Displaying 1-10 letters out of 321 published
What to conclude from the results of the LEGS study and what not?
Like probably many others, we have been waiting eagerly for the results of the LEGS study (1). The expectation was that this trial would bring light into the ongoing controversy about the value of chondroitin, glucosamine, and their combination in the treatment of osteoarthritis (OA) of the knee, and provide answers to several open questions. The LEGS study fully met this expectation as to the structure-modifying effect of the combination of chondroitin sulphate and glucosamine sulphate. However, what do the results of this trial tell us about the structure-modifying effect of chondroitin sulphate or glucosamine sulphate alone or about the symptomatic effect of chondroitin sulphate, glucosamine sulphate, or the combination thereof? Unfortunately, the results of the LEGS study add very little to this question as we will point out subsequently.
Symptomatic effect: The main symptomatic outcome measure in the LEGS study was changed from the use of NSAIDs to self-reported pain when the authors realized that only about 20 % of the patients recruited till that point in time were taking NSAIDs. The alternative primary outcome measure to assess the symptomatic effect was the maximum score of pain 'at its worst' recorded daily in a 7-day diary that the participants had to complete every two months. There are several problems with this alternative outcome measure: 1. It seems not to have been validated, i.e. we have not found any relevant validation study. 2. Experiences with it are lacking, i.e. we are not aware of any other trials in which this measure had been used. 3. Pain due to knee OA is activity- related (depending on the activity), i.e. a patient with knee OA may not suffer from pain while walking, but may does so when descending stairs. We do not know what activity caused 'pain at its worst' and how long that pain lasted. The activity that caused 'pain at its worst' likely was not always the same. Pain 'at its worst', therefore, may be largely an arbitrary measure. 4. Apart from being related to a very specific activity, pain 'at its worst' may lasted only seconds. Thus, potentially, this measure clinically may not be very relevant. 5. As 'average pain' - as opposed to 'pain at its worst' - decreases, patients may dare to indulge in more challenging activities. Such more challenging activities are likely to cause temporarily similar 'pain at its worst' even when 'average pain' decreases over time. Therefore, the alternative outcome measure actually may be more prone to a 'floor effect', i.e. contribute to what the authors wanted to avoid with its use. 6. We do not know how 'pain at its worst' correlates with 'average pain', pain on a standard visual analogue scale (VAS), or WOMAC pain, if at all. 7. As 'average' pain on a numerical rating scale is imperatively smaller than 'pain at its worst', the use of the alternative measure as an inclusion criterion (4 or more on a scale of 0-10) resulted in a very mildly symptomatic study population as documented by the WOMAC pain scores. These scores were between 6.5+/-3.4 (mean+/-SD) and 6.8+/-3.7 on a scale of 0-20 corresponding to 33+/-17 and 34+/-19, respectively, on a scale of 0-100. According to the EMA guideline CPMP/EWP/784/97 Rev. 1 (2) in order to assess the symptomatic effect of a drug, patients must have pain of at least 40 mm on a VAS of 100 mm. Judging on the basis of the above scores and SDs only about 30 % of the patients or about 50 patients per group met this criterion whereas about 100 are needed to observe statistically significant differences (3), not taking into account the dilution by those that are not sufficiently symptomatic.
With respect to the assessment of the symptomatic effect we would like to note also that the information about co-medications as well as their cessation and washout provided in the publication is very scarce. From some statements and tables we conclude that there were no restrictions regarding co-medications. Patients could take paracetamol, NSAIDs, and opioids at their own discretion (as long as they had been prescribed such co-medications earlier or during the trial). About 30 % of the patients had been on a dietary supplement containing glucosamine during the month before enrolment. Data regarding the use of a dietary supplement containing chondroitin or a combination of the two before enrolment is lacking. Thus, most likely there was no washout of potential effects of such supplements, and it remains unclear whether the patients actually had been asked to stop taking such supplements during the trial. Assuming that chondroitin, glucosamine, and the combination of the two have a symptomatic and a structure-modifying effect, and also carry-over effects as described in the literature (4), i.e. effects that last to some extent at least 3 months beyond cessation of treatment, the lack of any appropriate washout and the possible intake of (additional) dietary supplements with chondroitin, glucosamine, or a combination of the two are likely to have influenced the results, particularly those of the placebo group, and, thus, contributed to a diminishment of the differences between the active treatment groups and the one with placebo. If so, then this affected the observation of the symptomatic as well as the structure- modifying effect. In any case, under the circumstances summarized above, the authors should not only have adjusted their analysis of the symptomatic effect for baseline pain and repeated measurements over time, but at least also for all pain-relevant co-medications and for exercise. Exercise was potentially a strong confounder, because, according to the data provided in Table 4, the number of participants with inadequate exercise decreased in the placebo group whereas it remained more or less stable in the glucosamine and the combination group, and increased in the one with chondroitin.
Structure-modifying effect: The authors decided, a priori, that for valid estimates of joint space narrowing (JSN), a medial tibial inter-rim distance (TIRD) of <= 1.7 mm at each time point was required for an X-ray to be included in the analysis. Furthermore, they limited their analysis to pairs of X-rays with a difference in TIRD of <= 0.2 mm between the two X-rays. The first criterion was adopted from work by Vignon et al., 2010 (5). The LEGS study was registered with ClinicalTrials.gov (NCT00513422) on August 7, 2007, thus before the publication by Vignon et al., 2010. With 'a priori' the authors, therefore, mean that their decision to apply the above criterion had been taken prior to the data analysis. Nevertheless, the application of this criterion represents a deviation from the original protocol. The authors, therefore, first should have carried out the analysis according to the protocol, and also should have published the results of that analysis. The analysis actually carried out and presented in the publication could then have served as a sensitivity analysis to consolidate or question the results obtained according to the protocol and for discussion.
