The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database
D. L. Scott and
V. Strand1
Department of Rheumatology, GKT School of Medicine, Dulwich Hospital, East Dulwich Grove, London, SE22 9PT, UK and
1 Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028, USA
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Abstract
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Objective. A primary therapeutic goal in rheumatoid arthritis (RA) is to reduce functional disability. The recent introduction of several new drugs for RA creates a need for readily assessing the effectiveness of therapy. Because the consistent use of disease-modifying anti-rheumatic drugs (DMARDs) reduces long-term disability, we analysed the large database of 1817 RA patients from leflunomide trials to assess if changes in the Health Assessment Questionnaire (HAQ) can measure the effectiveness of RA therapy.
Methods. Data from three randomized double-blind RA trials were evaluated. The patients had received 100 mg leflunomide (then 20 mg/day in 807 cases), methotrexate (1520 mg/day in 669 cases), sulphasalazine (2 g/day in 132 cases) and placebo (in 209 cases). HAQ scores and outcomes were assessed using the American College of Rheumatology core data set. Detailed statistical analyses were made of changes in outcome variables at 1 and 6 months, changes in HAQ scores at 112 months, and effect sizes for outcome variables at 6 and 12 months. Multiple regression models of changes in HAQ scores were evaluated using backwards stepwise linear regression.
Results. Mean HAQ scores declined progressively with treatment with all three DMARDs. Changes occurred rapidly, and at month 1 were most pronounced with leflunomide. HAQ scores correlated closely with clinical response, as seen in changes in non-responders and ACR 20% and 50% responders. Regression analysis indicated that pain intensity and global assessments were significant determinants of HAQ.
Conclusion. HAQ scores are sensitive measures of effective DMARD therapy. HAQ may be especially useful early in the treatment process to assess patients responses to DMARDs that show rapid onset of action, such as leflunomide.
KEY WORDS: Rheumatoid arthritis, Health Assessment Questionnaire, Disease-modifying anti-rheumatic drugs, Leflunomide.
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Introduction
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Functional disability is an important consequence of rheumatoid arthritis (RA) that results in reduced health-related quality of life [1]. Valid and reliable measures of disability based on physical examination or observation are considered relatively unsuccessful compared with self-reported disability assessments [2]. These self-reported assessments of disability form the international standard and are recommended for clinical trials and observational studies. The Health Assessment Questionnaire (HAQ) [3], which is the most common assessment tool, is invariably included within the core data set used in RA clinical studies.
Following more than a decade of international collaboration, there is an agreed core data set for RA clinical trials. This comprises tender and swollen joint counts, measures of pain and patient and physician global assessments, measures of the acute-phase response, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration, and measures of disability, such as the HAQ. This core data set is used to generate both the American College of Rheumatology (ACR) response criteria and the Disease Activity Score. It is especially used in phase II and III randomized controlled trials of new drugs.
For observational studies and phase IV trials it may be preferable to collect a restricted data set. There is some evidence that HAQ scores reflect disease activity as well as disability, indicating that HAQ could be a key component in such a minimal data set. The large pre-existing clinical data set generated in the phase III trials of leflunomide has allowed us to explore this possibility. We achieved this by testing the hypothesis that HAQ scores provide a simple assessment of disease activity that can be used to evaluate responses to DMARDs in groups of RA patients.
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Methods
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Study design
Three multicentre, randomized, controlled trials compared the clinical efficacy of leflunomide with sulphasalazine and placebo, methotrexate and placebo, and methotrexate alone. All trials were approved by appropriate ethical review boards and conducted in accordance with the principles established by the Declaration of Helsinki. All three studies have been reported in peer-reviewed publications. The rheumatologists contributing patients to these trials are shown in the Appendix.
In protocol US301 [4], treatment with leflunomide or methotrexate was compared with placebo given for 412 months using a 3:3:2 randomization ratio. In protocol MN301 [5], treatment with leflunomide or sulphasalazine was compared with that of compared placebo given for 6 months using a 3:3:2 ratio randomization; blinded treatment was continued in the active control arms for 12 months. In study MN302 [6], 12 months of treatment with leflunomide was compared with methotrexate treatment with equal randomization. The studies were extended for 2 yr; two of these have been published [7, 8] and the data from the extension of MN302 are on file.
