Dear Editor,

Recently a collaborative initiative of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) resulted in novel classification criteria for systemic sclerosis (SSc) [1]. These criteria were first selected in a derivation cohort and, next, confirmed in a validation cohort. From a laboratory perspective it is interesting that the new criteria include, besides the classical anti- centromere and anti-topoisomerase I antibodies, also the anti-RNA polymerase III antibodies (ARA). These ARA have been associated with diffuse cutaneous involvement and increased risk for renal crisis. Although candidate parameters to be included in the novel classification criteria were selected in a multistep process, the respective parameter is expected to significantly discriminate between well-defined SSc patient and a cohort of relevant disease controls. Although ARA eventually appeared to significantly discriminate patients from controls in the validation cohort, this happens not to be the case for the derivation cohort. Therefore, it is to be questioned whether inclusion of ARA was valid.

More importantly, as a consequence of inclusion of ARA in the classification criteria, ARA will be increasingly incorporated in the routine diagnostic laboratory algorithm for systemic autoimmune rheumatic diseases (SARD). Obviously, classification criteria are not designed for diagnostic purposes, but in clinical practice they are not independent. Integration of the detection of novel SSc-associated antibodies, like ARA, in routine laboratory settings requires novel, multistep strategies to avoid high numbers of false-positive results. Bonroy et al recently calculated that in routine laboratory settings a patient/control ratio of 0.002 is realistic [2], i.e., only 2 out of each 1000 patients being suspected for SARD, and thus are tested for autoantibodies according to local algorithms, eventually are diagnosed with SSc. The ARA prevalence in SSc is about 11% (95% CI: 8-14; being in line with data obtained in the validation cohort) [3], while the specificity of the distinct test-systems varies between 99.0% and 99.5% [4,5]. Taking these data together, at least 25x more false-positive ARA results are to be expected than true positives. These data reinforce the necessity to provide clinical information together with the request for testing for SARD-related autoantibodies [6]. In that case, testing for ARA, and also other novel SSc-associated antibodies, can be restricted to those patients that really are suspected for SSc and may benefit from the result.

References

1. Van den Hoogen F, Khanna D, Frasen J, et al. 2013 classification criteria for systemic sclerosis. an American College of Rheumatology/European League against Rheumatism collaborative initiative. Ann Rheum Dis 2013; 65: 2737-2747.

2. Bonroy C, Smith V, Van Steendam K, et al. The integration of the detection of systemic sclerosis-associated antibodies in a routine laboratory setting: comparison of different strategies. Clin Chem Lab Med 2013; 51: 2151-2160.

3. Sobanski V, Dauchet L, Lef?vre G, et al. Prevalence of anti-RNA polymerase III antibodies in systemic sclerosis: new data from a French cohort, systematic review and meta-analysis. Arthritis Rheum DOI 10.1002/art.38219.

4. Villalta D, Imbastaro T, Di Giovanni S, et al. Diagnostic accuracy and predictive value of extended autoantibody profile in systemic sclerosis. Autoimmun Rev 2013; 12: 14-120.

5. Maes L, Blockmans D, Verschueren P, et al. Anti-PM/Scl-100 and anti-RNA-polymerase III antibodies in scleroderma. Clin Chim Acta 2010; 411: 965-971.

6. Agmon-Levin N, Damoiseaux J, Shoenfeld Y. Response to: 'Detection of anti-nuclear antibodies, added-value of solid phase assay?' by Bossuyt and Fieuws. Ann Rheum Dis DOI 10.1136/annrheumdis-2013-204797.

Conflict of Interest:

None declared

Dear Editor,

We read with great interest the elegant systematic review on cardiovascular (CV) comorbidities in patients with psoriatic arthritis (PsA) published in the February 2013 issue of ARD by Jamnitski et al.[1] Overall, we agree that there is an increased CV risk in patients with PsA similar to that observed in patients with rheumatoid arthritis (RA).[2] Therefore, adequate CV risk stratification is also required in PsA patients.
The authors confirmed that subclinical atherosclerosis and CV risk factors are increased in patients with PsA when compared with controls.[1] It is well known that inflammation promotes endothelial cell activation in patients with chronic inflammatory rheumatic diseases like RA.[3] The presence of a chronic inflammatory state is responsible for the development of subclinical atherosclerosis and increased incidence of CV events in these patients.[4-6] Interestingly, several noninvasive imaging techniques offer a unique opportunity to study the relation of surrogate markers to the development of atherosclerosis. More specifically, brachial flow-mediated dilation (FMD) and carotid artery intima-media thickness (IMT) measurements have been used to assess endothelial function and establish subclinical atherosclerosis respectively. With respect to this, in table 4 of their review article, Jamnitski et al mentioned two studies by Gonzalez-Juanatey et al in which both parameters, FMD and IMT, were abnormal without being correlated with inflammatory markers.[7,8] This is in contradiction with the generalized concept supporting that persistent inflammatory burden causes endothelial dysfunction, subclinical atherosclerosis and increased risk of CV death. However, Gonzalez-Juanatey et al demonstrated that in patients with PsA without clinically evident CV disease or classic atherosclerosis risk factors, there was significant correlation between CRP and ESR levels at the time of disease diagnosis and the presence of endothelial dysfunction, manifested by FMD impairment.[7] This observation was in keeping with epidemiological data that highlighted the relevance of baseline level of CRP as a predictor of CV mortality in patients with inflammatory polyarthritis.[9] PsA patients from the studies by Gonzalez-Juanatey et al were being actively treated and had low disease activity at the time of the ultrasonography assessment. This may explain the lack of significant correlation between ESR and CRP and surrogate markers of subclinical atherosclerosis at that time.[7,8] Nevertheless, when data from carotid ultrasound were evaluated, it was seen that PsA patients exhibited greater carotid artery IMT than did matched controls, and it was correlated with age at diagnosis, disease duration, total cholesterol and LDL cholesterol.[8]
In any case, correlation between FMD and carotid IMT does not always occur.
In a former study on patients with RA we observed that carotid IMT was negatively associated with FMD when the time from disease diagnosis ranged from 7.5-20 years but not within the first 5 years after disease diagnosis. It is probably due to the fact that abnormal IMT and endothelial dysfunction reflect different stages of atherosclerosis disease.[10]
Finally, in agreement with Jamnitski et al,[1] we support the claim that further studies are needed to confirm whether inflammatory suppression or modification of traditional CV risk factors, or both, will reduce CV risk en patients with PsA.

References

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. Del Rincon I, O'Leary DH, Freeman GL, et al. Acceleration of atherosclerosis during the course of rheumatoid arthritis. Atherosclerosis 2007;195:354-60.

3. Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J. Rheumatoid arthritis: a disease associated with accelerated atherogenesis. Semin Arthritis Rheum 2005;35:8-17.

4. Sattar N, McCarey DW, Capell H, et al. Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis [review]. Circulation 2003;108:2957-63.

5. Del Rincón I, Williams K, Stern MP, et al. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum 2003;48:1833-40.

6. Gonzalez-Gay MA, Gonzalez-Juanatey C, Lopez-Diaz MJ, et al. HLA-DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis. Arthritis Rheum 2007;57:125-32.

7. 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.

8. 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.

9. Goodson NJ, Symmons DP, Scott DG, et al. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum 2005;52:2293-9.

10. González-Juanatey C, Llorca J, González-Gay MA. Correlation between endothelial function and carotid atherosclerosis in rheumatoid arthritis patients with long-standing disease. Arthritis Res Ther 2011;13:R101.

Conflict of Interest:

None declared

Dear Editor,

We read with interest the editorial by Ferraccioli and Houssiau proposing the specific targeting of long lived plasma cells (PCs) in human lupus nephritis (LN) [1]. The authors present a cogent summary of experiments showing that long-lived PCs alone are sufficient to induce murine LN, and that targeting of PCs in these models is successful. However, we believe that clinical experience with the treatment of human SLE indicates that plasmablasts and short-lived PCs, recently derived from autoreactive B-cells, are more important in the generation of autoantibody and clinical disease activity.

The literature on antibody secreting cell subsets are in some cases difficult to interpret due to the use of the terms plasmablast and plasma cell interchangeably, and different surface phenotypes in mouse and human [2]. Human plasmablasts and PCs (latter labelled CD27-ve in article) both express CD27.

Adoptive transfer of plasmablasts alone that mature into long-lived PCs is sufficient to cause LN in Rag-/- mice, which have no B-cells [3]. This situation is analogous to therapeutic B cell depletion in human SLE, with continued plasma cell activity in the absence of B cells. Rituximab therapy profoundly depletes B-cells, but does not directly affect long- lived PCs - demonstrated by the maintenance of total IgG including anti- microbial antibodies [4,5]. Evidence of clinical efficacy of B cell depletion in human SLE is controversial with contradictory RCTs [6,7] and open label studies [8]. However, there is abundant evidence that anti- dsDNA titre falls after rituximab [4-7]. We have previously shown that reduction in anti-dsDNA was only observed in patients with complete depletion of both B-cells and plasmablasts [5]. We also found that clinical relapse following rituximab was strongly associated with plasmablast repopulation [5]. Collectively, the effects of B cell depletion therapy in SLE suggest that autoantibodies are secreted by shorter-lived antibody secreting cells compared to those that maintain steady state antimicrobial immunoglobulin levels. This selective effect of B cell depletion on the antibody secreting cell pool may be crucial to its safety.

We therefore believe that targeting of PCs in isolation would have limited efficacy since these cells would be replenished from autoreactive memory B-cells. It is possible that, in a subset of SLE patients resistant to rituximab, combined targeting of long-lived plasma cells is required. However, there would be important safety considerations for such indiscriminate complete ablation of autoreactive and antimicrobial antibody production.

