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

Dear Editor,

We read with great interest the report by Dejaco and co-authors related to diagnosis of carpal tunnel syndrome (CTS) by ultrasound [1]. Dejaco et al. compared ultrasound measurement of median nerve cross- sectional area (CSA) at different anatomical landmarks in great detail and evaluated the value of intranerval power Doppler signals for CTS diagnosis. It provided a good data support for the ultrasonic evaluation of CTS. However, this study prompts questions on the three following points:

1. CSA as an important indicator for CTS diagnosis also has limitations. We do agree that CSA is the most commonly used for evaluation of nerve swelling. However, some patients had typical clinical symptoms, but those median nerves did not necessarily present obviously swelling and compression at the carpal tunnel inlet or outlet. Instead, the ultrasonography showed the abnormal echo of contents within carpal tunnel. Several reports also have been published on CTS caused by space occupying lesions including tenosynovitis [2-4], tumors[2,4,5], calcified mass[4,6] or tophaceous gout[4,7]. We also found such cases were common in systemic diseases such as rheumatoid arthritis, diabetes mellitus, gout and so on. Take tenosynovitis for example, transverse sonography of the median nerve at the level of the pisiform bone showed an ovoid hypoechoic reticular structure without swelling. However, the deep tissue of nerve showed swelling and hypoechoic (Fig.1A). On the longitudinal sonograms, the nerve appeared as a consistent thickness of strip structure without a sudden thinning or thickening (Fig.1B). However, power Doppler showed increased blood flow signal within the nerve and carpal tunnel (Fig.1B, 1C). CSA as a diagnostic criterion will increase the false negative rate of CTS.

2. Ultrasound also has disadvantages for diagnosis of CTS. As we know, the diagnosis of CTS is based primarily on clinical examination and nerve conduction studies (NCS). In the last 20 years, Ultrasound has been employed as an important imaging tool for CTS. The value of sonographic assessment for CTS depended mainly on three sonographic techniques: measurement of median nerve CSA at differential locations along the carpal tunnel, structural analysis of the median nerve and bowing of the flexor retinaculum [8]. We agree ultrasound can evaluate morphological changes of median nerve and provide a good data support for CTS. More specifically, ultrasound is not much an evaluation as a diagnostic tool for CTS..

3. The term "volume" mentioned in the title was used inappropriately. Volume of median nerve should be measured on the 3-dimensional space image. However, Dejaco et al. [1] measured CSA of nerves on the 2D image. In order to avoid ambiguity, we proposed to use the term "area".

References

1. Dejaco C, Stradner M, Zauner D et al. Ultrasound for diagnosis of carpal tunnel syndrome: comparison of different methods to determine median nerve volume and value of power Doppler sonography. Ann Rheum Dis 2013;72:1934-9.

2.Chen CH, Wu T, Sun JS et al. Unusual causes of carpal tunnel syndrome: space occupying lesions. J Hand Surg Eur Vol 2012;37:14-9.

3.Klauser AS, Faschingbauer R, Bauer T et al. Entrapment neuropathies II: carpal tunnel syndrome. Semin Musculoskelet Radiol. 2010;14:487-500.

4. Kang HJ, Jung SH, Yoon HK et al. Carpal tunnel syndrome caused by space occupying lesions. Yonsei Med J 2009;50:257-61.

5. Ait Essi F, Younsi A, Abkari I et al. Diffuse tenosenovial giant cell tumor of the wrist revealed by carpal tunnel syndrome: report of a case. Chir Main 201;31:256-8.

6. Takada T, Fujioka H, Mizuno K. Carpal tunnel syndrome caused by an idiopathic calcified mass. Arch Orthop Trauma Surg 2000;120:226-7.

7. Patil VS, Chopra A. Watch out for 'pins and needles' in hands--it may be a case of gout. Clin Rheumatol 2007;26:2185-7.

8. Nakamichi K, Tachibana S. Ultrasonographic findings in isolated neuritis of the posterior interosseous nerve: comparison with normal findings. J Ultrasound Med 2007;26:683-687.

ELetter and Figures will be available on the Electronic Pages soon

Figure Legends
Figure 1
Transverse and longitudinal sonograms of the median nerve at the carpal tunnel
A Transverse sonogram of the median nerve at the level of the pisiform bone (CSA:7mm2)
B Longitudinal sonogram of the median nerve
C Transverse sonogram of the carpal tunnel with abundant blood flow signal

Conflict of Interest:

