Dear Editor,

“A finger in the wound” is put by Condon et al. in their very interesting paper treating severe lupus nephritis with rituximab and mycophenolate, additionally to i.v. methyl-prednisolone, but not long-term oral steroids, achieving a good clinical response in most patients. 1

Rheumatologists and nephrologists have the notion that glucocorticoids are the cornerstone for the treatment of autoimmune diseases, particularly lupus nephritis, where steroids are considered the base of the therapeutic pyramid. Recently, and according to the absence of controlled studies and no agreement regarding the best dosage of steroids to achieve clinical and histological remission, this old accepted paradigm could be not further accepted.2,3

Several years ago, our group reported an open trail study including patients with refractory lupus nephritis with not use steroids (6 out of 22) and in most of the others the doses of glucocorticoids were not increased, showing most of patients an adequate clinical and immunological response to variable-low doses of rituximab.4 These results are not limited to lupus nephritis, reaching adequate responses without conventional doses of steroids in haematological, neurological and other lupus manifestations, as well as in different connective tissue diseases (inflammatory immune myositis, primary vasculitis). In addition, this type of therapeutic response was also observed in patients that had been receiving immunosuppressive therapy and presented a relapse.

Therefore, our data further support the main conclusion of the study of Condon et al. stating that oral steroids can be avoided without affecting the effectiveness of immunosuppressive therapy in lupus nephritis and other autoimmune inflammatory conditions. In addition, it is expected that those patients not receiving long-term oral steroids show a diminished frequency of osteoporosis, cataracts and ischemic bone necrosis. The possibility to include other therapeutic arms with variable doses of rituximab could be interesting, moreover because B cell depletion can be induced with low doses, as we emphasized previously. 4,5

References

1. Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013;0:1–7. doi: 10.1136/annrheumdis-2012-202844

2. Fischer-Betz R, Chehab G, Sander O, et al. Renal outcome in patients with lupus nephritis using a steroid-free regimen of monthly intravenous cyclophosphamide: a prospective observational study. J Rheumatol. 2012; 39: 2111–7.

3. Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. Cochrane Database Syst Rev. 2012; 12, http://dx.doi.org/10.1002/14651858. CD002922.pub3.

4. Vigna-Perez M, Hernández-Castro B, Paredes-Saharopulos O, et al. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther. 2006; 8(3): R83. Published online 2006 May 5. doi: 10.1186/ar1954 PMCID: PMC1526618

5. Abud-Mendoza C, Moreno-Valdés R, Cuevas-Orta E, Borjas A, et al. Treating severe systemic lupus erythematosus with rituximab. An open study. Reumatol Clin. 2009;5(4):147-52.

Conflict of Interest:

None declared

Dear editor,

With interest we read the article of Sciré et al.,(1) evaluating the association between remission and mortality in patients with inflammatory polyarthritis (IP). This study shows that patients achieving remission early in the disease course, have an improved survival rate compared to patients never achieving remission. Based on this observation the authors conclude that achieving remission early in the disease influences the long -term outcome. The question arises which processes underlie their observation. Rheumatoid Arthritis (RA) has been associated with an increased mortality risk, which has been attributed to the effects of long -term inflammation.(2) We hypothesized that the observation in which patients with remission have an improved survival rate, might actually be driven by the association between prolonged inflammation and increased mortality risk. We addressed this hypothesis by taking advantage of long-term outcomes of 556 patients with early undifferentiated arthritis (UA) or RA that were included in the Leiden EAC between 1993-1998.(3) Treatment in this era was delayed and DMARDs were mild. We previously observed that patients included in this era had an increased mortality rate compared to the general Dutch population(4); an effect which was not present in patients that were diagnosed more recently and treated more aggressively.(4)
Presently, we evaluated the remission status in relation to mortality. In our study remission was defined as the persistent absence of synovitis for at least one year after cessation of contingent DMARD-therapy. This is the most stringent definition of remission and differs of the definitions used by Sciré et al., which were based on the number of tender and swollen joints at a point in time. Presence of DMARD-free sustained remission was assessed within 3 years after inclusion (similar to Sciré et al.) and also at any point during follow-up (median 15 years, IQR 13.2-17.1). Mortality data on patients were tracked nationally using the civic registries (Gemeentelijke Basis Administratie). First, mortality rates were compared between patients with versus patients without remission, similar as performed by Sciré et al. Secondly, we compared the mortality rates of both groups with the mortality rates of the general Dutch population. Kaplan Meier-curves were constructed. Cox proportional hazard regression models for multivariable comparisons were made; all analyses were adjusted for age and sex. Subsequent adjustments were made also for rheumatoid factor and smoking (ever versus never). Patients were censored at date of death or 1st May 2012 whichever came first. Standardized mortality ratios (SMR) were calculated using the general Dutch population matched on age, sex and inclusion year (Statistics Netherlands). Out of 556 patients, 162 (29%) patients died during the total follow-up of 7,682 person years. The mean age was 52.6?17.2, 60% was female. DMARD-free sustained remission was achieved in 124 (22%) patients within 3 years after inclusion and in 182 (33%) patients during the total follow-up.
Patients that achieved remission within 3 years had a reduced mortality compared to patients without remission (HR 0.49 95%CI 0.32-0.75), also after additional adjustments for rheumatoid factor and smoking (HR 0.60 95%CI 0.39-0.93). Likewise, patient that achieved remission at any point during follow-up had a lower mortality risk (HR 0.41 95%CI 0.28-0.60 and HR 0.50 95%CI 0.33-0.74, respectively)
Next we questioned whether patients with remission had a decreased mortality rate compared to the general Dutch population and/or whether patients without remission had an increased mortality rate.