In all three studies, a 3-day loading dose of leflunomide (100 mg/day) was followed by daily doses of 20 mg. In protocol US301, methotrexate was initiated at 7.5 mg/week and increased to 15 mg/week over weeks 69 in 60% of the patients, all of whom had active disease at week 6. In MN301, sulphasalazine was started at 500 mg/day and increased to 2000 mg/day in weekly increments of 500 mg. In MN302, methotrexate treatment was initiated at 7.5 mg/week, increased to 10 mg/week at week 4 and to 15 mg/week on or after week 12, at the discretion of the investigator, in 53% of the patients.
Patients
The details of the patients evaluated in the various studies are summarized in Table 1
. Overall, 1817 patients were studied. These comprised 807 cases given leflunomide [581 females and 226 males of mean age 57.4 yr (S.D. 10.7), with 122 (15%) having disease durations of less than 6 months and 470 (58%) having disease durations of over 24 months]; 669 cases given methotrexate [484 females and 185 males of mean age 56.5 yr (S.D. 11.3), with 92 (14%) having disease durations of less than 6 months and 382 (57%) having disease durations of over 24 months]; 132 cases given sulphasalazine [92 females and 40 males of mean age 58.9 yr (S.D. 11.4), with 42 (32%) having disease durations of less than 6 months and 77 (58%) having disease durations of over 24 months]; and 209 cases given placebo [151 females and 58 males of mean age 56.4 yr (S.D. 11.5) with 35 (17%) having disease durations of less than 6 months and 128 (61%) having disease durations of over 24 months].
Two studies involved 12 months of blinded treatment (US301 and MN302) and one study 6 months of blinded treatment (MN301). At 6 months, 1361 patients remained on therapy. The studies were then extended for up to 2 yr. MN301 had a 612 month extension as well as a 1224 month extension. Blinding was retained throughout the extension phase. There were 931 cases enrolled in the extension studies between 12 and 24 months, comprising 450 on leflunomide, 421 on methotrexate and 60 on sulphasalazine. At 24 months 796 remained on therapy.
Assessments
Data on age, sex and disease duration, which were recorded on all patients, were extracted from the database compiled from the three trials. In all studies the HAQ was administered monthly and was included as a component of the ACR response criteria. Data on the HAQ were missing from some patients in these studies; for example, a validated Yugoslavian translation of the HAQ was not available at the time these studies were initiated and this meant that data could not be collected in the 20 cases from Yugoslavia. Other clinical data collected monthly comprised swollen joint counts (28 joints), tender joint counts (28 joints), pain scores (on a 100 mm visual analogue scale), patient and physician global responses (on 100 mm visual analogue scales), and ESR and CRP levels. These data were used to determine the ACR response rates (ACR20 and ACR50).
Statistical analysis within first year
Data from the leflunomide phase III clinical trial database were analysed for all drugs in all studies, for all drugs combined across studies and all cases for both the intention-to-treat and the valid compliant completer method. The following analyses were evaluated in detail: changes in outcome variables at 1 and 6 months for different drugs combined across all studies; changes in HAQ scores at 1, 3, 6 and 12 months for valid compliant completers; effect sizes (or proportion positive) for outcome variables at 6 and 12 months for different drugs combined across all studies and for each individual study; and multiple regression analyses for changes in components of HAQ scores in backwards stepwise linear regression models for separate studies using valid compliant completers data.
Statistical analysis within second year
Data from cases who were enrolled in the 2-yr extension studies were analysed to show mean HAQ scores in the different treatment groups at baseline, 12 and 24 months and changes between 0 and 24 and between 12 and 24 months. The 95% confidence intervals of the mean changes in HAQ were calculated for the 1224 month data.
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Results
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Changes in first year
The intention-to-treat analysis of pooled data from all three studies showed that at 1 month mean HAQ scores had fallen by 0.21 with leflunomide, 0.09 with sulphasalazine and 0.11 with methotrexate but only 0.04 with placebo. By 6 months they had fallen by 0.38 with leflunomide, 0.29 with sulphasalazine and 0.34 with methotrexate but had risen by 0.01 with placebo (Table 2
). The valid compliant completer analysis showed very similar improvements. The changes in HAQ scores were in keeping with improvement in other clinical and laboratory variables. The improvements in HAQ scores with active therapy continued at 12 months; this is shown for valid compliant completers in Fig. 1
.

