Dear Editor,

An association has been made between systemic lupus erythematosus (SLE) and NHL. A common genetic aetiology is suggested by the observation of a marked over representation of lymphoma cases in families with SLE. Likewise, families have been described with both lymphoma and SLE. A tumour suppressor gene PTEN may link the two disorders via a defective apoptosis pathway to eliminate hyperactive B and T cells in SLE. The accumulation of clonally expanded hyperactive B-cells that recognize self-antigens in the lymph nodes of SLE may predispose these B-cells to DNA breaks, facilitating tumourigenesis.

Dear Editor,

We thank Dr Klauser and colleagues for their comments to our paper "Ultrasound findings in healthy joints using two different contrast media".

We would like to take the opportunity to respond to their comments.

Please bear in mind the findings that made us perform this study: In the literature, the injection of contrast lead to more vessels being visualised in inflamed joints while non-inflamed joints remained without Doppler activity.[1-3] Opposed to this, two studies showed Doppler activity in normal joints without the use of contrast agents.[4,5] One explanation for this discrepancy could be that the latter used machinery/settings with a higher Doppler sensitivity and our hypothesis was that we would find Doppler activity in some normal joints before contrast injection and in more normal joints after contrast injection. We did not believe that contrast injection was so ideal that it would only enhance and bring to visualisation flow in RA-joints. Our study supported our hypothesis.

The appearance of blooming artefact is well know to us and is also mentioned in the paper page 825 top section. We accept the presence of blooming artefacts – to avoid blooming artefacts we would need to adjust Doppler gain to an unacceptably low level, which would lead to non-visualisation of true flow. Another alternative to minimising blooming artefact is to increase the Doppler frequency. Again an unsatisfactory approach since it leads to reduced sensitivity. The blooming artefact is of course present, since we see flow in vessels that we cannot see with grey-scale imaging! All in all we do not regard blooming artefact as a problem and accept its presence as a systematic error since it is flow-generated.

When Dr Klauser addresses the issue of blooming artefact it may be to challenge our findings that were: 1) More joints were colour Doppler positive after contrast injection, 2) A higher mean colour fraction was found after contrast injection. Perhaps dr. Klauser implies that the extra blooming caused by contrast explains our findings. The blooming artefact cannot explain why a joint without Doppler activity before contrast injection becomes Doppler-positive after. The elevation in colour fraction after contrast injection is of course partly due to increased blooming but as seen in our illustration extra vessels became visible.

Dr Klauser states that bolus injection causes blooming, that blooming causes bubble destruction before entering synovial vessels and that this could explain our statement concerning vessel size! Vessel size? Nowhere in our paper does the word size appear. Most of the synovial vessels we see with colour Doppler are below the resolution of grey-scale US and cannot be measured. With Doppler, measurements cannot be trusted due to blooming artefacts.

Dr Klauser advocates the use of continuous contrast infusion because it reduces significantly blooming artefacts, is cost-effective, and because “Using this protocol, increased vascularity detection in early rheumatoid arthritis joints was found, but no vascularity in healthy controls”. We find the latter as an indication of low Doppler sensitivity. With contrast injection they were not able to disclose flow in normal joints – flow that we see without the use of contrast. We fail to understand what it is Dr. Klauser questions in our equipment and settings since our results cannot be called surprising: We saw flow before contrast injection and more after.

We chose to use a bolus injection for both contrast agents as for these two to be comparable. To our knowledge, Dr. Klauser and colleagues are the only group to have used continuous contrast injection in the evaluation of inflammatory flow.[3] All other studies have used bolus injection or a slow injection.[1;2;6-8] That is another reason for choosing bolus injection: the study would be comparable to most of those already existing.

Dr Klauser shows some concern as to the time spent examining the joints: First of all we think it is important to remember that this study is carried out on healthy persons – this means that the positive Doppler findings are much less compared to those seen in inflammatory conditions. Bearing this in mind the time used for investigation of each joint is less than for joints with pathology. Dr. Klauser and colleagues also mentions the use of 3 RI measurements which also we recommend to be used for a mean RI. When possible, as we state in methods, we obtained a mean RI. However, only seldom did we obtain three measurements for lack of vessels. We did not have difficulties with the time. The investigator has 23 years experience with full time ultrasound. Our scanning protocol was first to evaluate the joints in a predefined order for colour Doppler activity (our highest priority) and then return to the colour Doppler positive joints for the RI measurements (that were performed after the critical 60 seconds mentioned by dr. Klauser). The reason for measuring the RI was twofold: 1) Obtaining the Doppler spectrum proved that we were seeing true flow and not some artefact, and 2) The vessels we were seeing had a high (normal) RI.

Dr. Klauser worries about microbubble destruction in our study. We fail to see that there is any indication of this in our findings. We do find more vascularity after contrast injection and with our RI-measurements we know that we are not seeing artefacts.