The protocol allowed a single repeat of each X-ray if the TIRD was > 2.0 mm. Thus, the limitation of the analysis to X-rays with a TIRD of <= 1.7 mm is largely redundant. Therefore, it is likely that the reduction of the number of 'valid' pairs of X-rays predominantly can be attributed to the application of the second criterion, a difference of TIRD of <= 0.2 mm between pairs of X-rays. This second criterion is not only too severe - Vignon et al., 2010 set the cut-point at 0.5 mm and not at 0.2 mm -, it is also unnecessary: Vignon and co-workers only applied the second criterion to pairs of X-rays in which both TIRDs were > 1.7 mm. They, however, did not investigate any subgroup of pairs of X-rays meeting both of the above criteria. In fact, the first criterion is already sufficient to guarantee a high accuracy and the best responsiveness. They found a JSN of 0.13+/-0.51 mm (mean+/-SD) over one year and a standardized response mean (SRM) of 0.25 for all pairs of X- rays (n=590) as well as a JSN of 0.15+/-0.43 mm and a SRM of 0.34 for all pairs of X-rays with a TIRD of <= 1.7 mm in both of them (n=256). All other results in their publication refer to situations where one or both of the two X-rays of a pair had a TIRD > 1.7 mm. Their results clearly indicate that the application of the first criterion is absolutely adequate, and, furthermore, that the gain in accuracy and responsiveness disproportionately is at the expense of statistical power. Again, as the loss of 'valid' pairs of X-rays by the application of the first criterion had not been accounted for in the sample size calculation, the authors should have carried out the analysis of the X-rays according to the protocol and then applied the first criterion for sensitivity analysis. As for the second criterion, there is no evidence that it contributes anything when applied to pairs of X-rays in which both TIRDs are <= 1.7 mm, with the exception of an unacceptable loss of statistical power.
In summary: Symptomatic effect: The inclusion of very little symptomatic patients, the switch of the primary symptomatic endpoint to an unusual, unpredictable, and not validated alternative outcome measure, and the lack of exclusion or control of confounding factors do not allow to draw any substantial conclusions regarding the symptomatic effects of chondroitin sulphate, glucosamine sulphate or the combination of the two.
Structure-modifying effect: With only about 50 % of valid pairs of X- rays, i.e. about 75 per group and one third less than required according to the sample size calculation, the results of the LEGS study as presented in the publication do by no means exclude a structure-modifying effect of chondroitin sulphate or glucosamine sulphate alone.
Several characteristics of the LEGS study discussed above are suited to underestimate or impede the detection of the investigated effects. The fact, however, that the combination of chondroitin sulphate and glucosamine sulphate nevertheless did achieve a meaningful reduction in JSN over 2 years, compared with placebo, in patients with mostly early radiographic knee OA in this study adds even more weight and importance to this finding.
1. Fransen M, Agaliotis M, Nairn L, et al. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo- controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis Published Online First: January 6, 2014. doi:10.1136/annrheumdis -2013-203954.
2. EMA guideline CPMP/EWP/784/97 Rev. 1. EMA European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on Clinical Investigation of Medicinal Products Used in the Treatment of Osteoarthritis. London, January 20, 2010.
3. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 2007;146:580-90.
4. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one- year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cart 2004;12:269-276.
5. Vignon E, Brandt KD, Mercier C, et al. Alignment of the medial tibial plateau affects the rate of joint space narrowing in the osteoarthritic knee. Osteoarthritis Cart 2010;18:1436-40.
Conflict of Interest:
Andreas G. Helg is employed by IBSA Institut Biochimique SA, a Swiss manufacturer and distributor of a chondroitin sulphate prescription drug and a glucosamine sulphate dietary supplement. Analysis of the publication of the LEGS study and the preparation of this letter were carried out on behalf of IBSA.
Response to Dr Iannone's eLetter
We thank Dr. Iannone et al for their comment on our recent study on drug survival on etanercept, infliximab and adalimumab in patients with RA. They noted similarities between our findings and their previously published data on 853 Italian patients starting TNF inhibitor treatment in 2003-2004 in terms of best drug survival on etanercept, similar 4- vs 5 -year drug survival for etanercept and infliximab, and some shared findings regarding predictors. We agree that there are several similarities, but also differences. We also apologize for not including their study in our non-exhaustive review in the appendix, and not citing their study together with the study by Kievit et al.
Specifically, we investigated whether drug survival differed between the selected TNF inhibitors, whether these differences were modified by time on treatment, and whether discontinuation rates have changed across calendar periods. We also looked at predictors of drug discontinuation. We did this in more than 9000 prospectively followed patients who initiated their first biologic treatment between 2003 and 2011.
We found, similar to many previous European investigators (including Iannone et al)[3-8], that etanercept had the best drug survival in overall analyses. We did, however, find that the difference was modified by time, with etanercept being superior to adalimumab only the first year. Interestingly, Iannone et al show data potentially supporting our finding of effect modification by time, although they provide no statistical test of what could be a greater difference in the first and second year (compared to later years) between etanercept and adalimumab.
In contrast to our study, Iannone et al found similar drug survival on adalimumab and infliximab (4-year unadjusted drug survival: 36.4% vs 37.6%). In our data, the 5-year drug survival for adalimumab was 50%.
Regarding predictors of drug discontinuation, we used Cox regression when evaluating age, sex, education level, calendar period, HAQ, concomitant DMARD use, disease duration, and two measures of general frailty. All variables but age were statistically significant predictors in the multivariable model, although the magnitude was small to moderate for most. Iannone et al investigated predictors using stepwise logistic regression, and it is unclear whether or how they took censoring into account. In contrast to our findings, they could detect few statistically significant independent predictors, although disease duration and concomitant DMARD use were statistically significant, similar to our findings.
Considering the recognition of the importance of contextual factors (such as the number of alternative treatment options available) on the real-world effectiveness and drug survival of existing treatment options in RA, we welcome further studies of drug survival and predictors for long-lasting response to therapy.