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FIG. 1. Mean changes (S.E.) in HAQ scores with DMARD therapy (analysed for valid compliant completers).
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The effect size of changes in assessments, shown for the intention-to-treat analysis in Table 3
, showed that the only variables that had an effect size of 0 or -0.1 in the placebo group at 6 and 12 months were HAQ, ESR and CRP. These variables had effect sizes between -0.3 and -0.7 with the various active DMARDs at 6 and 12 months. Other clinical measures showed larger effect sizes with active treatment, varying from -0.9 for pain at 6 months with sulphasalazine to -1.9 for patient's global assessment at 12 months with methotrexate. However, they all had moderately large effect sizes with placebo therapy, varying from -0.2 for VAS pain scores at 12 months to -0.6 for physician's global assessments at 6 and 12 months.
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TABLE 3. Effect sizes of changes in HAQ scores and other clinical and laboratory variables at 6 and 12 months using intention-to-treat population
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A more detailed review of changes in HAQ, ESR and CRP for each study by intention-to-treat and valid compliant completer analyses at 6 months showed a consistent pattern in the effect sizes (Table 4
). There was either no or minimal change (0 to -0.2) with placebo therapy and moderate change with all active DMARD therapies (up to -0.8).
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TABLE 4. Effect size or proportion positive in different studies at 6 months in intention-to-treat (ITT) and valid compliant completer (VCC) analysis
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Linear regression models for each of the three studies showed that it was possible to predict 4446% of the variation in change in HAQ scores from other clinical measures recorded in the studies. The main determinants of change in HAQ scores in all studies were the initial HAQ, the change in pain score and the change in physician's global assessments. There were minor contributions from change in swollen joint count, change in ESR and age in some studies.
Changes in second year
Mean HAQ scores in the all patients in the 2-yr cohorts fell within the first 12 months by 0.59 (41% of initial HAQ). Between 12 and 24 months they showed a small increase of 0.029. The patterns of change are shown for the different treatment groups in Fig. 2
and summarized in detail in Table 5
. There were differences between studies, especially with leflunomide, which showed an insignificant increase in the US301 extension, an insignificant fall in the MN301 extension and a small, significant increase in the MN302 extension. Methotrexate and sulphasalazine showed small but statistically insignificant increases in all studies. Combining data from the three studies showed that the average increase between 12 and 24 months was 0.029, and this included an average increase with leflunomide of 0.020, with methotrexate of 0.035 and with sulphasalazine of 0.060.
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Discussion
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Previous studies have categorized the many factors that influence HAQ scores [9]. They increase with age [10], are higher in women [11, 12] and are inversely related to socioeconomic status [13, 14]. High HAQ scores are associated with high pain scores [15] and other features of active RA. The effects of pain on HAQ are particularly strong in early RA [16, 17]. HAQ scores are related to other measures of disease activity. One North American observational study showed that joint counts, ESR, global self-assessment and radiographic scores influence HAQ scores in established RA [18]. A comparable European study showed correlations with the Ritchie articular index and ESR [19]. These relationships transcend culture as HAQ scores modified for Chinese patients in an Asian setting showed similar correlations with pain and physicians assessments of disease activity [20]. HAQ scores are also influenced by rheumatoid factor positivity [21, 22], especially IgA rheumatoid factor [23], fatigue [24] and depression [25, 26].
HAQ scores show moderate correlations with disease duration. Several studies have examined the annual rate of increase in HAQ scores with time [2735] and the average annual increase in these was 0.034, equivalent to 1% of the maximal change [36]. Interestingly, a further 5-yr study of 63 patients first seen within 1 yr of diagnosis [37] showed that the progression of disability was not linear but had highly variable courses in individual patients.
The significance of changes in HAQ scores has been evaluated from several different perspectives. Overall, these indicate that the smallest change in average HAQ scores that can be detected by groups of patients is in the region of 0.190.24. One study reports that patients considered they were somewhat better with mean differences of 7% in HAQ scores [38]. Another study found that patients rated themselves somewhat better when their HAQ scores differed by 0.19 units [39]. In randomized controlled trials, average changes in HAQ scores of 0.24 correspond with clinically detectable improvements [40]. This corresponds broadly with the mean improvement of 0.28 in HAQ score seen in the patients in our present study who had HAQ ACR-20 responses at 1 month.