Dr. Klauser argues that our hypothesis (as to the behaviour of low- end and high-end equipment) is only a hypothesis and not based on data. We can only agree. We have not investigated the behaviour of low-end equipment. That is why it is a hypothesis as also stated in the paper!

We find that the one of our core statements was not understood. Namely, that in rheumatology, resources may probably be better spent on improving the Doppler sensitivity (acquiring high-end equipment) than on injecting contrast agents (expensive and invasive) both serving the purpose of seeing more vascularity. The methodological limitations mentioned by dr. Klauser should (if present at all) have resulted in poor sensitivity after contrast injection, which was not the case in our study!

Respectfully

Lene Terslev
Søren Torp-Pedersen
Michael Bachmann Nielsen

References:

1. Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Ostergaard M. Contrast-enhanced power Doppler ultrasonography of the metacarpophalangeal joints in rheumatoid arthritis. Eur Radiol 2003; 13:163-168.

2. Magarelli N, Guglielmi G, Di Matteo L, Tartaro A, Mattei PA, Bonomo L. Diagnostic utility of an echo-contrast agent in patients with synovitis using power Doppler ultrasound: a preliminary study with comparison to contrast-enhanced MRI. Eur Radiol 2001; 11(6):1039-1046.

3. Klauser A, Frauscher F, Schirmer M, Halpern E, Pallwein L, Herold M et al. The value of contrast-enhanced color Doppler ultrasound in the detection of vascularization of finger joints in patients with rheumatoid arthritis. Arthritis Rheum 2002; 46(3):647-653.

4. Hau M, Schultz H, Tony HP, Keberle M, Jahns R, Haerten R et al. Evaluation of pannus and vascularization of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis by high-resolution ultrasound (multidimensional linear array). Arthritis Rheum 1999; 42(11):2303-2308.

5. Terslev L, Torp-Pedersen S, Qvistgaard E, Von der Recke P, Bliddal H. Doppler Ultrasound Findings In Healthy Wrists And Finger Joints. Ann Rheum Dis 2004; 63:644-648.

6. Qvistgaard E, Rogind H, Torp-Pedersen S, Terslev L, Danneskiold- Samsoe B, Bliddal H. Quantitative ultrasonography in rheumatoid arthritis: evaluation of inflammation by Doppler technique. Ann Rheum Dis 2001; 60(7):690-693.

7. Carotti M, Salaffi F, Manganelli P, Salera D, Simonetti B, Grassi W. Power Doppler sonography in the assessment of synovial tissue of the knee joint in rheumatoid arthritis: a preliminary experience. Ann Rheum Dis 2002; 61(10):877-882.

8. Salaffi F, Carotti M, Manganelli P, Filippucci E, Giuseppetti GM, Grassi W. Contrast-enhanced power Doppler sonography of knee synovitis in rheumatoid arthritis: assessment of therapeutic response. Clin Rheumatol 2004; 23(4):285-290.

Dear Editor

The article "Cost effectiveness of adalimumab in the treatment of patients with moderate to severe rheumatoid arthritis in Sweden" by Bansbeck, Brennan, and Ghatnekar [1] deals with an important subject, i.e. is it justifiable from a cost-effectiveness point of view to use tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA).

We acknowledge that the authors have used data from our publications (references 14,15 in the article). We are concerned when these data are used in a context that they were not intended for. The authors draw wide ranging conclusions on adalimumab cost-effectiveness from results in our observational study describing early experience of etanercept, infliximab, and leflunomide but not of adalimumab. We were very clear in pointing out that the patients treated with these remedies in southern Sweden at that time were not randomly selected, but were the most severely affected and difficult to treat patients that had tried almost all treatment modalities in the pre-TNF blocking years. On the other hand we agree with the authors, that observational data may mirror clinical reality more closely, and is complimentary to randomised control trials, which represent a different patient mix. However, the uncritical modelling of data from different data sets without accounting for differences in the patient mix raises our concern.

From our perspective as rheumatologists we would like to raise several points of concern regarding the study:

• Although it is reasonably correct to state that an ineffective treatment in RA patients is replaced by a new treatment remedy, this has not been formally investigated. In contrast, it is not true that treatment decisions in Sweden rely on changes in DAS28 and fulfilment of a specific response criteria set. This is not stipulated in the guidelines issued from Swedish Rheumatology Society. Instead treatment cessation relies on clinician’s and patient’s consensus (be it due to adverse events or inadequate response).
• It is questionable to equate ACR20=EULAR moderate responders and ACR50=EULAR good responders. The authors may possibly not take into account that all ACR50 responders are included in the ACR20 responders, whereas EULAR moderate responders are separate from EULAR good responders. We have investigated how different response criteria set perform in our setting and warned against their uncritical use in treatment decisions in clinical practice [2]. We believe that drug adherence is a better measure of drug continuation in clinical practice.
• The systematic translation of a certain ACR response into a specific HAQ improvement needs validation, as well as the translation of a DAS score into a specific HAQ score (table 2 in the article). These instruments have been developed for quite different purposes and measures different aspects of the disease. We actually found that HAQ alone was not sufficiently exact as utility and economic outcome measure in our particular patient setting [3].
• Annual HAQ progression of 0.132 in post anti-TNF treated as opposed to 0.03 in other RA patients seems little substantiated but the almost 4- fold increased HAQ progression rate has huge impact on long term estimated functional and economic outcome in patients stopping anti-TNF drugs in the model and therefore favours such drug continuation.
• It is not likely that three disease modifying drugs (DMARDs) will be used after failure of one biologic drug and no further biologic agent will be tried. The use and performance of post-biologic DMARD treatment is not known with any reasonable certainty but real life experience in southern Sweden shows that 44 % of initiation of a biologic drug in 2003 occured in patients previously being treated with another such drug [4].
• We seriously doubt that our relatively restricted leflunomide adherence and efficacy data can be used as a surrogate for all post-TNF blocking DMARD outcomes.

Finally we find the statement "indirect comparisons are almost universal in health economic analyses" troublesome. From a clinician´s perspective we think that health economic analyses in RA should always be done with intimate knowledge of the patient cohort on which the calculations are based. Any projection and modelling in other settings must be carried out with great care in close collaboration between scientists trained in health economics, which the authors are, and rheumatologists. We thoroughly agree with Symmons that this type of investigation is a legitimate scientific endeavour and should therefore always be submitted to critical scientific appraisal [5].

References

1. Bansback NJ, Brennan A, Ghatnekar O. Cost effectiveness of adalimumab in the treatment of patients with moderate to severe rheumatoid arthritis in Sweden Ann Rheum Dis 2005;64:995-1002.

2. Gülfe A, Saxne T, Geborek P. Response criteria for rheumatoid arthritis in clinical practice: how useful are they? Ann Rheum Dis 2005;64:1186-1189

3. Kobelt G, Eberhardt K, Geborek P. TNF-Inhibitors in the Treatment of Rheumatoid Arthritis in Clinical Practice. Costs and outcomes in 1 year follow-up of patients with rheumatoid arthritis treated with etanercept or infliximab in Southern Sweden. Ann Rheum Dis 2004;63:4-10.

4. Geborek P, Leden I, Nitelius E, Noltorp S, Petri H, Jacobsson L, Larsson L, Saxne T. Regional population based studies of biological anti- rheumatic drug use in southern Sweden validated against pharmaceutical sales. Ann Rheum Dis in press

5. Symmons DPH. Anti-tumour necrosis factor therapy: can we afford it? Ann Rheum Dis 2005; 64: 969-970.

Dear Editor,

The answer is generally “No”.

Antiphospholipid antibodies/ beta2-glycoprotein I complexes are associated with arterial and venous thrombosis, fetal loss and sometimes with thrombocytopenia, i.e. the antiphospholipid syndrome. However, immune-complex mediated platelet destruction is not a specific mechanism restricted to certain types of immune-complexes.

Platelets have both immunoglobulin receptor (FcR) and complement receptors (C1q, CR2, CR4) which enable platelets to interact in immunological reactions. The cell membrane of platelets is also equipped with several regulatory complement proteins (DAF, MCP, MIRL, C8bp) which protect them from complement attack induced by the binding of platelet autoantibodies or non-specific immune- complexes.

It has been shown that blood cells and platelets act not only as effector cells in the inflammatory process but also in transporting the complexes in their clearance from the circulation. This mechanism may become clinically important in humans at high immune-complex loads, due to less efficient handling of immune-complexes in complement deficient individuals or increased generation of complexes in individuals with a high antigen load, such as systemic lupus erythematosus (SLE), leading to increased platelet turnover. This mechanism is compatible with our finding that SLE patients with low C3 or CH50 were more likely to be thrombocytopenic and explains a part of the multifactorial etiology of lupus thrombocytopenia.

Thrombocytopenia has been identified as a component of a severe familial form of SLE and with genes at 1q22-23 and 11p13 contributing to this severe phenotype and the subsequent morbidity and mortality. Although genes are related to thrombocytopenia, they may also be related to severe disease and early demise. Morever the genetics of human SLE are obviously extremely complicated to draw safe conclusions.

The pathophysiology of lupus seems to be a complex process, where antiplatelet antibodies, antiphospholipid syndrome, thrombotic microangiopathies, hemophagocytic syndrome, cytotoxic therapy and infections are important. To our knowledge so far, there is not a distinctive clinical, serological and genetic profile predisposing to thrombocytopenia.

Even if it were such a profile, its clinical usefulness would be questionable, since thrombocytopenia is mostly a benign complication and amenable to treatment, and adverse outcome is not directly related to this complication.