1. Neovius M, Arkema EV, Olsson H, et al. Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab. Ann Rheum Dis. 2013.
2. Iannone F, Gremese E, Atzeni F, et al. Longterm retention of tumor necrosis factor-alpha inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors. J Rheumatol. 2012; 39:1179-1184.
3. Kievit W, Adang EM, Fransen J, et al. The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis. 2008; 67:1229-1234.
4. Du Pan SM, Dehler S, Ciurea A, et al. Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthritis and rheumatism. 2009; 61:560-568.
5. Marchesoni A, Zaccara E, Gorla R, et al. TNF-alpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice. Annals of the New York Academy of Sciences. 2009; 1173:837-846.
6. Kristensen LE, Saxne T, Nilsson JA, et al. Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden. Arthritis Res Ther. 2006; 8:R174.
7. Hetland ML, Christensen IJ, Tarp U, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis and rheumatism. 2010; 62:22- 32.
8. Brocq O, Roux CH, Albert C, et al. TNFalpha antagonist continuation rates in 442 patients with inflammatory joint disease. Joint, bone, spine : revue du rhumatisme. 2007; 74:148-154.
Conflict of Interest:
Is an extra dose of rituximab an efficacious and safe alternative to improve outcomes in rheumatoid arthritis? Comment on the article by Vital et al.
I read with interest the paper by Vital el al. (1), a pilot study testing the efficacy of an extra dose of rituximab (completing 3x1000 mg over four weeks) in comparison to the standard-dose regimen (2x1000 mg) in rheumatoid arthritis (RA) patients with incomplete depletion of B cells after a first 1000 mg dose of RTX. The study represents an advance in the knowledge about the effects of rituximab, but I have some concerns about the interpretation of the results.
The overall analysis of the efficacy outcomes at week 28 (when no patient had yet received a repeat course of rituximab) did not favor the extra-dose regimen. Good EULAR response, EULAR remission, ACR50 and ACR70 responses were numerically (but not statistically) better in the standard- dose group. After 28 weeks, the efficacy results are difficult to interpret, because imputation of no response for ACR20 and EULAR responses was used for patients presenting reactivation of disease (i.e., a DAS28 increase >0.6), even if they improved after a repeat course of RTX.
The authors commented in the abstract that the extra dose of RTX produced no worsening in safety. However, the study is clearly underpowered to detect safety problems due to the small sample sizes. At 12 months, infections and serious adverse events (SAE) were more incident in the extra-dose group (rate ratios 1.42 [95% CI 0.65, 3.17] and 4.33 [95% CI 0.43, 231.41], respectively), although the differences were not statistically significant. The incidence of SAE in the extra-dose group (33/100 patients/year) is numerically higher than the expected based on historical data of RTX therapy (14.4/100 patients/year ).
Recent evidence (3,4) has suggested that low-dose RTX (2x500 mg or a single infusion of 1000 mg) has an efficacy that is noninferior to the standard dose (2x1000 mg) of RTX, and is possibly safer. Aiming at complete depletion of B cells using an extra dose of RTX may possibly lead to a higher incidence of late- onset neutropenia (5), hypogammaglobulinemia (6,7), and serious adverse events, which may reduce the effectiveness and increase the costs of the treatment of rheumatoid arthritis with RTX.
1. Vital EM, Dass S, Buch MH, et al. An extra dose of rituximab improves clinical response in rheumatoid arthritis patients with initial incomplete B cell depletion: a randomised controlled trial. Ann Rheum Dis 2014. doi:10.1136/annrheumdis-2013-204544
2. van Vollenhoven RF, Emery P, Bingham CO 3rd, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013;72:1496-502.
3. Bredemeier M, de Oliveira FK, Rocha CM. Low- versus high-dose rituximab for rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2014;66:228-35.
4. Mariette X, Rouanet S, Sibilia J, et al. Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid arthritis: a non- inferiority randomised controlled trial. Ann Rheum Dis 2013. doi:10.1136/annrheumdis-2013-203480
5. Tesfa D, Ajeganova S, Hagglund H, et al. Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum 2011;63:2209-14.
6. Isvy A, Meunier M, Gobeaux-Chenevier C, et al. Safety of rituximab in rheumatoid arthritis: a long- term prospective single-center study of gammaglobulin concentrations and infections. Joint Bone Spine 2012;79:365-9.
7. Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther 2013;8:87-100.
Response to Dr Yazici's eLetter: Ethical issue of withholding treatment from patients with active rheumatoid arthritis
The ethical consideration in placebo-controlled studies of antirheumatic drugs is of primary importance. We thank Dr Yazici for his questions regarding the ethical aspect of our study.
The GO-MONO study was designed to have placebo crossover to methotrexate (MTX) at Week 16, as a Registration Study to Japan Health Authority, following the MHLW Guideline for the Clinical Study and Evaluation of Drugs for Rheumatoid Arthritis, which is similar to the US Food and Drug Administration's Guidance for Industry Rheumatoid Arthritis (1). The US guidance recommends sponsors to limit the use of placebo as a control and consider the use of an active comparator as the control or the escape to rescue treatment in studies longer than 12 weeks. In the event of aggravation of rheumatoid arthritis (RA) symptoms, subjects were to be withdrawn from study immediately and receive appropriate rescue treatment, which was explicitly written in the informed consent. The investigators and IRBs of the participating medical institutions and the Japanese health authorities considered that the GO-MONO study had adequate ethical considerations. Twelve or 24-week placebo-controlled studies were conducted in the clinical development of recently approved antirheumatic drugs in Japan after the golimumab studies without being questioned about the ethical conduct (2,3,4). Even allowing for the disadvantages in subjects receiving placebo, conducting a placebo-controlled study of golimumab monotherapy was thought to be imperative not only because it would meet the requirement by the Japanese health authorities to demonstrate the true efficacy of an antirheumatic drug in a placebo-controlled study, but because the approval of golimumab monotherapy provide an alternative treatment option to MTX- intolerable patients with active RA.