None declared

Dear Editor,

Sieper et al. evaluated whether combination therapy with Infliximab (IFX) and naproxen (NPX) was superior to treatment with NPX alone in patients who had active moderate-to-severe early (disease duration under 3 years) active axial spondyloarthritis (SpA) and who were naive to nonsteroidal anti-inflammatory drugs (NSAIDs) or had only been treated with a submaximal dose of NSAIDs (1). This study is the first investigation of the potential benefits of early TNF-antagonist treatment in active axial SpA patients who are not yet refractory to NSAID therapy. Additionally, this represents the first randomised controlled clinical trial to use the imaging portion of the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA with active inflammation of the SI joints on MRI at baseline. Most importantly, the evidence from this study supports early diagnosis and treatment of SpA with a full dose of NSAIDs first, escalating to combination NSAID+TNF antagonist treatment in patients who have insufficient response.
Moreover, this study provides important insights about the application of the new classification criteria for axial SpA in a clinical trial.
Approximately 60 % of patients had ankylosing spondylitis (AS) fulfilling the modified New York radiographic criteria. Thus 40% of patients had nonradiographic axial SpA classified by MRI; it would be of interest to know if in these patients the additional SpA features for classification were different from AS patients. Arthritis was quite often in both treatment arms (45.3% vs 26.9%, respectively). Importantly, the 66- joint swollen joint count and 68- joint tender joint count was ameliorated considerably in both treatment arms and significantly better for swollen joints with NSAID+TNF antagonist treatment. Also in other studies testing adalimumab against placebo and etanercept against sulfasalazine, respectively, arthritis was found in 29% up to 52% of patients with early axial SpA (2, 3, 4). Evidently, simultaneous peripheral symptoms are frequent in nonradiographic and early axial SpA.
This raises the question if future studies should include together patients fulfilling the axial and/or peripheral SpA criteria to establish treatment evidences for SpA in general; thus would be possible to promote approval of established and new treatments for most conditions unified under the umbrella of SpA instead of testing for each individual diagnosis and subgroup of clinical manifestations. However, this requires more attention to infections associated with reactive arthritis which have been included in the criteria for peripheral but not for axial SpA (5, 6, 7).
Preceding infection (balanitis, urethritis, cervicitis and/or acute diarrhea) is noted in 37% of patients with peripheral SpA (8). Furthermore 35% of the patients with peripheral SpA have radiographic sacroiliitis (8). This overlap between axial and peripheral symptoms demonstrates that the construct of separating SpA into predominant clinical manifestations is somewhat artificial and only partially reflect the clinical reality given the heterogeneous character and fluctuating course of the diseases belonging to the SpA concept. Especially in the early years of the disease, the main target of the new classification criteria, AS progresses by a series of flares involving localized area such as the knee, neck, ankle, or localized area of the back (9, 10, 11). Many patients with SpA at some time of the disease can have either prominent peripheral and axial symptoms concurrently or peripheral and axial symptoms successively. The classification may change from axial to peripheral and vice versa at different times in a given study, compromising the consistency of classification in long-term trials. Finally, the description of increased frequency of Chlamydia-positive synovial tissue samples in patients with chronic undifferentiated SpA, the growing insight into the etiology of persistent chlamydial infection, and the promising treatment of Chlamydia- induced arthritis with combination antibiotic therapy indicate the necessity of further splitting SpA into underlying disease entities such as reactive arthritis (c. f. 12).

References

1. Sieper J, Lenaerts J, Wollenhaupt J, et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo- controlled INFAST study, Part 1. Ann Rheum Dis Published Online First: [21 May 2013] doi:10.1136/annrheumdis-2012-203201

2. Sieper J, van der Heijde D, Dougados M et al. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013;72:815-22.

3. Haibel H, Rudwaleit M, Listing J, et al. Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo- controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 2008;58:1981-91.

4. Song IH, Hermann K, Haibel H et al. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial. Ann Rheum Dis 2011;70:590-6.

5. Rudwaleit M, van der Heijde D, Landew? R, et al. The Assessment of SpondyloArthritis international Society (ASAS) Classification Criteria for peripheral Spondyloarthritis and for Spondyloarthritis in general. Ann Rheum Dis 2011;70:15-21.

6. Zeidler H, Amor B. The Assessment in Spondyloarthritis International Society (ASAS) classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general: the spondyloarthritis concept in progress. Ann Rheum Dis 2011;70:1-3.

7. Zeidler H. The historical concept of interrelated conditions lumped together as a family of distinct diseases is not outdated. Arthritis Rheum 2013;65:2214-5.

8. van den Berg R, van Gaalen F, van der Helm-van Mil A, Huizinga T, van der Heijde D. Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden Early Arthritis cohort. Ann Rheum Dis 2012;71:1366-9.

9. Wilkinson M, Bywaters EG. Clinical features and course of ankylosing spondylitis; as seen in a follow-up of 222 hospital referred cases. Ann Rheum Dis 1958;17:209-28.

10. Brophy S, Calin A. Definition of disease flare in ankylosing spondylitis: the patients' perspective. J Rheumatol 2002;29:954-8.

11. Stone MA, Pomeroy E, Keat A et al. Assessment of the impact of flares in ankylosing spondylitis disease activity using the Flare Illustration. Rheumatology 2008;47:1213-8.

12. Zeidler H, Hudson AP. New insights into Chlamydia and arthritis. Promise of a cure? Ann Rheum Dis 2013 (in press).

Conflict of Interest:

None declared