Dear Editor,

Thrombocytopenia in SLE results from various mechanisms and can be predicted in certain patients with high levels of immune complexes containing beta-2-glycoprotein I. They have also higher levels of serum lipoprotein(a). Thrombocytopenia is considered to be a component of a severe familial form of SLE. The genes at 1q22-23 and 11p13 are linked to this phenotype and to the subsequent high mortality associated with thrombocytopenia in SLE.

Dear Editor,

In their article Terslev and colleagues [1] compared bolus administration of two different ultrasound (US) contrast agents to detect joint vascularity in healthy volunteers. We would like to offer several comments concerning use and behavior of US contrast media.

First, bolus administration of Levovist and SonoVue when using colour/power Doppler (CDUS) results in strong blooming of colour signals after injection, resulting in high microbubble destruction, so that microbubbles are destroyed before entering small synovial vessels in a mean enhancement duration of 4 –5 minutes.[2] This could explain the statement of Terslev et al. that contrast enhanced CDUS depicts vessels of a size, which can be observed by unenhanced CDUS using high end US equipment; assessment of vessel size is inaccurate, since blooming causes overestimation of vessel diameter. In recent studies continuous infusion enabled mean enhancement duration of 15 minutes, which besides offering a cost-effective approach reduces significantly blooming artefacts.[3,4] Using this protocol, increased vascularity detection in early rheumatoid arthritis finger joints was found, but no vascularity in healthy controls.[3]

Second, SonoVue is a "new generation" contrast media, designed for "low Mechanical Index" Grey scale US, using lower acoustical output settings, resulting in less microbubble destruction. Improved spatial resolution allows for direct detection of microbubbles, sized from 2-8 micron.[5] No change in scanning protocol between using the two different contrast media is mentioned by Terslev and colleagues. If MI and acoustic output are not adapted accordingly, microbubble lifetime is shortened, they cannot enter small vessels and early microbubbles destruction and artefacts results.

Furthermore Resistive Index (RI) measurement were performed, resulting additionally in increased microbubble destruction, therefore representing further major limitations for sensitive contrast detection in small vessels. This might explain why the well-known effect of 20 dB CDUS signal increase after contrast administration, affecting also RI measurements was not observed.[6] Furthermore bolus administration can lead to artificially increased Peak Systolic Velocity (PSV) within first 30 – 60 seconds, influencing RI measurements.

Third we are wondering concerning their timely scanning protocol: altogether 8 joints in every patient were investigated regarding enhancement and RI, resulting in scanning time less than 30 sec for each joint. Moreover 3 RI measurements per vessel are recommended and the median value should be taken.[6] It might be interesting how long the examiner should be experienced to perform such measurements. The exact examination protocol should be stated, because this provides important information for interested reader.

Finally, it was not evaluated if high-end systems detect only increased numbers of "normal vessels" in contrary to low end systems, which may detect more inflamed vessels by using contrast. Based on missing results, this represents a hypothesis only, and it has to be further investigated if low-end systems using contrast can detect angiogenetic vessels. Even using newest CDUS high-end systems their maximal spatial resolution at the moment is under that of Grey scale low MI techniques, detecting microbubbles with a sizes varying from 2-8 micron. Several studies have shown sensitive detection of vascularity after contrast administration, especially in lower or subclinical inflammatory activity, used for therapy follow-up or therapy modification.[3,7,8] Only 2 studies evaluated healthy volunteers, as controls [3,9] both showed no increased vascularity after Levovist administration. However, investigation by using appropriate settings for SonoVue as a low MI agent for Grey-scale Harmonic imaging and other second-generation contrast media would be interesting.

Unfortunately, because of methodological limitations on Dr Terslev and colleagues’ study, these results should be further proven by dedicated US contrast settings for the contrast media used.

Respectfully,

Andrea Klauser, M.D.
Department of Radiology II
Medical University Innsbruck

Michael Schirmer, M.D.
Department of Internal Medicine
Medical University Innsbruck

Hilde Zunterer, M.D.
Department of Radiology II
Medical University Innsbruck

Ferdinand Frauscher, M.D.
Department of Radiology II
Medical University Innsbruck

References

1. Terslev L, Torp-Pedersen S, Bang N, Koenig MJ, Nielsen MB, Bliddal H. Doppler ultrasound findings in healthy wrists and finger joints before and after use of two different contrast agents. Ann Rheum Dis. 2005;64:824-7.