The second issue Dr Yazici raises is the credibility of the data from our studies based on the different results for the effect on radiographic progression between the studies.
As we discussed in the paper describing our earlier 2 studies of golimumab (5), subjects in all treatment groups of the GO-FORWARD study had lower disease activity and less radiographic progression at baseline than those in the earlier studies of TNF-? inhibitors in patients with an inadequate response to MTX (6,7,8), and this may have resulted in the lack of statistically significant differences between treatment groups. The GO- FORWARD study failed to adequately assess the effects of golimumab on radiographic progression in patients with established disease, In the GO- MONO study, however, subjects had more active RA inflammation at baseline than those in the GO-FORWARD study, and golimumab showed a significantly greater effect of preventing radiographic progression. This result is consistent with the results in our other studies of golimumab, the GO- FORTH study (9) and the GO-BEFORE study (10). A similar relationship was seen between the radiographic progression and response to certolizumab in patients with active RA despite MTX (11). Dr Yazici points out that radiographic benefit was not demonstrated with golimumab until post hoc analysis of the data was done. As explained in the literature of the GO-MONO study, the post hoc analysis using normalized data was appropriate for radiographic analyses because the radiographic change scores were not normally distributed. For instance, the median of the golimumab 100 mg group was skewed because of a single outlier. Data normalization is the standard statistical analysis technique used in the literature and for Health Authority submissions. Significantly less radiographic progression than placebo was noted when the data were analyzed post hoc using normalized scores. The 100 mg dose was associated with better clinical outcome than the 50 mg dose (not statistical comparison) as measured using the American College of Rheumatology criteria and Disease Activity Scores. The effect of the 100 mg dose for the use in golimumab monotherapy was appropriately evaluated and approved by the Japanese health authorities.
1. Guidance for Industry Rheumatoid Arthritis: Developing Drug Products for Treatment (Draft guidance). :http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM354468.pdf
2. Fleischmann R et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis 2009;68:805-11
3. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, Eguchi K, et al. Efficacy and safety of certolizumab pegol without MTX co- administration in Japanese patients with active rheumatoid arthritis: the HIKARI randomized, placebo-controlled trial. Mod Rheumatol 2013 Nov 1.
4. Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose- ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64:617-29.
5. Emery P, Fleischmann R, van der Heijde D, et al. The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. Arthritis Rheum 2011;63:1200-10.
6. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789-96.
7. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594-602.
8. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50: 1400-11.
9. Tanaka Y, Harigai M, Takeuchi T, et al. Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study. Ann Rheum Dis 2012;71:817-24.
10. Emery P, Fleischmann RM, Moreland LW, at al. Golimumab, a human anti-tumor necrosis factor ? monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 2009;60:2272-83.
11. Keystone E, Heijde Dv, Mason D Jr, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 2008;58:3319-29.
Conflict of Interest:
Diagnosing Erdheim-Chester Disease
Although we generally agree with Dr Juanos-Iborra et al  who noted that some of the most common manifestations of Erdheim-Chester disease (ECD) at time of onset (such as skeletal, constitutional or even neurological symptoms) may lack adequate specificity for a timely and prompt diagnosis, it is conceivable that the same manifestations, if unexplained, may often lead to further imaging and histological studies, which will eventually suggest a correct diagnosis. Undoubtedly, as the authors themselves stated and as highlighted in our recent study published in Annals of the Rheumatic Diseases, other more typical manifestations of ECD, such as the radiologic evidence of 'coated aorta', of 'hairy kidneys', or of 'pseudotumoral' infiltration of the right atrium, as well as the typical bone scan finding of a symmetrical and abnormally increased uptake in the distal ends of long bones, should be clearly indicative of the disease [1-3]. However, our study and others, including the descriptions of the largest reported cohort of patients with ECD, highlighted a striking diagnostic delay (up to 29 years) even in those patients presenting with the aforementioned typical manifestations [3-5]. To allow a more timely diagnosis, we believe that the broader medical audience should be privy to both the specific and sensitive manifestations of this protean and multifaceted disease. Encouragingly, it has been observed that the average diagnostic delay for ECD has dramatically shortened in the recent years because of a better recognition of the disease . As Sir William Osler said, "many diseases [...] are seen so rarely and yet are so distinctive, requiring only to be seen to be recognized, that it is incumbent upon members to use the [medical] society to show such cases" .
1. Juanos-Iborra M, Solanich-Moreno J, Selva-O'Callaghan A. Erdheim- Chester disease. Ann Rheum Dis 2013 Mar 16.
2. Della Torre E, Dagna L, Mapelli P, et al. Erdheim-Chester disease: imaging-guided therapeutic approach. Clinical nuclear medicine. 2011;36(8):704-6.
3. Cavalli G, Guglielmi B, Berti A, et al. The multifaceted clinical presentations and manifestations of Erdheim- Chester disease: comprehensive review of the literature and of 10 new cases. Ann Rheum Dis 2013 Feb 8.
4. Haroche J, Amoura Z, Wechsler B, et al. [Erdheim-Chester disease]. Presse Med. 2007 ;36(11 Pt 2):1663-8.
5. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al. Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine. 1996 ;75(3):157-69.
6. Haroche J, Arnaud L, Amoura Z. Erdheim-Chester disease. Curr opin in rheumatol. 2012 ;24(1):53-9.
7. Osler W. On the Educational Value of the Medical Society. In: Aequanimitas, With other addresses to Medical Students, Nurses and Practitioners of Medicine. Philadelphia, PA: Blackiston, 1932.