Previous conventional analyses have reported the beneficial effects of leflunomide, methotrexate and sulphasalazine on physical function over 2 yr of treatment in these groups of patients. All the analyses undertaken have provided strong and consistent evidence for improvement in patients physical function resulting from DMARD treatment throughout 24 months of treatment [41, 42]. One study of leflunomide and methotrexate has evaluated an alternative approach to comparing outcome measuresthe relative efficiencies of the various outcome measures to detect a treatment effect relative to tender joint count (for which the relative efficiency was 1) [43]. This showed that the relative efficacy was 1.88 for patient's global assessment of disease activity. In decreasing order, it was 1.84 for HAQ, 1.63 for SF-36 (Short Form Health Survey) bodily pain scale and 1.33 for physician's global assessment; other assessments had lower levels of efficiency. In the present report we confirm and extend these previous observations. The data available from the whole leflunomide data set indicate that HAQ scores are amongst the most sensitive indicators of clinical improvement in patients receiving DMARD therapy. There is some evidence from this overall analysis that leflunomide gives both a larger and a more rapid reduction in average HAQ scores, but as the data were not collected specifically to demonstrate such a difference the finding must be interpreted with caution.
A comparative analysis of some other recent randomized trials of DMARDs and immunotherapies, shown in Table 6
, indicates that changes in HAQ scores are of similar magnitude in those studies that report the standard deviation of the initial HAQ score and the mean change in HAQ score. As many trials do not report HAQ scores in such a way that the effect size can be calculated, this analysis only involves a minority of studies. Nevertheless, it shows that the average change in HAQ score with active DMARD therapy was 0.39 (effect size 0.55) (Table 7
) compared with an average change in HAQ score at 6 months in all cases in the leflunomide database who received active DMARD therapy of 0.36 (effect size 0.54). It is therefore likely that using HAQ scores to assess the efficacy of treatment can probably be generalized for all DMARDs. Although conventionally the effects of DMARDs are classified in terms of benefits for synovitis, function and X-ray damage, and these form different types of claim accepted by regulatory bodies, there may be no reason to consider that changes in HAQ scores are actually different from changes in clinical activity. Indeed, the data in Table 5
suggest that changes in HAQ scores mainly reflect changes in pain and other subjective measures of disease activity.
Several aspects of the analyses presented in this paper can reasonably be criticised. First and foremost, the data were collected for the rather different purpose of defining the efficacy of leflunomide; therefore any secondary analyses of the type we have performed are imperfect methods of examining our specific hypothesis. Although this point cannot be denied, the data set collected for the evaluation of leflunomide is one of the most comprehensive ever collected and it is unlikely that better data will be available in the near future. Secondly, adding together data from diverse studies may overlook methodological inconsistencies between studies. This criticism is also reasonable, but the clinical methods used were comparable and differences between centres and countries are likely to remain however such studies are constructed. Finally, the leflunomide data set is very large and the analyses reported are, by their very nature, selective and therefore likely to give an incomplete picture of a complex situation. Once again, this is an unavoidable problem but, by approaching the data from different directions, we have attempted to give as comprehensive an account as possible of the effects of DMARDs on HAQ scores. In any event, all our varied analyses give a broadly similar picture and suggest that the HAQ is a relatively good indicator of disease activity in groups of patients given DMARDs.
Conventional wisdom and regulatory bodies both indicate that drugs can have different types of effect in RA and, in particular, that there is a difference between effects on symptoms and on function. Our results suggest that, at least as far as DMARDs are concerned, this is too simple an analysis. It follows that dividing the effects of DMARDs into categories may be inappropriate. A more likely scenario is that effective DMARDs will influence symptoms and function equally. Our analysis of the leflunomide database provides strong evidence that leflunomide is effective in improving both symptoms and disability over 2 yr and that the extent of disability continues to be improved in those patients who show continuing clinical benefit during the 2-yr period of treatment.
