondroitin sulfate (CS), and celecoxib treatment were not better than placebo, although safe and well tolerated.
The study results are not surprising in view of the original GAIT study report (2), which assessed the results from the first 6 months of the study. From the latter report a number of issues have been raised, including the unusually high level of responders in the placebo group
(60.1%). These issues have prompted many experts in the field to express concern about the validity of the study. The fact that patients were entitled to receive rescue analgesics (acetaminophen) and a large number of them had low levels of pain (symptoms) at baseline may explain why
better results were found with the combined treatment (CS + GHCl) only in patients with moderate-to-severe pain.
The current report concerns the subgroup of patients who were enrolled in the structural study (3). This study was found to be underpowered with an unusually high drop-out rate of over 50% in some treatment groups and very low pain levels at baseline (normalized WOMAC score less than or equal to 15). Under these circumstances, in addition to the limitations imposed by the original cohort, it is hard to believe that any definitive conclusion could be arrived at from these findings, as acknowledged by the investigators. Indeed, these results are in contrast to a number of
previous reports showing long term efficacy of glucosamine (4; 5) and CS (6; 7) in the treatment of knee OA pain and symptoms. Furthermore, performing intent to treat (ITT) analysis on knee OA symptoms after 2 years combined with such high drop-out rate may further dilute the potential beneficial results of active treatment over placebo. There is the distinct possibility that an unsatisfied patient may prematurely leave the study. In this instance, the ITT process of adjudication would consider such patient's treatment as a failure at 2 years of follow-up while long term administration of such products may prove to be otherwise beneficial. An according to protocol (ATP) analysis would always be performed as well to yield a broader and clearer picture of the long term efficacy of slow acting agents.
The combination of all the above factors would pose a significant threat to the reliability of data from any clinical trial. The discrepancies between the results of different DMOAD trials exploring the effect of treatment on disease symptoms and structure are a concern at this time.
Among the possible explanations, certainly the lack of uniformity between study protocols creates multiple biases. There are a number of useful recommendations to avoid this. Better homogeneity of inclusion and exclusion criteria would define more precisely the patient population
selected. The number of patients included in a trial should be carefully established to allow for sufficient power to ensure the validity of statistical analysis and for the stratification of patients, if needed.
Only patients with a clinically significant pain level (moderate-severe) should be randomized. Patient selection and management should be optimized to decrease the drop-out rate and concomitant treatment should be taken into account, especially rescue medication. This is not the first time that such advice is offered (8) and, unfortunately, is probably not the last.
In summary, the reliability of long term OA trials testing drugs and agents needs to be improved. A better standardization of study protocols would be a first step in the right direction.
References
1. Sawitzke AD, Shi H, Finco MF, 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 2010;69:1459-64.
2. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808.
3. Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum 2008;58:3183-91.
4. Pavelka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee
osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113-23.
5. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357:251-256.
6. Kahan A, Uebelhart D, De Vathaire F, et al. Long-term effects of chondroitins 4 and 6 sulfate on knee osteoarthritis: The study on osteoarthritis progression prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2009;60:524-533.
7. Uebelhart D, Malaise M, Marcolongo R, DeVathaire F, Piperno M, Mailleux E, Fioravanti A, Matoso L, Vignon E: Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage
2004;12:269-76.
8. Brandt KD, Mazzuca SA. Lessons learned from nine clinical trials of disease-modifying osteoarthritis drugs. Arthritis Rheum 2005;52:3349-59.
Gorter and collagues (1) cover elegantly the literature on the
efficacy of systemic glucocorticoids (GCs) in rheumatoid arthritis (RA).
Nevertheless, we would like to draw attention to an error concerning the
results of the FIN-RACo Trial (2). The authors are correct when presenting
the treatment strategies used in the FIN-RACo Trial and stating the
implausibility of mere systemic GCs explaining the...
Gorter and collagues (1) cover elegantly the literature on the
efficacy of systemic glucocorticoids (GCs) in rheumatoid arthritis (RA).
