Dear Editor,

We read with interest the article by Rudwaleit et al [1]. "How to diagnose early spondyloarthropathy" and "Comment in leading" by Barkham et al [2]. We agree that MRI, particullary with the special techniques, could be very helpful in detecting signs of sacroiloiitis not yet visible on standard radiographs.

MRI is most sensitive (95 %)and superior to Quantitative SI scintigraphy (48 %) or conventional radiography (19 %)[3]. Although MRI scoring system for sacroiliac and spinal pathology have developed still remains same concern about reliability and validity of MRI, and its implications to prognosis and outcome. High costs and availability of MRI are limiting factors for the widespread use.

Standard radiographs, a single x-ray of the pelvis, or barsony technique still remain common investigational method. A single AP film of the pelvis showing inflammatory changes in the sacroiliac joints has a 55 sensitivity for spondyloarthropathy. Where changes are equivocal additional techniques can increase sensitivity to 80 % [4]. Unfortunatelly additional x-ray films increase the dose of radiation and costs.

In the last 10 years we performed diascopy method in the standing position. With this technique we can better visualis ventral and dorsal intraarticular space and with the greater accuracy and lower degree of the radiation, the diagnosis of the sacroiliitis can be made. In the follow up of the patients it is possible to perform the same position [5].

References

(1). Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004;63.535-543.

(2). Barkham N, Marzo-Ortega H, Mcgonagle D, Emery P. How to diagnose axial spondyloarthropathy early. Ann Rheum Dis 2004;63:471-472.

(3). Blum U, Buitrago-Tellez C, Mundinger A et al. Magnetic resonance imaging (MRI) for detection of active sacroiliitis- a prospective study comparing conventional radiograph, scintigraphy, and contrast enhanced MRI. J Rheumatol 1996;23:2107-2115.

(4). Yelland M. Diagnostic imaging for back pain. Aus Fam Physician 2004;33:415-419.

(5). Potoèki K, Æurkoviæ B, Babic-Naglic D. Advantage of diascopy of the sacroiliac joints versus barsony x-ray views. J Rheumatol 1998;25(suppl.54):42 (abst.)

Dear Editor,

We read with interest the report of the WOSERACT trial [1] that compared the addition of 7 mg daily prednisolone or placebo to sulfasalazine in early rheumatoid arthritis (RA). There are a number of important aspects of the trial which have been dealt with well: the sample size is adequate; appropriate attention has been paid to confounders; two separate and independent readers scored the radiographs; the two year trial was of adequate length and there was satisfactory completeness of the data. Given these strengths, it is all the more disappointing that the results of the main outcome, radiographic damage, cannot be adequately interpreted as they are reported. Indeed, the validity of these results is open to serious doubt. We feel there is a real possibility of a Type II statistical error (missing a true difference between treatment arms). There are two (possibly three) reasons for this.

First, there is an absolute difference between the x-ray scores of the two readers of about 40 Sharp points. This raises strong doubts over the proficiency of either or both readers. In early RA Sharp scores are typically very low, with most patients scoring 0 and only a few with higher scores. Scores of 80, let alone 159 after one year of RA are without precedent in the literature, and even the baseline medians of 6 and 8 recorded for the conservative reader are quite high. In contrast to the authors, we cannot be ‘reassured’ by their assertion that ‘the change in x-ray score was consistent between the two readers’: these data are simply not provided in the report. All we have is an unsatisfactory correlation of absolute scores between readers of 0.8 (where in most trials the intra-class correlation coefficient [the recommended and more severe test of reliability between readers] exceeds 0.9), and the comparison between readers of differences between the median start and end scores in the two study groups. Unfortunately the difference between medians at baseline and endpoint is not the same as the median change.

Second, most trials choose two readers that read either with sequence known or unknown (the jury is still out which is the preferred method), and report the mean of these two readings. This report has two readers each of whom uses a different one of these options and this makes it impossible to pool the results. Also, even with sequence unknown films should be read as sets (all films belonging to one patient assessed simultaneously), not totally at random. Reading totally at random strongly decreases the signal-to-noise ratio [2]. Which method did the ‘random’ reader apply exactly?

A third concern is with the analysis, although this may only be a question of the way the data are presented. Although the authors state the main outcome measure is the change in radiographic damage, they only report medians and ranges of the absolute scores in the groups. From our reading of the report, we fear the analysis has (statistically) compared the distributions of these absolute scores rather than their changes.