References

1. Ferraccioli G, Houssiau FA. Which B-cell subset should we target in lupus? Ann Rheum Dis 2013;72(12):1891-2.

2. Gordon CJ, Grafton G, Wood PM, et al. Modelling the human immune response: can mice be trusted? Commentary. Curr Opin Pharmacol 2001;1(4):431-5.

3. 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(12):2011-7.

4. Cambridge G, Leandro MJ, Teodorescu M, et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 2006;54(11):3612 -22.

5. Vital EM, Dass S, Buch MH, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum 2011;63(10):3038-47.

6. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62(1):222-33.

7. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64(4):1215-26.

8. Ramos-Casals M, Soto MJ, Cuadrado MJ, et al. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009;18(9):767-76.

Conflict of Interest:

None declared

Dear Editor

I read with interest the study by Takeuchi et al (1) looking at the role of monotherapy golimumab in Japanese rheumatoid arthritis (RA) patients, who had active disease despite disease modifying anti-rheumatic drug (DMARD) therapy. Inclusion criteria for the study stipulated that patients have 2/3 criteria which were: elevated inflammatory markers, erosions on radiograph or positive serology, in addition to more than 6 swollen and tender joints despite DMARD therapy for at least 3 months. They had mean disease duration of close to 9 years and mean swollen and tender joint counts of roughly 16 and 13. They were then randomized to placebo, golimumab 50 or golimumab 100 mg injections. Primary efficacy outcome was at 14 weeks, as the authors state "due to ethical concerns about the potential for an inadequate response to placebo". At 14 weeks both golimumab doses showed better efficacy than placebo. In the introduction section, the justification for looking into monotherapy was explained as "some patients cannot tolerate MTX treatment; therefore, it is clinically relevant to evaluate the safety and efficacy of monotherapy...".
In the discussion, authors state that 100 mg golimumab was studied as monotherapy in a previous publication (2) but in that study primary end point was not reached by this monotherapy arm. Various reasons are presented to possibly explain this difference. However, in the current study this time the 50 mg monotherapy did not show any significant difference in radiographic inhibition from placebo and neither did the 100 mg until post hoc adjustments were made and the data were reanalyzed.
There are several serious methodological and ethical issues with this study that are not addressed in the paper. First, the trial was registered at the clinicaltrials.gov site in October 2008. It is unclear to me how the ethical justification of withholding active treatment from patients with RA, for up to 4 months, including the 4 weeks of washout before the study medication was administered, who were failing their current therapy and were at risk for destructive disease as reflected by the inclusion criteria (high joint counts, serological or radiographic evidence for higher risk for erosions) was made. In 2008 there is no more equipoise about how patients fare when they are not given DMARDs, biologics or combinations of these agents.
Authors state, as mentioned previously, that "due to ethical concerns about the potential for an inadequate response to placebo" they were analyzed at 14 weeks and switched to active drug at 16 weeks. What is meant by "potential for an inadequate response to placebo"? Is it only a potential or a near certainty? How is it that authors truly believe this is not a resolved issue in this day and age of RA treatment, that active RA patients need treatment not placebo, and how is that any IRB would think this to be ethical? It would be of interest to see what the informed consent document actually read and how the information that despite available active medications that the patients could have been switched to including other biologic agents, , instead of enrolling in this trial, treatment was withheld for over 4 months (including the 4 weeks of washout before the study medication was administered), when overwhelming published data suggest early and aggressive treatment is the best way to get RA under control.
The second issue is that even though the similar intervention was tried in an earlier study (2) , the need to try again was felt. This time there were some differences that suggest golimumab 100 mg has radiographic (no such benefit was seen with 50 mg, the approved dose in the US) and clinical benefit but who is to say the reasons listed by the authors that affected the first trials results in one way, did not affect the results of the second trial in the other direction? Which one is the "true" study? This is now the second study where radiographic benefit was not demonstrated with golimumab until post hoc analysis of the data was done. Several explanations for this state of affairs come to mind; 1) either radiographic progression is not a clinically important outcome, as was argued previously (3), since the actual differences are so small to have clinical relevance 2) golimumab does not work as well as some other biologics, which have shown effects on radiographic progression as a primary outcome with no need for posthoc analysis, or 3) the authors would like to think and are trying to prove golimumab is no different than any other biologic, despite what the data show. None of these are good reasons for withholding treatment from active RA patients for close to 4 months in the guise of scientific experimentation.

References

1. Takeuchi T, Harigai M, Tanaka Y, et al. Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicenter, randomized, double-blind, placebo-controlled GO-MONO study through 24 weeks. Ann Rheum Dis. 2013;72:1488-95.

2. 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.

3. Yazici Y, Yazici H. Tumor necrosis factor alpha inhibitors, methotrexate or both? An inquiry into the formal evidence for when they are to be used in rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:449- 52.

Conflict of Interest:

None declared