Nevertheless, we would like to draw attention to an error concerning the
results of the FIN-RACo Trial (2). The authors are correct when presenting
the treatment strategies used in the FIN-RACo Trial and stating the
implausibility of mere systemic GCs explaining the difference between the
groups. They argue, however, incorrectly that the combination DMARD
therapy group outperformed the single DMARD therapy group with respect to
clinical parameters only at one year, but that the benefits disappeared
thereafter. In fact, the primary FIN-RACo study continued for 2 years and
at the end of that follow up the combination DMARD group had higher rates
of remissions and ACR 50 % clinical improvements, and less radiographic
progression than the single DMARD group (2). After that, with liberal,
remission targeted treatments in both groups, the differences in clinical
outcomes were not statistically significant at 5 years, but the radiologic
progression was still slower in the original combination DMARD group (3).
At 11 years, the patients of the original combination DMARD group were
more often in remission (4) and had less radiographic progression (5) than
the patients of the original single DMARD group. As both groups had well
preserved functional ability, low disease activity, and only slight
radiographic progression even after 11 years of RA, we think that the FIN-
RACo study supports the contemporary remission targeted treatment
strategy, with GCs used according to the treating physician's
consideration.
References
1. Gorter SL, Bijlsma JW, Cutolo M, et al. Current evidence for the
management of rheumatoid arthritis with glucocorticoids: a systematic
literature review informing the EULAR recommendations for the management
of rheumatoid arthritis. Ann Rheum Dis 2010;69:1010-4.
2. Mottonen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of
combination therapy with single-drug therapy in early rheumatoid
arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999;353:1568-
73.
3. Korpela M, Laasonen L, Hannonen P, et al. Retardation of joint
damage in patients with early rheumatoid arthritis by initial aggressive
treatment with disease-modifying antirheumatic drugs: five-year experience
from the FIN-RACo study. Arthritis Rheum 2004;50:2072-81.
4. Rantalaiho V, Korpela M, Hannonen P, et al. The good initial
response to therapy with a combination of traditional disease-modifying
antirheumatic drugs is sustained over time: The eleven-year results of the
Finnish rheumatoid arthritis combination therapy trial. Arthritis Rheum
2009;60:1222-31.
5. Rantalaiho V, Korpela M, Laasonen L, et al. Early combination
disease-modifying antirheumatic drug therapy and tight disease control
improve long-term radiologic outcome in patients with early rheumatoid
arthritis: the 11-year results of the Finnish Rheumatoid Arthritis
Combination Therapy trial. Arthritis Res Ther 2010;12:R122.
When writing their comment on the recent EULAR recommendations for
the management of RA (1), Drs. Graudal and Jurgens must have overlooked
several important aspects related to these recommendations. First, the set
of recommendations was based on five separate systematic literature
reviews (SLRs) and, indeed, items 5, 7 and 8 quoted by them are largely
based on two of these 5 SLRs (2;3) rather than,...
When writing their comment on the recent EULAR recommendations for
the management of RA (1), Drs. Graudal and Jurgens must have overlooked
several important aspects related to these recommendations. First, the set
of recommendations was based on five separate systematic literature
reviews (SLRs) and, indeed, items 5, 7 and 8 quoted by them are largely
based on two of these 5 SLRs (2;3) rather than, as they suggest, on a past
review article (4). Second, the recommendations were not the work of a few
individuals, but were the result of consensus finding by a large task
force that included authors of studies on combination therapy, and all had
ample opportunity to review the SLRs and discuss the text of individual
recommendations. Third, within the task force, the agreement with these
points was high.
Fourth, combination of synthetic DMARDs is still proposed as an
option (see also the Figure presenting the algorithm on the
recommendations), although it is not regarded as more effective than
monotherapy based on the SLRs performed. Finally, they disregard the fact
that recommendation number 6 clearly addresses the superiority of
combining synthetic DMARDs with glucocorticoids (GC), while stating that
there is insufficient evidence for a superiority of starting GC with
combinations of synthetic DMARDs versus starting GC with DMARD
monotherapy.
The authors of the letter relate their critique to their own SLR in
which they presented an indirect comparison of the effects of DMARD
monotherapy, DMARDs plus GC and combinations of DMARDs on radiographic
progression (5). Aside from methodological concerns regarding this paper
and from the fact that our SLRs looked at all aspects of response rather
than just radiographic progression, their results actually fully confirm
our conclusions - they just interpret their data differently. In their
paper, the vast majority of the studies on combinations of synthetic
DMARDs (8 of 12) did not show superiority of the combination. Moreover,
of the remaining 4 studies, one is mislabelled and examined cyclosporine A
plus methotrexate (MTX) vs cyclosporine A monotherapy (rather than, as
they stated, MTX monotherapy) and thus lacked MTX monotherapy as
comparator, and another one employed MTX at a dose of 11mg/week and thus
at about half of the usually most effective dose (6) that we likewise have
recommended. Also regarding recommendation 6 we feel endorsed by their
publication, since the majority of the studies on GC plus synthetic DMARDs
versus synthetic DMARDs alone which they had assessed (7 of 11) showed
superiority of this particular combination, pointing towards the
importance of GC in combination regimens.