We therefore compared the mortality rates of both patients groups to the mortality rates of matched controls from the general Dutch population. Patients who did not achieve remission during three years of disease or during the total follow-up duration had an significantly increased mortality rate (SMR 1.49 95% CI 1.26-1.76 and 1.66 95%CI 1.40-1.98 respectively). Patients that achieved remission within the first three years or the total follow-up duration did not have an increased mortality (SMR 0.70 95% CI 0.47-1.02 and SMR 0.66 0.47-0.92 respectively).

In conclusion, we studied the relation between DMARD-free sustained remission and mortality. Similar as Sciré et al. we observed that patients that achieve remission have an improved survival compared to patients without remission. Furthermore, when using the general population as a reference, we observed that patients with persistent arthritis had 49-66% increased mortality risk. This is in line with previous observations , in these patients and in other studies, which show that rheumatoid arthritis is associated with a decreased survival.(1;4) This increased mortality risk was no longer present in patients that achieved DMARD-free sustained remission, indicating that the survival probability returns to normal in patients that are cured from RA. In our view the slightly decreased SMR in these patients can be explained by a healthy inclusion bias or by good medical care while being under specialist's control.(4)

References

(1) Sciré CA, Lunt M, Marshall T, et al. Early remission is associated with improved survival in patients with inflammatory polyarthritis: results from the Norfolk Arthritis Register. Ann Rheum Dis 2013 Jun 7;Epub ahead of print doi:10.1136/annrheumdis-2013-203339 .

(2) Sokka T, Abelson B, Pincus T. Mortality in rheumatoid arthritis: 2008 update. Clin Exp Rheumatol 2008;26(5 Suppl 51):S35-S61.

(3) de Rooy DP, van der Linden MP, Knevel R, et al. Predicting arthritis outcomes--what can be learned from the Leiden Early Arthritis Clinic? Rheumatology (Oxford) 2011;50(1):93-100.

(4) van Nies JA, de Jong Z., van der Helm-van Mil AH, et al. Improved treatment strategies reduce the increased mortality risk in early RA patients. Rheumatology (Oxford) 2010;49(11):2210-6.

Conflict of Interest:

None declared

Dear Editor,

In an article published in Annals of the Rheumatic Diseases, Chowalloor et al. suggested, based on a literature review, that ultrasonography (US) is a promising tool which could be used in the diagnosis and management of gout [1]. In this letter, we wish to add further data to the Chowalloor et al. conclusion. We have performed a meta-analysis (up to July 2012) to investigate the frequency of ultrasonographic signs, i.e. joint effusion, synovitis, bone erosion, tophi and double contour (DC), in gout and asymptomatic hyperuricaemia compared with controls.
We searched MEDLINE to identify all reports of interest published prior to July 2012 using the following search terms: (“echography” OR “sonography” OR “ultrasonography” OR “US”AND (“gout” OR “urate” OR “uric acid”. We retrieved a total of 195 articles. In addition, we searched for congress abstracts from the annual scientific meetings held by the French Society for Rheumatology, European League Against Rheumatism and American College of Rheumatology between 2008 and 2012 using the terms “echography” AND “gout”. Comprehensive Meta-analysis (version 2, BioStat Corporation) was used to conduct the meta-analytical statistical analysis [2]. Heterogeneity in the study results was evaluated by examining forest plots, confidence intervals and formal tests for homogeneity based on the I² statistics. Random effects meta-analyses were conducted when data could be pooled.
After reading the title, abstract and full text of all articles, we retained eight, along with four abstracts, involving a total of 446 patients with gout, 102 with asymptomatic hyperuricaemia and 249 controls. The prevalence of ultrasonographic signs in patients with gout is summarized in Table 1. In patients with asymptomatic hyperuricaemia and controls, data were only available and analyzed for a DC sign that was reported in one healthy control. Pineda found this sign in 42 joints (42/200, 21%) in asymptomatic hyperuricaemia and Howard in just 8.8% of joints (6/68) [3,4].
Our study results provide information that reinforces the conclusion of Chowalloor et al., who suggested that ultrasonography is useful in the diagnosis of gout.
However, not all sonographic signs have the same importance in this diagnosis. Joint effusion and synovitis are not very specific whereas a DC sign or tophus, especially in the first metatarsal joint, points more towards gout. Naredo et al. recently confirmed the importance of looking for DC signs in the first metatarsal [5].
The diagnosis of gout is confirmed by the microscopic demonstration of monosodium urate crystals in synovial fluid analysis. In the absence of joint effusion, or to support the diagnosis, joint and cartilage ultrasonography, especially in the first metatarsal joint, is indeed very useful.

References

1 Chowalloor PV, Keen HI. A systematic review of ultrasonography in gout and asymptomatic hyperuricaemia. Ann Rheum Dis 2013; 72(5):638-45.

2 Borenstein M, Hedges L, Higgins J, et al. Comprehensive Meta-Analysis Version 2. Engelwood NJ. BioStat; 2005.

3 Pineda C, Amezcua-Guerra LM, Solano C, et al. Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. Arthritis Res Ther 2011;13(1):R4.

4 Howard RG, Pillinger MH, Gyftopoulos S, et al. Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: concordance between readers. Arthritis Care Res (Hoboken) 2011;63(10):1456-62.

5 Naredo E, Uson J, Jim?nez-Palop M, et al. Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout?

This letter contains a table and a figure that can be found at the ePage on the ARD website, accompanying an issue.

Conflict of Interest:

None declared

Dear Editor,

Radner and colleagues report a systematic literature search analysing the numerous articles and conference proceedings which examined the performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis (RA) (1). The comprehensive evaluation identified if the 2010 criteria were correctly applied as suggested in the original publication, explored the performance of the criteria according to different methods to assess the criteria components and with use of different reference standards, and finally, directly compared the results obtained upon classification when using the 2010 or the 1987 criteria.
The overall sensitivity of the criteria was 82% and overall specificity was 61%, when applied to the intended target population. Eight studies and five meeting abstracts directly compared 1987 and 2010 criteria using different reference standards within different target populations. When excluding patients with other diagnosis, the 2010 ACR/ EULAR criteria demonstrated almost 21% higher sensitivity compared with 1987 ACR criteria, whereas specificity was 16% lower. Therefore, Radner et al. conclude that the 2010 criteria are more sensitive than the 1987 criteria at the cost of a slight decrement in specificity, which might increase the possibility that a few non-RA patients are classified as RA patients and, for example, entered into clinical trials (1). Another recent systematic literature review and a meta-analysis including 6 full papers and 4 abstracts reported identical performance stating that the new classification criteria have good sensitivity, lower specificity and an overall moderate diagnostic accuracy (2). Sakellariou et al. interpret the results as confirmation of the value of the criteria for classification but not for diagnosis (2).
Indeed, the first prospective study of consecutive patients seen in routine care of an outpatient clinic of a university rheumatology centre using the doctor's diagnosis as the gold standard, different from using medication start, found that the sensitivity and specificity of the 2010 criteria in classifying RA were 97% and 55%, respectively, compared with the 1987 RA criteria which were 93% and 76%, respectively (3). More specifically, 66.7% of systemic lupus erythematosus patients, 50% of osteoarthritis, 37.5% of psoriatic arthritis and 27.2% of others fulfilled the new criteria and could have been incorrectly classified as RA. Thus, testing the criteria for the first time in a broad spectrum of rheumatological diseases seen in routine rheumatology care confirm the concern that the poor specificity may lead to over- and misdiagnosis of patients with RA, leading to inappropriate medication use (4, 5). Vunkemann and van de Laar reviewing the performance of the criteria very recently concluded:"Especially, when the classification criteria are used as diagnostic criteria this carries the risk of overtreatment. It remains to be determined whether or not the new criteria when used to diagnose and treat patients provide an acceptable balance between efficacy and safety and in these days also of major importance, cost-effectiveness"(6). In keeping with overclassification, several evaluation studies revealed that patients classified as RA according to the 2010 criteria are more likely to achieve drug-free remission than those who meet the 1987 criteria (7, 8, 9). Moreover, an ongoing prospective study of early arthritis demonstrated that 51% of 2010 criteria "non-RA" patients compared to 86% of patients with RA were treated with methotrexat (MTX) in the first year, suggesting that the rheumatologists in their clinic had a more aggressive approach to early arthritis during the same period than the rheumatologists treating the cohorts that were used to derive the criteria (10). Obviously, MTX is neither a "gold standard" for RA nor a static feature, as rheumatologists have a tendency to treat earlier and more aggressively. In addition, MTX and DMARD medications are also prescribed for other chronic inflammatory diseases, such as psoriatic arthritis and peripheral spondyloarthritis. Most importantly, classification criteria serve as a tool to arrive at homogeneous groups of patients with comparable features to make data obtained by different researchers at different places comparable why they should have a high specificity (preferably close to 100%), in order to prevent misclassification and inclusion of patients who do not have the disease (11). Also a balance of sensitivity and specificity is required in validation of criteria sets for use in clinical trials and epidemiologic studies (12).
Obviously, these requirements are hardly met if in the appropriate intended population the area under curve for receiver operating characteristic curves are rather weak between 0.72 and 0.78 indicating misclassification in 22% to 28% and limited accuracy to separate RA from other early arthritides (10, 13, 14). Overall, the question arises whether the loss of specificity is a price worth paying to use the criteria for classification in clinical trials.