There is growing recognition that HAQ scores provide a good indication of the clinical response in groups of RA patients. Broadly similar conclusions have been drawn by Wolfe from the long-term follow-up of 1843 [44] and 1905 [45] RA patients. Observational data from 318 RA patients seen in a community setting has shown that HAQ scores can be used as a benchmark for the management of RA [46]. Observational data from the hospital follow-up of a cohort of 732 RA patients showed that high HAQ scores could be used to identify a group who respond poorly to conventional treatment [47]. Although it lies outside the remit of this study, it is interesting to note that there is some evidence that HAQ scores may be of less value when applied to individual RA patients in a routine clinical setting [48], though this is a matter of substantial controversy [49]. We conclude that HAQ scores can be used to give overall assessments of the response to DMARDs in groups of patients with RA. It is therefore suitable for use in a truly minimum data set for disease activity in large, simple clinical trials in RA.
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Appendix
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Rheumatologists involved in clinical trials of leflunomide
US301
L. Anderson (Portland, USA); A. Baldessare (St Louis, USA); S. Baumgartner (Spokane, USA); B. Bockow (Seattle, USA); A. Brodsky (Dallas, USA); J. Caldwell (Daytona Beach, USA); G. Cannon (Salt Lake City, USA); D. Cheatum (Dallas, USA); A. Chubick (Dallas, USA); S. Cohen (Dallas, USA); F. Dietz (Rockford, USA); R. Dore (Anaheim, USA); R. Ettlinger (Tacoma, USA); R. Fleischmann (Dallas, USA); R. Fox (La Jolla, USA); C. Franklin (Willow Grove, USA); R. Furie (Manhasset, USA); D. Furst (Seattle, USA); R. Harris (Whittier, USA); S. Hartman (Decatur, USA); M. Heller (Peabody, USA); P. Howard (Paradise Valley, USA); J. Kaine (Sarasota, USA); S. Lee (New York, USA); R. Levy (Olympia, USA); M. Liebling (Torrance, USA); M. Lowenstein (Palm Harbor, USA); L. Moreland (Birmingham, USA); H. Offenberg (Gainesville, USA); N. Olsen (Nashville, USA); J. Poiley (Orlando, USA); P. Romain (Burlington, USA); J. Rutstein (San Antonio, USA); M. Sack (Austin, USA); M. Schiff (Denver, USA); G. Senter (Salisbury, USA); J. Silverfield (Tampa, USA); J. Tesser (Phoenix, USA); E. Tindall (Portland, USA); A. Weaver (Lincoln, USA); N. Wei (Frederick, USA); D. Yocum (Tucson, USA).
MN301
I. Andreasson (Gothenburg, Sweden); P. Andresen (Gråsten, Denmark); P. Beck (Frederiksberg, Denmark); H. A. Bird (Leeds, UK); D. Brackertz (Mainz, Germany); S. Brighton (Pretoria, South Africa); H. Bröll (Vienna, Austria); A. K. Clarke (Bath, UK); O. Duke (Surrey, UK); W. Graninger (Vienna, Austria); R. Grigor (Auckland, New Zealand); B. Hazleman (Cambridge, UK); P. Jones (Rotorua, New Zealand); R. Kalden (Erlangen, Germany); A. A. Kalla (Cape Town, South Africa); G. H. Kingsley (London, UK); R. Kreuzeder (Vienna, Austria); T. K. Kvien (Oslo, Norway); G. M. Mody (Durban, South Africa); P. Nash (Cotton Tree, Queensland, Australia); G. Nuki (Edinburgh, UK); T. G. Palferman (Yeovil, Somerset, UK); M. Pattrick (Manchester, UK); P. Pitt (Orpington, UK); P. J. Prouse (Basingstoke, UK); F. Rainer (Graz, Austria); B. Rozman (Ljubljana, Slovenia); D. Sahlberg (Oskarström, Sweden); M. Schattenkirchner (Munich, Germany); D. L. Scott (London, UK); S. Smolen (Vienna, Austria); S. F. Sørensen (Copenhagen, Denmark); M. Tikly (Johannesburg, South Africa); L. B. A. van de Putte (Nijmegen, Netherlands); R. Westhovens (Pellenberg, Belgium); B. D. Williams (Cardiff, UK); R. Williams (Hereford, UK).