2. Albrecht T, Urbank A, Mahler M, Bauer A, Dore CJ, Blomley MJ, Cosgrove DO, Schlief R. Prolongation and optimization of Doppler enhancement with a microbubble US contrast agent by using continuous infusion: preliminary experience. Radiology. 1998;207:339-47.

3. Klauser A, Frauscher F, Schirmer M, Halpern E, Pallwein L, Herold M, Helweg G, ZurNedden D. The value of contrast-enhanced color Doppler ultrasound in the detection of vascularization of finger joints in patients with rheumatoid arthritis. Arthritis Rheum. 2002; 46:647-53.

4. Klauser A, Frauscher F, Halpern EJ, Mur E, Springer P, Judmaier W, Schirmer M. Remitting seronegative semitting seronegative symmetrical synovitis with pitting edema (RS3PE) of the hands: ultrasound, color doppler ultrasound and magnetic resonance imaging findings. Arthritis Rheum. 2005;53:226-33.

5. Klauser A, Demharter J, De Marchi A, Sureda D, BarileA, Masciocchi C, Faletti C, Schirmer M, Kleffel M, Bohndorf K Contrast Enhanced grey- scale Sonography in Assessment of Joint Vascularity in Rheumatoid Arthritis: Results from the IACUS study group. Eur Radiol. in press.

6. Tublin ME, Bude RO, Platt JF. The resistive index in renal Doppler sonography: where do we stand? Am J Roentgenol.2003;180:885-92.

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;61:877-82.

8. 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;11:1039-46.

9. 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;13:163-8.

Dear Editor,

We were interested to read the article by Linn-Rasker and colleagues who report that smoking is a risk factor for anti-cyclic-citrullinated (anti-CCP) antibodies only in RA patients that carry HLA-DRB1 shared epitope (SE) alleles.[1] They claim that an interaction is found between tobacco exposure (TE) and carriage of the SE which leads to anti-CCP production in RA. They find a similar effect for presence of rheumatoid factor (RF), but suggest that the interaction is primarily with the anti- CCP antibody response. Although an attractive hypothesis, our analysis of the data presented does not agree with their interpretation.

We have used the data provided in Table 2 to investigate the independent and combined affects of RF, TE and SE (independent variables) on the presence of anti-CCP antibodies (dependent variable) using multivariate logistic regression models. Firstly we examined for evidence of interaction. In a model which includes TE only there is significant association with the presence of anti-CCP (OR 1.6, 95% CI 1.01 – 2.6, p = 0.04). Addition of SE to the model indicates that TE and SE are independently associated with anti-CCP since both are significant (OR 1.7, 95% CI 1.04 – 2.8, p = 0.03, and OR 3.3, 95% CI 2.01 – 5.6, p <0.0001, respectively). However, if the interaction term (product of TE and SE) is added into the model together with the main effects (TE and SE separately) there is no association between the interaction term and anti-CCP (p = 0.2). This does not rule out the possibility of an additive effect of TE and SE but argues against a multiplicative interaction. In a similar way we have previously shown that RF production is associated with an additive, but not multiplicative interaction between smoking and the HLA- DRB1*0401 SE allele.[2]

We have also investigated more closely the influence of RF on the association between TE and anti-CCP. Analysis of SE+ patients only in a logistic regression model without adjustment for RF suggests that TE is associated with the presence of anti-CCP (OR 2.1, 95% CI 1.2 – 3.9, p = 0.016). However inclusion of RF as well as TE in the same model reveals a strong association with RF (OR 16.1, 95% CI 7.6 – 34.1, p <0.00001), while the association with TE loses significance (OR 1.7, 95% CI 0.9 – 3.6, p = 0.17).