Last but not least, a recent Cochrane analysis compared MTX
monotherapy with MTX combination therapy with non-biologic DMARDs and
concluded that there was "no statistically significant advantage of the
MTX combination versus monotherapy" (7), fully in line with our SLRs and
recommendations1-3 and opposed to Graudal's and Jurgens' contention.
Thus, we do not agree with Graudal's and Jurgens' suspicion of a flaw
in the EULAR recommendations - on the many accounts detailed above.
Nevertheless, this does not preclude that combinations of certain
synthetic DMARDs may, indeed, be superior to DMARD monotherapy - it is
just that the currently available data are too meagre to support such a
conclusion and, therefore, addressing this question with the proper
controls is an important part of the research agenda we have brought
forward.
Reference List
(1) Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux
-Viala C et al. EULAR recommendations for the management of rheumatoid
arthritis with synthetic and biological disease-modifying antirheumatic
drugs. Ann Rheum Dis 2010; 69(6):964-975.
(2) Gaujoux-Viala C, Smolen JS, Landewe R, Dougados M, Kvien TK,
Mola EM et al. Current evidence for the management of rheumatoid arthritis
with synthetic disease-modifying antirheumatic drugs: a systematic
literature review informing the EULAR recommendations for the management
of rheumatoid arthritis. Ann Rheum Dis 2010; 69(6):1004-1009.
(3) Gorter SL, Bijlsma JW, Cutolo M, Gomez-Reino J, Kouloumas M,
Smolen JS et al. Current evidence for the management of rheumatoid
arthritis with glucocorticoids: a systematic literature review informing
the EULAR recommendations for the management of rheumatoid arthritis. Ann
Rheum Dis 2010; 69(6):1010-1014.
(4) Smolen JS, Aletaha D, Keystone E. Superior efficacy of
combination therapy for rheumatoid arthritis. Fact or Fiction? Arthritis
Rheum 2005; 52:2975-2983.
(5) Graudal N, Jurgens G. Similar effects of disease modifying anti
rheumatic drugs, glucocorticoids and biologics on radiographic progression
in rheumatoid arthritis: meta-analysis of 70 randomised placebo or drug
controlled studies including 112 comparisons. Arthritis Rheum 2010.
(6) Visser K, van der Heijde D. Optimal dosage and route of
administration of methotrexate in rheumatoid arthritis: a systematic
review of the literature. Ann Rheum Dis 2009; 68(7):1094-1099.
(7) Katchamart W, Trudeau J, Phumethum V, Bombardier C. Methotrexate
monotherapy versus methotrexate combination therapy with non-biologic
disease modifying anti-rheumatic drugs for rheumatoid arthritis. Cochrane
Database Syst Rev 2010; 4:CD008495.
We thank dr Bannwarth for his comments, indicating that dividing
prednison treatment over the day might be as effective as using a modified
release preparation. This has not been evaluated in a clinical study, so
there is no evidence to support or refute this suggestion. However, the
discussed modified release preparation is especially developed to target
the nadir in the cortisol rhythm, which is quite different from div...
We thank dr Bannwarth for his comments, indicating that dividing
prednison treatment over the day might be as effective as using a modified
release preparation. This has not been evaluated in a clinical study, so
there is no evidence to support or refute this suggestion. However, the
discussed modified release preparation is especially developed to target
the nadir in the cortisol rhythm, which is quite different from divided
doses of glucocorticoids during the day.
Johannes WJ Bijlsma
Johannes WG Jacobs
Thank you for your letter, and the possibility to reply. We fully appreciate the favorable HAQ outcomes of the intensive strategy arm in the TICORA study [1]. However, based on the systematic literature search for the Treat to Target Initiative, the impact of strategic
treatment on functional outcome was controversial: of the four trials that assessed functional outcome[1-4], three [2-4] stated no ben...