Conflict of Interest:
Response to 'In erosive hand osteoarthritis more inflammatory signs on ultrasound are found than in the rest of hand osteoarthritis' by Kortekaas et al
We read with interest the article 'In erosive hand osteoarthritis more inflammatory signs on ultrasound are found than in the rest of hand osteoarthritis' by Kortekaas et al . The authors found that interphalangeal joints of erosive osteoarthritis (EOA) patients, with erosions being defined by conventional radiography (CR), demonstrated more sonographic inflammatory changes in adjacent non CR-eroded joints compared to patients without EOA. This may give the impression that a joint showing erosions on hand CR points towards a more severe generalised inflammatory phenotype and we would like to clarify this.
We are unsure what the significance and robustness of these observations is, given the increasing pathophysiological understanding of hand osteoarthritis that has emerged from high-resolution MRI [2, 3], that overcomes problems encountered in ultrasound including overlying osteophytes that may obstruct views of erosions. Utilising 23mm 'microscopy' surface coil to study early hand osteoarthritis and compared to CR, we found 4 times more erosions were detected on MRI, in particular marginal erosions that lay within the joint capsule, but beyond the margins of the articular cartilage (1 on CR, 19 on MRI, p<0.05). According to Kortekaas et al, EOA was defined by one or more erosions on CR at the interphalangeal joints. The limitation of CR in determining erosions is due to its 2-dimensional capability and inability to detect very small erosions. However the sensitivity of MRI can potentially increase the number of joints considered as true EOA compared to CR by a factor of 4 . As Kortekaas et al acknowledge in their discussion ultrasound has also been shown to be more sensitive to the detection of erosions in EOA than conventional radiography in recent studies . We believe that most published prevalence of EOA may be under-estimated due to the relative insensitivity of CR used for diagnosis. In a nutshell, it is likely that many of the joints the authors term non-erosive on CR, actually have extensive pathoplysiologically identical, but smaller, lesions in adjacent "non erosive" joints.
Of particular importance our study demonstrated that enhancing synovitis post contrast, akin to that seen in inflammatory arthritis such as rheumatoid or psoriatic arthritis, was present in all cases and filled the erosion on MRI, further supporting the idea that non-radiographic hand OA inflammation is linked to erosions . We have previously shown on histology that synovial tissues do line the surface cavity of bone erosions, which potentially can be subjected to an inflammatory process . So we envisage that the joints that have power Doppler synovitis on ultrasound but no radiographic erosions observed by Kortekaas et al may also have a high likelihood of being erosive had cross sectional modalities been used to categorise them.
We agree with the authors that their cross sectional study is unable to clarify if the inflammation observed in EOA may lead to further erosive changes. However work showing that suppression of inflammation with anti- TNF halts erosive progression in hand OA, suggests that uncontrolled inflammation in non-erosive hand OA does progress to radiographic EOA . We argue that the observation by Kortekaas et al was limited by the lack of sensitivity of the imaging modality (CR) used to call EOA. Therefore the sonographic changes of inflammation in hand OA joints are likely to be already strongly linked to erosion in the same joints.
1. Kortekaas MC, Kwok WY, Reijnierse M, et al. In erosive hand osteoarthritis more inflammatory signs on ultrasound are found than in the rest of hand osteoarthritis. Ann Rheum Dis. 2013;72(6):930-4.
2. Grainger AJ, Farrant JM, O'Connor PJ, et al. MR imaging of erosions in interphalangeal joint osteoarthritis: is all osteoarthritis erosive? Skeletal Radiol. 2007 ;36(8):737-45.
3. Tan AL, Grainger AJ, Tanner SF, et al. High-resolution magnetic resonance imaging for the assessment of hand osteoarthritis. Arthritis Rheum. 2005 ;52(8):2355-65.
4. Wittoek R, Jans L, Lambrecht V, Carron P, Verstraete K, Verbruggen G. Reliability and construct validity of ultrasonography of soft tissue and destructive changes in erosive osteoarthritis of the interphalangeal finger joints: a comparison with MRI. Ann Rheum Dis. 2011 ;70(2):278- 83.
5. McGonagle D, Tan AL, Moller et al. Microanatomic studies to define predictive factors for the topography of periarticular erosion formation in inflammatory arthritis. Arthritis Rheum. 2009 ;60(4):1042-51.
6. Verbruggen G, Wittoek R, Vander Cruyssen B, et al. Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification. Ann Rheum Dis. 2012 ;71(6):891-8.
Conflict of Interest:
Comments on recent advances and recommendations for the assessment of autoantibodies to cellular antigens referred as anti-nuclear antibodies
Despite significant efforts and advances in the field of autoimmune diagnostics, the standardization and proper use of antinuclear antibody (ANA) testing in clinical practice remains a challenge. In 2013, important contributions attempting to clarify and add rigor to this area have been published [1, 2]. In particular, the recent recommendations published by Agmon-Levin et al.  address very important issues that confront contemporary laboratory medicine. Using a Delphi approach, the authors generated 25 recommendations for the detection of anti-cellular antibodies, previously referred to ANA and anti-dsDNA antibodies. In a second important paper, Bossuyt and Fieuws reported added value of solid phase assays . Considering the high impact of published recommendations and associated editorials, careful verification, validation, clarification, education and, if necessary, adjustments are crucial. Some of the recommendations requiring further clarification are summarized in Table 1 or discussed in the text.