This is an important study, and has the potential to add valuable information to our understanding of the best way to treat RA, but in its present form the radiographic results are more likely to cloud the issues than clarify them. We suggest that the radiographs are made available to be re-read by two new, experienced readers with either the sequence known or unknown to both. We also suggest that the analysis should present the median, range etc. of the changes in each group, and the test of the difference between these. (If they have a skewed distribution, then either transformation before parametric analysis or the use of non-parametric methods would be the best way to compare the groups.)

There are other difficulties with the study, although these are less important than the essential concerns noted above. For example, we are baffled by the statement in the introduction that the COBRA combination [3] ‘showed radiological advantage over sulfasalazine alone but the study was not powered to detect differences in x-ray change’. In fact, the differences in x-ray change were among the COBRA study’s key findings, and have since been shown to increase over time [4]. So the study was not only adequately powered but also showed an unexpectedly large effect.

The authors diminish the value of the report by inappropriate interpretation of their secondary data, especially on the adverse effects. In the discussion they comment, ‘While observed toxicity from corticosteroids in terms of hypertension, weight gain, and osteoporosis could be reduced by active assessment and prompt intervention, there is no room for complacency’. However, in their results section they report that, ‘Low dose aspirin and treatment for ischaemic heart disease remained similar, whereas the use of anti-hypertensive agents increased in both groups, as did prescription of lipid lowering agents. The use of any treatment for osteoporosis also increased in both groups’. In fact there was no difference between the groups and thus there was no observed toxicity from glucocorticoids in their study. Further, the authors make no comment on their observation that (many) more patients stopped sulfasalazine treatment due to side effects in the placebo than in the glucocorticoid group.

In relation to weight gain, inappropriate attention to within-group changes leads the authors to conclude body weight ‘increased significantly’ in the glucocorticoid group (median gain, 4 kg), with only a ‘borderline increase’ in the placebo group (median gain, 3 kg). Body mass index is handled in the same way. However, the only really relevant comparisons, those between groups, do not even show a trend to significance (all p values at or above 0.10). As with the radiographic findings, the presentation of the table suggests endpoint results were compared rather than change scores.

Our interpretation of the clinical results contradicts that of the investigators, and we conclude that the effects on symptoms are in line with previous reports of limited and temporary advantages for disease activity, blunting of sulfasalazine toxicity, and extremely limited side effects when appropriate caution is applied. It is not possible to adequately assess the main results on x-ray progression, which are at variance with several previously published studies [3-8] and we urge the authors to allow a second read of the radiographs so that their important dataset can be added to the existing evidence.

References

(1). Capell HA, Madhok R, Hunter JA, et al. Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial. Ann Rheum Dis 2004; 63: 797–803.

(2). Van der Heijde D, Boonen A, Boers M, Kostense P, van Der Linden S. Reading radiographs in chronological order, in pairs or as single films has important implications for the discriminative power of rheumatoid arthritis clinical trials. Rheumatology (Oxford) 1999; 38: 1213-20.

(3). Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis [see comments] [published erratum appears in Lancet 1998 Jan 17;351(9097):220]. Lancet 1997; 350: 309-18.

(4). Landewe RB, Boers M, Verhoeven AC, Westhovens R, van De Laar MA, Markusse HM, et al. COBRA combination therapy in patients with early rheumatoid arthritis: Long-term structural benefits of a brief intervention. Arthritis Rheum 2002; 46: 347-56.

(5). Kirwan JR, Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995; 333: 142-146.

(6). Hickling P, Jacoby RK, Kirwan JR. Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Br J Rheumatol 1998; 37: 930-936.

(7). Rau R, Wassenberg S, Zeidler H. Low dose prednisolone therapy (LDPT) retards radiographically detectable destruction in early rheumatoid arthritis--preliminary results of a multicenter, randomized, parallel, double blind study. Z Rheumatol. 2000;59 (Suppl 2): II/90-6.

(8). van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002; 136(1): 1-12.

Dear Editor

It was interesting to read the recent report of systemic lupus erythematosus associated with atrophy of brain and spinal cord.[1] However, I would like to make certain observations.