Thank you for your letter, and the possibility to reply. We fully appreciate the favorable HAQ outcomes of the intensive strategy arm in the TICORA study [1]. However, based on the systematic literature search for the Treat to Target Initiative, the impact of strategic
treatment on functional outcome was controversial: of the four trials that assessed functional outcome[1-4], three [2-4] stated no benefit of a targeted treatment approach, including the only study in which function was the primary outcome [4]. For these reasons, the results were interpreted by the T2T committee to be insufficient to claim functional benefits of a strategic treat-to-target approach, although we agree that the TICORA study indicates that the last word on this might not yet be spoken.
References
[1]Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial Lancet 2004;364:263-9.
[2]Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2007;66:1443-9.
[3] Fransen J, Bernelot Moens H, Speyer I, et al. Effectiveness of systematic monitoring of rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised control trial. Ann Rheum Dis 2005;64:1294-8.
[4] Symmons D, Tricker K, Roberts C, et al. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis. Health Technol. Assess 2005; 9:iii-iv, ix-x, 1-78.
Dear Editor,
With large enthusiasm I read the paper on the 2010 ACR/EULAR RA classification criteria,[1,2] which in the interest of our patients allow earlier diagnosis of rheumatoid arthritis (RA). I congratulate the authors for their hard and successfull work, which I am sure will benefit our patients.
Being interested in imaging methods and the way they can assist rheumatologists in improving the care of patient...
Dear Editor,
We thank Dr. Smolen for commenting our criticism. As Dr. Smolen correctly states we did not pay attention to the fact that the EULAR recommendations (1) are based on 5 different systematic reviews. However, we assumed that the authors of the recommendations would attempt to reach an unambiguous position on the basis of the different reviews. Comparing the 15 recommendations in Table 1 with the treatment al...
Dear Sir
The article describing '2010 Rheumatoid Arthritis Classification Criteria' is very informative and contains much useful practical guidance. However there are factual errors regarding the measurement of ACPA/CCP which ought to be corrected.
With a high specificity anti CCP is very useful for early diagnosis of rheumatoid arthritis. [1, 2, 3] While the definition of positivity is understandably va...
Dear Editor,
In the paper "EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis" [1] it is stated that microscopic polyangiitis (MPA) was described in 1948 [2]. In fact, the first description of MPA I know of is considerably older than that, dating back to 1923 [3].
References
[1] Basu N, Watts R, Bajema I et al. EULAR points to consi...
Dear Editor,
We read with interest the above publication which we found to be very informative.
The article presents the results of a systemic literature review of patients with established rheumatoid arthritis (RA) (>2 years disease duration) treated with stable and effective disease modifying anti-rheumatic drug (DMARD) therapy, with a metaanalysis to determine the effect of therapy withdrawal...
Dear Editor,
Sawitzke et al (1) reported on the results from the GAIT study assessing the long term effects of 2-year treatment on knee osteoarthritis (OA) symptoms. The findings indicate that the effects of glucosamine hydrochloride (GHCl), chondroitin sulfate (CS), and celecoxib treatment were not better than placebo, although safe and well tolerated.
The study results are not surprising in view of the original G...
Dear Editor,
Gorter and collagues (1) cover elegantly the literature on the efficacy of systemic glucocorticoids (GCs) in rheumatoid arthritis (RA). Nevertheless, we would like to draw attention to an error concerning the results of the FIN-RACo Trial (2). The authors are correct when presenting the treatment strategies used in the FIN-RACo Trial and stating the implausibility of mere systemic GCs explaining the...
Dear Editor,
When writing their comment on the recent EULAR recommendations for the management of RA (1), Drs. Graudal and Jurgens must have overlooked several important aspects related to these recommendations. First, the set of recommendations was based on five separate systematic literature reviews (SLRs) and, indeed, items 5, 7 and 8 quoted by them are largely based on two of these 5 SLRs (2;3) rather than,...
We thank dr Bannwarth for his comments, indicating that dividing prednison treatment over the day might be as effective as using a modified release preparation. This has not been evaluated in a clinical study, so there is no evidence to support or refute this suggestion. However, the discussed modified release preparation is especially developed to target the nadir in the cortisol rhythm, which is quite different from div...
Dear Editor,
Thank you for your letter, and the possibility to reply. We fully appreciate the favorable HAQ outcomes of the intensive strategy arm in the TICORA study [1].
However, based on the systematic literature search for the Treat to Target Initiative, the impact of strategic treatment on functional outcome was controversial: of the four trials that assessed functional outcome[1-4], three [2-4] stated no ben...
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