Terminology of diseases and autoantibodies Agmon-Levin et al., make an exceedingly important point with respect to the nomenclature of autoantibodies found in systemic autoimmune rheumatic disease (SARD) sera is inconsistent, misleading and/or not in keeping with contemporary cell and molecular biology terminology. The terms 'anti- nuclear antibodies' (ANA) and 'extractable nuclear antigens' (ENA) are no longer technically correct and do not cover the entire spectrum of relevant autoantibodies. 'ANA' using indirect immunofluorescence (IIF) as well as some other screening assays detect antibodies directed against nuclear and non-nuclear elements (as in their recommendation 13), while 'ENA' may refer to some antigens that are neither extractable nor nuclear. Therefore, it is highly desirable to change these terms to more appropriate and informative ones, such as anti-cellular antibodies and specific antibodies, respectively. Such a change in nomenclature requires broad agreement and adoption within the broad stakeholder medical community and then a transition period, as most manuscripts and textbooks would continue to use the older 'classic terms'. In addition to the autoantibody terminology, a new terminology for connective tissue disorders is also required. In their recommendations, the authors used the term SARD without specifying which diseases should be included in this group. Recently, the term ANA associated rheumatic disease (AARD) was introduced . Although this term uses the inappropriate abbreviation `ANA`, this terminology or a slightly modified version might be preferred and should include systemic lupus erythematosus (SLE), Sj?gren's syndrome (SjS), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM). Rheumatoid arthritis (RA) is thought of as a SARD by some because it clearly has critical extra-articular manifestations. However, since only a subpopulation of RA patients has a positive ANA, and because other serological markers such as anti- citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) have more clinical utility, RA should not be included in the AARD group. Changing the terminology of a disease is a challenge and requires careful considerations, but evolving knowledge about disease phenotypes, disease specific biomarkers and pathogenesis makes a review of disease nomenclature mandatory. Recently, it has been suggested that the nomenclature of SSc might be adjusted to one based on serological markers and autoantibodies  and the names of several autoimmune mediated diseases including granulomatosis with polyangiitis (GPA, formerly known as Wegener`s granulomatosis) have been changed.
Change in referral pattern
Historically, primarily rheumatologists and clinical immunologists ordered ANA testing as an aid to the diagnosis of systemic lupus erythematosus (SLE) . Much of this was due to the embedding of ANA and certain ENA in the older  and now more recent  classification criteria for SLE. Nowadays, a broad spectrum of clinicians order the ANA test including but not limited to rheumatologists, internists, dermatologists, nephrologists, oncologists, cardiologists, neurologists, gastroenterologists, psychiatrists and even primary care physicians. This can be attributed to the appreciation that the ANA test has clinical value in multiple diseases including autoimmune liver diseases such as autoimmune hepatitis and primary biliary cirrhosis (PBC), and might also provide clinical information in vasculitis, inflammatory bowel disease (IBD), a widening spectrum of autoimmune neurological diseases and malignancies. This has significant impact on the pre-test probability and an even more pronounced effect on the post-test probability of the ANA test. An important aspect for the use of ANA is the likelihood ratio SARD. Using this information, calculation and understanding of the post-probability of disease based on the respective patient population should be a vital part of the diagnostic process .
Methods for ANA detection and sensitivity and specificity of ANA testing
Although significant improvements have been made and several solid phase assays are available for ANA detection, the IIF HEp-2 method was recently recommended as the method of choice for ANA detection .
The authors recommended that a serum screening dilution yielding 95% specificity should be selected in each laboratory based on the respective patient population. On the same note, they also point out that the sensitivity in SLE should be >90% . Although historical data demonstrate such high diagnostic accuracies , more recent data do not support a diagnostic accuracy of a combined 90% sensitivity and 95% specificity [2, 11]. Based on a large population based study it was reported that 13.8% of apparently healthy individuals were ANA positive at a screening dilution of 1:80 . Since this study used commercial HEp-2 substrates but a clinically unvalidated secondary antibody and did not include SARD patients, further studies with large patient cohorts are needed.
Limitations of the IIF test and lack of standardization
The authors also acknowledged that the IIF ANA test lacks sensitivity for several clinically relevant autoantibodies including but not limited to SS -A/Ro60, Ro52/TRIM21, ribosomal P and Jo-1 . Although related observations have been published , further emphasis and education is needed to ensure that laboratorians and clinicians are fully aware of this limitation. Not addressed in detail is the variability of HEp-2 kits from different manufacturer in terms of sensitivity and specificity as well as IIF pattern interpretations. Although a study along these lines has been previously reported , evidence from systematic and multi-center studies analyzing the sensitivity and specificity of various contemporary commercial HEp-2 kits seem are missing.
Added value of solid phase immunoassays
Bossuyt and Fieuws  showed that adding a solid phase assay (SPA) to the IFA HEp-2 testing algorithm increased the diagnostic utility for SLE, SjS (all samples on both assays) and SSc (all samples by IIF and positives by SPA). However, this likely would have impact on health care costs and, in many jurisdictions, only one ANA test is reimbursed, limiting the parallel approach using IFA and SPA for ANA testing. However, early and accurate diagnosis and then appropriate treatment of patients with AARD are important aspects of favourable clinical outcomes, although they also have significant benefits for the health economy. A delayed diagnosis is attended by the dangers of higher morbidity and mortality due in large part to irreversible tissue damage while false positive results may lead to unnecessary referrals, misdiagnosis or even inappropriate treatment [5, 13].
Clinical association of indirect immunofluorescence patterns and autoantibodies
In Table 2, the authors list anti-CENP-F antibodies as a target structure of anti-centromere antibodies and describe this autoantibody as associated with SSc and Raynaud's phenomenon (RP). However, anti-CENP-F antibodies, in contrast to anti-CENP-A/B/C antibodies, are not associated with SSc and RP. Approximately 50% of patients with anti-CENP-F antibodies have a malignancy . In addition, the IIF pattern associated with anti-CENP-F antibodies is distinct from the classical centromere staining pattern. Anti-CENP-A/B/C antibodies stain multiple nuclear dots in interphase and mitotic cells while anti-CENP-F antibodies produce a cell-cycle dependent pleomorphic pattern . Additionally, although historically known as a marker for SLE, anti-PCNA antibodies have recently been found in various conditions and their disease association has been questioned [16, 17]. Therefore, further studies are needed to re-validate the clinical association of anti-PCNA antibodies. Lastly, it is correctly noted that anti-Ro60 and anti-Ro52 antibodies impart different clinical meaning [18, 19]. Notably, another aspect concerning anti-SSA/Ro antibody is the detection of its variants directed at SS-A/Ro60 and Ro52/TRIM21, as some tests currently include only the SS-A/Ro60 antigen . Detection of anti -SSA/Ro is recommended in different clinical scenarios including counselling of patients with autoimmune disease who contemplate a pregnancy. The latter are mainly related to anti-Ro52/TRIM21 antibodies in neonatal lupus syndrome . Therefore, specifying the antigen used and evaluation of both anti-Ro52/TRIM21 and anti-SS-A/Ro60 should be considered.