Computerised tomography (CT) of brain presented in the report showed bilateral hypodense lesions in the frontal and parietal regions. Though Mok et al attribute this CT appearance to diffuse cerebral atrophy; other possibilities too need to be considered in this setting. Chronic subdural haematoma (SDH) is the foremost among these. In a recent report, all chronic SDH appeared hypodense on CT, and were predominantly located in the parietal and frontal regions,[2] which is similar to the case presented by Mok et al. Hypodensity in chronic SDH could occur due to gradual absorption of erythrocytes from the haematoma, typically with haemoglobin concentration falling below 15 mg/dl.[3] Another mechanism responsible for differing densities of acute and chronic SDH could be related to their varying compositions. In a pathological study, hyperdense picture on CT resulted with haematomas predominantly consisting of erythrocytes and erythrocyte-fibrin component, whereas hypodense picture resulted with haematomas consisting of fibrin and inflammatory cells.[4]

It should also be noted that bilateral chronic SDH is a recognized complication of vasculitic syndromes and could even be a presenting symptom.[5] Moreover, SLE too could produce focal angiitis of a cerebral artery with secondary aneurysm formation, rupture of which leads to SDH.[6]

In conclusion, though I agree with Mok et al. that cerebral atrophy is a known finding in patients with SLE, chronic SDH is a distinct possibility in patients with bilateral fronto-parietal hypodense lesions on CT.

References

1. Mok CC, Mak A, Tsui EYK. Shrinking central nervous system in systemic lupus erythematosus. Ann Rheum Dis. 2004; 63:603-4.

2. Agunloye AM, Adeyinka AO, Obajimi MO, Malomo A, Shokunbi MT. Computerised tomography of intracranial subdural haematoma in Ibadan. Afr J Med Med Sci. 2003; 32:235-8.

3. Ito H, Maeda M, Uehara T, Yamamoto S, Tamura M, Takashima T. Attenuation values of chronic subdural haematoma and subdural effusion in CT scans. Acta Neurochir (Wien). 1984; 72:211-7.

4. Poljakovic Z, Petrusic I, Kalousek M, Brzovic Z, Jadro-Santel D. Correlative pathology of subdural hematoma with computerized tomography. Neurol Croat. 1991; 41:21-32.

5. Shiotani A, Mukobayashi C, Oohata H, Yamanishi T, Hara T, Itoh H, et al. Wegener's granulomatosis with dural involvement as the initial clinical manifestation. Intern Med. 1997; 36:514-8.

6. Sakaki T, Morimoto T, Utsumi S. Cerebral transmural angiitis and ruptured cerebral aneurysms in patients with systemic lupus erythematosus. Neurochirurgia (Stuttg). 1990; 33:132-5.

Dear Editor

I read the recent study by Klocke et al. with great interest.[1]

The authors reported increased arterial stiffness as estimated by the analysis of arterial waveforms with aplanation tonometry in patients with rheumatoid arthritis (RA) when compared to healthy controls. Their findings can yield an important clue to understanding the increased cardiovascular mortality in RA. However, the statistical analysis they used for their data was problematic. They state in several parts of the article that the haemodynamic parameters (including the augmentation index) of eligible cases and controls were compared by the two tailed, paired t test, accepting a significance level of p<_0.05. by="by" use="use" of="of" such="such" statistical="statistical" method="method" they="they" found="found" significant="significant" differences="differences" in="in" the="the" augmentation="augmentation" index="index" between="between" subjects="subjects" with="with" ra="ra" and="and" normal="normal" controls.="controls." p="p"/> When using a paired t test, it is assumed that the number of points in each data set must be the same, and they must be organized in pairs, in which there is a definite relationship between each pair of data points. The paired t test is generally used when measurements are taken from the same subject before and after some manipulation. For example, an appropriate use of the paired t test might be to compare the differences in the augmentation index in subjects with rheumatoid arthritis before and after an intervention. Given that the data in Klocke’s study were taken from two different samples, the use of a paired t test is simply not appropriate. Since a violation of the underlying assumptions of the test was present, the results of the analysis may be incorrect or misleading. In particular, a type I error might have occurred when accepting p values obtained from such t test. In addition, the authors did not state the distribution of their data. A t test (paired or unpaired) would be appropriate for normally distributed data, but a non-parametric method would be preferred for non-normally distributed data. The authors should inform the readers about the probability values for the differences obtained with a non-paired test (such as non-paired t test or Mann-Whitney U test as appropriate).

Reference

1. R Klocke, J R Cockcroft, G J Taylor, I R Hall, and D R Blake. Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rheumatoid arthritis. Ann Rheum Dis 2003; 62: 414-418