In conclusion, the good news of better sensitivity is considerably limited by the loss of specificity and related risk of overtreatment of patients with self-limiting disease as RA with potentially toxic agents, even considering that poor recognition and inadequate intervention in the earliest phases of inflammatory arthritis may occur more often. The improvement of the accuracy of diagnosis and classification of early and very early RA remain a continuous challenge. Recently we reviewed proposals and suggestions how to overcome the problems and limitations of the 2010 criteria by clinical practice and future research (4):
1) the rheumatologist as the expert strikes a balance between possible or probable RA, depending on the level of confidence (15),
2) the rheumatologist uses a diagnostic certainty scale at baseline (0 to 100 visual analog scale) (16),
3) use of the prediction rule developed by van der Helm-van Mil et al. (17, 18) to estimate the chance of progression to RA in individual patients presenting with undifferentiated arthritis,
4) use of imaging techniques (sonography, MRI) to identify erosions earlier (19, 20, 21),
5) testing the discriminative value of HLA-B27 and diagnostic programs for reactive arthritis (22, 23),
6) testing likelihood ratios for diagnostic decision-making based on the Bayesian approach (24),
7) use of automated, multiplex biomarker assay testing for autoantibodies, cytokines, and bone-turnover products (25). Finally, future research should focus on validating the 2010 criteria in terms of important long-term outcomes in RA such as radiological damage, disability and mortality (5). In this regard, most recently a study of early arthritis patients evaluated the ability of the 2010 ACR/ EULAR and the 1987 ACR classification criteria to predict radiographic progression after 10 years of follow-up (27). The data suggests that both classification criteria predict poorly erosive disease in patients with early RA. The discriminative power of the 2010 criteria is only slightly better than that of the 1987 criteria with area under the curve of 0.72 and 0.65, respectively. Another most recent study reported that the 2010 criteria appear to be as efficient as the 1987 criteria in identifying increased risk of mortality but the 2010 criteria identify a greater proportion of at-risk patients soon after their first presentation to health care with a hazard ratio of 1.35 compared to 1.24 (28).

References

1 Radner H, Radner H, Neogi T, Smolen JS, et al. Ann Rheum Dis Published Online First: [April 16, 2013] doi:10.1136/ annrheumdis-2013-203284

2 Sakellariou G, Scire` CA, Zambon A et al. Performance of the 2010 Classification Criteria for Rheumatoid Arthritis: A Systematic Literature Review and a Meta-Analysis. PLoS ONE 2013;8:e56528.

3 Kennish L, Labitigan M, Budoff S et al. Utility of the new rheumatoid arthritis 2010 ACR/EULAR classification criteria in routine clinical care. BMJ Open 2012;2:e001117.

4 Zeidler H. The need to better classify and diagnose early and very early rheumatoid arthritis. J Rheumatol 2012;39:212-7.

5 Humphreys JH, Symmons DP. Postpublication validation of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: where do we stand? Curr Opin Rheumatol 2013;25:157-63.