With emerging novel disease modifying drugs for autoimmune diseases, the autoantibody response and levels might change over the course of the disorder, which also might impact the utility of certain assays.
Additionally, disease criteria and activity scores evolve which also can impact the performance of autoantibody assays. Therefore, large studies using well defined patient cohorts (such as the Systemic Lupus International Collaborating Clinics (SLICC)) are needed to re-evaluated anti-cellular and anti-dsDNA antibody assays for clinical use.
Tables will be published on the Electronic Pages.
1 Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 2013.
2 Bossuyt X, Fieuws S. Detection of antinuclear antibodies: added value of solid phase assay? Ann Rheum Dis 2013.
3 Abeles AM, Abeles M. The clinical utility of a positive antinuclear antibody test result. Am J Med 2013;126:342-8.
4 Walker UA, Tyndall A, Czirjak L, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis 2007;66:754- 63.
5 Mahler M, Fritzler MJ. The Clinical Significance of the Dense Fine Speckled Immunofluorescence Pattern on HEp-2 Cells for the Diagnosis of Systemic Autoimmune Diseases. Clin Dev Immunol 2012;2012:494356.
6 Smolen JS, Butcher B, Fritzler MJ, et al. Reference sera for antinuclear antibodies. II. Further definition of antibody specificities in international antinuclear antibody reference sera by immunofluorescence and western blotting. Arthritis Rheum 1997;40:413-8.
7 Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677- 86.
8 Bossuyt X. Clinical performance characteristics of a laboratory test. A practical approach in the autoimmune laboratory. Autoimmun Rev 2009;8:543-8.
9 Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis 2010;69:1420-2.
10 Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum 1997;40:1601-11.
11 Op De Beeck K, Vermeersch P, Verschueren P, et al. Detection of antinuclear antibodies by indirect immunofluorescence and by solid phase assay. Autoimmun Rev 2011;10:801-8.
12 Satoh M, Chan EK, Ho LA, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum 2012;64:2319-27.
13 Lyons R, Narain S, Nichols C, et al. Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease. Ann N Y Acad Sci 2005;1050:217-28.
14 Fritzler MJ, Rattner JB, Luft LM, et al. Historical perspectives on the discovery and elucidation of autoantibodies to centromere proteins (CENP) and the emerging importance of antibodies to CENP-F. Autoimmun Rev 2010.
15 Fritzler MJ, Rattner JB, Luft LM, et al. Historical perspectives on the discovery and elucidation of autoantibodies to centromere proteins (CENP) and the emerging importance of antibodies to CENP-F. Autoimmun Rev 2011;10:194-200.
16 Mahler M, Miyachi K, Peebles C, et al. The clinical significance of autoantibodies to the proliferating cell nuclear antigen (PCNA). Autoimmun Rev 2012;11:771-5.
17 Vermeersch P, De Beeck KO, Lauwerys BR, et al. Antinuclear antibodies directed against proliferating cell nuclear antigen are not specifically associated with systemic lupus erythematosus. Ann Rheum Dis 2009;68:1791-3.
18 Schulte-Pelkum J, Fritzler M, Mahler M. Latest update on the Ro/SS-A autoantibody system. Autoimmun Rev 2009;8:632-7.
19 Peene I, Meheus L, De KS, et al. Anti-Ro52 reactivity is an independent and additional serum marker in connective tissue disease. Ann Rheum Dis 2002;61:929-33.
20 Wiik AS, Hoier-Madsen M, Forslid J, et al. Antinuclear antibodies: A contemporary nomenclature using HEp-2 cells. J Autoimmun 2010;35:276-90.
21 Yazdany J, Schmajuk G, Robbins M, et al. Choosing wisely: the American College of Rheumatology's Top 5 list of things physicians and patients should question. Arthritis Care Res (Hoboken ) 2013;65:329-39.
22 Hoffman IE, Peene I, Veys EM, et al. Detection of specific antinuclear reactivities in patients with negative anti-nuclear antibody immunofluorescence screening tests. Clin Chem 2002;48:2171-6.
23 Mahler M, Fritzler MJ. Anti-dsDNA antibody testing in the clinic: Farr or ELISA? Nat Clin Pract Rheumatol 2007;3:72-3.
24 Derksen RH, Bast EJ, Strooisma T, et al. A comparison between the Farr radioimmunoassay and a new automated fluorescence immunoassay for the detection of antibodies against double stranded DNA in serum. Ann Rheum Dis 2002;61:1099-102.
25 Smeenk RJ, van den Brink HG, Brinkman K, et al. Anti-dsDNA: choice of assay in relation to clinical value. Rheumatol Int 1991;11:101- 7.
26 Isenberg DA, Dudeney C, Williams W, et al. Measurement of anti- DNA antibodies: a reappraisal using five different methods. Ann Rheum Dis 1987;46:448-56.
27 Isenberg DA, Dudeney C, Williams W, et al. Measurement of anti- DNA antibodies: a reappraisal using five different methods. Ann Rheum Dis 1987;46:448-56.