Our analyses indicate that the apparent association between TE and anti-CCP can be explained by the confounding association of RF with smoking. The dominant association of RF with anti-CCP can be seen in the last section of Table 2 where non smokers carry as much risk of developing anti-CCP (OR 3.83) as smokers (OR 3.86) if they are positive for both the SE and RF. Further examination of the data in Table 2 also shows that, with or without tobacco exposure, SE negative patients who are RF positive actually have a higher risk of developing anti-CCP antibodies than SE positive smokers who are RF negative (68% v 43.3%, OR 2.7 and 66.7% v 43.3%, OR 2.5, respectively).

Our analyses of these data are consistent with a previous preliminary report on the association of RF and SE, but not smoking, with anti-CCP.[3] This was a study on 271 RA patients in which we also examined the association of HLA-DRB1*0401 with the presence of anti-CCP. Our results showed that patients who were smokers were more likely to be positive for anti-CCP antibodies than those who had never smoked. However, inclusion of RF, together with smoking status as independent variables in logistic regression analyses caused loss of significance between smoking and anti- CCP, while RF remained significantly associated (OR 6.2, 95% CI 1.9 -10.2, p<_0.0001. additional="additional" inclusion="inclusion" of="of" hla-drb10401="hla-drb10401" status="status" in="in" a="a" logistic="logistic" regression="regression" model="model" demonstrated="demonstrated" that="that" this="this" was="was" also="also" strongly="strongly" associated="associated" with="with" anti-ccp="anti-ccp" or="or" _4.7="_4.7" _95="_95" ci="ci" _1.9="_1.9" _-11.4="_-11.4" p="p" independent="independent" rf.="rf." these="these" data="data" indicate="indicate" although="although" ra="ra" smokers="smokers" are="are" more="more" likely="likely" to="to" be="be" positive="positive" for="for" appears="appears" primarily="primarily" due="due" an="an" association="association" rf="rf" patients="patients" who="who" smoke.="smoke."/> Derek L. Mattey
Staffordshire Rheumatology Centre
University Hospital of North Staffordshire
Stoke-on-Trent
Staffordshire
UK
ST6 7AG

David Hutchinson
Royal Cornwall Hospital
Truro
Cornwall
UK
TR1 3LJ

Correspondence to Dr DL Mattey. d.l.mattey{at}keele.ac.uk

References

1. Linn-Rasker SP, van der Helm-van Mil AHM, Van Gaalen FA, Kloppenburg M, de Vries R, LE Cessie S, et al. Smoking is a risk factor for anti-CCP antibodies only in RA patients that carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis published online 13 Jul 2005;doi:10.1136/ard.2005.041079.

2. Mattey DL, Dawes PT, Clarke S, Fisher J, Brownfield A, Thomson W, Hajeer AH, Ollier WER. Relationship among the HLA-DRB1 shared epitope, smoking, and rheumatoid factor production in rheumatoid arthritis. Arthritis Rheum 2002;47:403-407.

3. Mattey DL, Nixon NB, Hutchinson D. Rheumatoid factor and HLA- DRB1*0401, but not cigarette smoking, are independently associated with antibodies to cyclic citrullinated peptides in rheumatoid arthritis. Rheumatology 2005;44(Suppl):i100.

Dear Editor,

I would like to offer some comments on the paper: Evaluation of clinically relevant changes in patient-reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement by Florence Tubach, et al.

The authors did a good job of collecting a mass of data and deriving a delta for the Minimal Clinically Important Improvement for the three core efficacy variables in osteoarthritis.

The result is, however, not quite convenient because three deltas are derived depending on the value of the baseline variable. This is awkward - as e.g. also the definition of three relevant difference delts for proportion of responders as given in the 80's by the FDA. I wonder whether one could derive a smooth, constant delta on another scale. The floor effect of the scale (0 - no pain) and the decrease of pain which often follows the shape of a proportional decrease suggest that a percentage scale of decrease or difference in logarithms might be easier to handle and also more appropriate for the data. (Andiometrists are very happy with their dB scale for andiometry perception.)

I would appreciate the authors doing some additional work to obtain a constant delta. A pre-post scattergram of BAS values would be a good starting point. (See, for example, Chambers, Cleveland, Kleiner, Tukev, Graphical Methods for Data Analysis, Duxbury Press, Boston).