6 Vonkeman HE, van de Laar MA. The new European League Against Rheumatism/American College of Rheumatology diagnostic criteria for rheumatoid arthritis: how are they performing? Curr Opin Rheumatol 2013;25:354-9.

7 Cader MZ, Filer A, Hazlehurst J, et al. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis 2011;70:949-55.

8 De Hair MJ, Lehmann KA, van de Sande MG, et al. The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria: is this still the same disease? Arthritis Rheum 2012;64:389-93.

9 Krabben A, Huizinga TW, van der Helm-van Mil AH. Undifferentiated arthritis characteristics and outcomes when applying the 2010 and 1987 criteria for rheumatoid arthritis. Ann Rheum Dis 2012;71:238-241.

10 Britsemmer K, Ursum J, Gerritsen M, van Tuyl LH et al. Validation of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: slight improvement over the 1987 ACR criteria. Ann Rheum Dis 2011;70:1468- 70.

11 van der Helm-van Mil AH, Huizinga TWJ. The 2010 ACR/EULAR criteria for rheumatoid arthritis: do they affect the classification or diagnosis of rheumatoid arthritis? Ann Rheum Dis 2012;71:1596-98.

12 Johnson SR, Goek ON, Singh-Grewal D et al. Classification criteria in rheumatic diseases: A review of methodologic properties. Arthritis Rheum 2007;57:1119-33.

13 van der Linden MP, Knevel R, Huizinga TW et al. Classification of rheumatoid arthritis: Comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria. Arthritis Rheum 2011;63:37-42.

14 Varache S, Cornec D, Morvan J et al. Diagnostic accuracy of ACR/EULAR 2010 criteria for rheumatoid arthritis in a 2-year cohort. J Rheumatol 2011;38:1250-7.

15 Benhamou M, Rincheval N, Roy C et al. The gap between practice and guidelines in the choice of first-line disease modifying antirheumatic drug in early rheumatoid arthritis: Results from the ESPOIR cohort. J Rheumatol 2009;36:934-42.

16 Morvan J, Berthelot JM, Devauchelle-Pensec V et al. Changes over time in the diagnosis of rheumatoid arthritis in a 10-year cohort. J Rheumatol 2009;36:2428-34

17 van der Helm-van Mil AH, Detert J, le Cessie S et al. Validation of a prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: Moving toward individualized treatment decision-making. Arthritis Rheum 2008;58:2241-7.

18 Huizinga TW, van der Helm-van Mil A. Quantitative approach to early rheumatoid arthritis. Bull NYU Hosp Joint Dis 2011;69:116-21.

19 Freeston JE, Wakefield RJ, Conaghan PG et al. A diagnostic algorithm for persistence of very early inflammatory arthritis: The utility of power Doppler ultrasound when added to conventional assessment tools. Ann Rheum Dis 2010;69:417-9.

20 Boutry N, do Carmo CC, Flipo RM et al. Early rheumatoid arthritis and its differentiation from other joint abnormalities. Eur J Radiol 2009;71:217-24.

21 Filer A, de Pablo P, Allen G et al. Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis. Ann Rheum Dis 2011;70:500-7.

22 Hülsemann JL, Zeidler H. Diagnostic evaluation of classification criteria for rheumatoid arthritis and reactive arthritis in an early synovitis outpatient clinic. Ann Rheum Dis 1999;58:278-80.

23 Soderlin MK, Borjesson O, Kautiainen H et al. Annual incidence of inflammatory joint diseases in a population based study in southern Sweden. Ann Rheum Dis 2002;61:911-5.

24 Corrao S, Calvo L, Licata G. The new criteria for classification of rheumatoid arthritis: What we need to know for clinical practice. Eur J Intern Med 2011;22:217-9.

25 Chandra PE, Sokolove J, Hipp BG et al. Novel multiplex technology for diagnostic characterization of rheumatoid arthritis. Arthritis Res Ther 2011;13:R102.

26 M?kinen H, Kaarela K, Huhtala H et al. Do the 2010 ACR/EULAR or ACR 1987 classification criteria predict erosive disease in early arthritis? Ann Rheum Dis 2013;72:745-7.

27 Humphreys JH, Verstappen SM, Hyrich KL et al. 2010 ACR/EULAR classification criteria for rheumatoid arthritis predict increased mortality in patients with early arthritis: results from the Norfolk Arthritis Register. Rheumatology (Oxford) 2013 Mar 5. [Epub ahead of print] doi:10.1093/rheumatology/ket113.

Conflict of Interest:

None declared