Conflict of Interest:
Response to Gonzalez-Gay's eLetter on Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review
In their comments about our systematic review on cardiovascular (CV) comorbidities in patients with psoriatic arthritis, (1) dr Gonzalez-Gay and colleagues, point out that in their studies, (2,3) in contrast to our Table 4, they did demonstrate a correlation between inflammatory parameters and flow-mediated dilatation (FMD) or intima media thickness (IMT). This is indeed correct when these tests are correlated with inflammatory parameters at the time of diagnosis. However, we felt that it is more appropriate to correlate the inflammatory parameters with the time when the (functional) vascular testing was done. Then the correlations of FMD and inflammatory parameters were not statistically significant (Table 3). (2)
Similarly, univariate analysis revealed no significant correlation between DAS28, ESR/CRP (at time diagnosis or at time of testing) with IMT (Table 2), (3) as also indicated in our Table 4, albeit that one may argue that some sort of AUC measure should have been used as IMT is more a reflection of a cumulative atherosclerotic burden. Finally, we fully agree with dr. Gonzalez-Gay and colleagues that further studies are needed that investigate if and to what extent anti- inflammatory treatment and/or modification of CV decreases the CV risk in patients with PsA.
1. Jamnitski A, Symmons D, Peters MJL, et al. Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review. Ann Rheum Dis 2013;72:211-6.
2. Gonzalez-Juanatey C, Llorca J, Miranda-Filloy JA, et al. Endothelial dysfunction in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum 2007;57:287-93.
3. Gonzalez-Juanatey C, Llorca J, Amigo-Diaz E, et al. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum 2007;57:1074-80.
Conflict of Interest:
Re:Are autoantibodies to RNA-polymerase III to be incorporated in routine diagnostic laboratory algorithms for systemic autoimmune rheumatic diseases?
In his letter, Jan Damoiseaux plees for testing of anti-RNA polymerase III antibodies (ARA), and also other (novel) SSc-associated antibodies, only for those patients who are really suspected for SSc. Damoiseaux argues that there is a necessity to provide clinical information together with the request for testing for rheumatic systemic autoimmune diseases.
We very much agree that testing for SSc-associated antibodies should only be requested for those people who really are suspected to have SSc. We feel that a correct request of testing for these auto-antibodies is first and foremost a responsibility of the requestor, i.e. the rheumatologist. However, immunologists and rheumatologists almost certainly can learn from each other in optimizing requests for antibody testing, which admittedly also may mean fewer requests but therefore for the right people at the right moment.
Curiously enough, in his letter Damoiseaux says that 'it is to be questioned whether inclusion of ARA was valid' and further he brings forward that '25x more false-positive ARA results are to be expected than true positives'. We do not agree with both of his points.
Indeed in the derivation cohort of 100 SSc patients and 100 controls with diseases similar to SSc, the occurrence of ARA positivity was extremely low, and consequently there was no difference between SSc patients and controls. While being eyebrow-raising (at least to us), it would have been an error to discard ARA for this reason solely, as the validation set showed later. ARA was included because many other studies showed its relevance in recognizing SSc (external knowledge) and because of the systematically assessed opinion of expert clinicians in SSc. Finding outlying results on a single item in a sample of this size most likely is the result of sampling error; which is uncomfortable, but no reason to question the inclusion of ARA as not valid. In the validation sample, 27/268 (10%) SSc patients were ARA positive, towards zero ARA positive patients in the 137 consecutively collected patients with a SSc- like disorder.
Second, in his reasoning, Damoiseaux states that in routine laboratory settings it is realistic to expect that only 2 out of each 1000 patients being suspected for systemic autoimmune rheumatic diseases, and thus are tested for autoantibodies according to local algorithms, eventually are diagnosed with SSc. Damoiseaux shows in his calculations persuasively that ARA is not suitable as a screening test. However, while a SSc/non-SSc ratio of 2/1000 probably may be realistic it can be debated whether that is usual in practice. Many referral centres for SSc may have patient domains with higher a priori probabilities for SSc than 0.002.
If we argue for example that ARA is ordered only when suspecting SSc and that in those situations it may be that non-SSc diseases are 5 times more prevalent and ARA specificity is only99%, then for every 100 SSc cases there would be 500 non-SSc cases with 5 positives while in the SSc cases there would be 11 positives (if we accept 11% sensitivity). Then there would be no where near 25 times more false positives.
We feel it is the responsibility of the rheumatologist to select those patients with a sufficiently high probability to have SSc for further testing. Notably, the SSc classification criteria for SSc consist of a number of items, including SSc-associated antibodies, that together inform of the probability of SSc being present. In diseases of the syndrome-type like SSc, it is difficult to interpret tests in isolation.
Conflict of Interest:
We thank Aramugakani et al. for their critical reading of our Editorial (1) accompanying Cheng et al. paper on the role of long-lived plasma cells (PC) in driving murine lupus nephritis (LN) (2). First, we obviously share - and explicitely mentioned - the safety issues related to long-lived PC depletion, in particular a possible high infection rate. Second, our purpose was not to question the effects of rituximab on anti- dsDNA production in active lupus patients, in particular when complete B- cell depletion is achieved (3), nor the importance of targeting plasmablasts and short-lived PC in acute lupus. Rather, we stressed that long-lived PC, including those homed in previously injured tissues, may well be responsible for relapses (sometimes after long periods of clinical and serological inactivity). In this respect, successful targeting of these cells may potentially offer a cure, as could be the case with haematopoietic stem cell transplantation.
Finally, we agree that combination (or sequential) therapy with agents targeting both plasmablasts/short-lived PCs and long-lived PCs would make sense from a theoretical viewpoint, with the obvious caveats regarding infections.
1. Ferraccioli G, Houssiau FA. Which B-cell subset should we target in lupus. Ann Rheum Dis 2013;72:1891-1892.
2. Cheng Q, Mumtaz IM, Khodadadi L, et al. Autoantibodies from long- lived 'memory' plasma cells of NZB/W mice drive immune complex nephritis. Ann Rheum Dis 2013;72 :2011-7.
3. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum 2011;63:3038-47.
Conflict of Interest:
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