MN302
T. Ahola (Kemi, Finland); J. Alegre (Burgos, Spain); P. Andresen (Gråsten, Denmark); T. H. Appelboom (Brussels, Belgium); E. Arfelt (Esbjerg, Denmark); R. Bernstein (Manchester, UK); H. A. Bird (Leeds, UK); O. Bjørnboe (Sandvika, Norway); D. R. Blake (London, UK); H. Bliddal (Copenhagen, Denmark); W. Bolten (Wiesbaden, Germany); U. Botzenhardt (Bremen, Germany); B. Bourke (London, UK); M. Bouvier (Pierre Benite, France); T. Brabant (Fulda, Germany); F. C. Breedveld (Leiden, The Netherlands); S. Brighton (Pretoria, South Africa); G. A. W. Bruyn (Leeuwarden, The Netherlands); G. R. Burmester (Berlin, Germany); E. Casey (Dublin, Ireland); C. Castermans (Liège, Belgium); B. Combe (Nîmes, France); J. Coppock (Coventry, UK); J. R. Corts (Valencia, Spain); N. Cox (Winchester, UK); J. E. Dacre (London, UK); B. Danneskiold-Samsøe (Fredriksberg, Denmark); P. Dawes (Stoke-on-Trent, UK); T. Daymond (Sunderland, UK); C. Deighton (Nottingham, UK); R. Dreher (Bad Kreuznach, Germany); L. Ejstrup (Odense, Denmark); H. Elling (Viborg, Denmark); P. Elling (Randers, Denmark); P. Emery (Leeds, UK); A. Engström-Laurent (Falun, Sweden); J. A. Ewals (The Hague, The Netherlands); O. Fitzgerald (Dublin, Ireland); R. Fricke (Sendenhorst, Germany); J. J. García Borrás (Valencia, Spain), H. Geidel (Dresden, Germany); J. E. Goobar (Östersund, Sweden); S. Goemaere (Ghent, Belgium); B. Gömör (Budapest, Hungary); E. Gromnica-Ihle (Berlin, Germany); W. L. Gross (Bad Bramstedt, Germany); R. Gustafsson (Stockholm, Sweden); K. H. Han (Rotterdam, The Netherlands); P. Hannonen (Jyväskylä, Finland); T. M. Hansen (Herlev, Denmark); B. Heilig (Cologne, Germany); G. Hein (Jena-Lobeda, Germany); K. Helmke (Munich, Germany); D. W. James (Grimsby, UK); A. Johannessen (Bergen, Norway); R. Jubb (Birmingham, UK); J. P. Kaltwasser (Frankfurt am Main, Germany); J. R. Kalden (Erlangen, Germany); W. Keitel (Vogelsang-Gommern, Germany); M. Keysser (Rostock, Germany); F. M. Khan (Bridgend, UK); K. J. Korff (Tiel, The Netherlands); I. Kötter (Tübingen, Germany); L. Krohn (Hellerup, Denmark); M. Leirisalo-Repo (Helsinki, Finland); E. M. Lemmel (Baden-Baden, Germany); D. Maas (Wiesbaden, Germany); B. A. Masek (Venlo, The Netherlands); F. McKenna (Manchester, UK); K. Mikkelsen (Lillehammer, Norway); G. M. Mody (Durban, South Africa); M. Molloy (Cork, Ireland); Z. B. Montnor-Beckers (Eindhoven, The Netherlands); C. Moran (Christchurch, UK); H. Müller-Fassbender (Bad Abbach, Germany); G. Myklebust (Arendal, Norway); D. Nordström (Helsinki, Finland); H. H. Nuver (Deventer, The Netherlands); L. Paimela (Helsinki, Finland); A. J. Peeters (Delft, The Netherlands); H.-H. Peter (Freiburg im Breisgau, Germany); T. Price (Cannock, UK); S. Rantapää-Dahlqvist (Umeå, Sweden); R. Rau (Ratingen, Germany); E. Rødevand (Trondheim, Norway); D. Sahlberg (Oskarström, Sweden); J. Sany (Montpellier, France); B. D. Sarembock (Cape Town, South Africa); M. Schattenkirchner (Munich, Germany); M. Schneider (Düsseldorf, Germany); K. L. Schmidt (Bad Nauheim, Germany); M. Schou (Næstved, Denmark); H. E. Schröder (Dresden, Germany); D. G. Scott (Norwich, UK); R. de la Serna (Barcelona, Spain); M. L. Snaith (Sheffield, UK); S. Freiesleben Sørensen (Copenhagen, Denmark); H. Sörensen (Berlin, Germany); W. Stierle (Wuppertal, Germany); G. D. Summers (Derby, UK); W. A. A. Swen (Alkmaar, The Netherlands); M. Tikly (Johannesburg, South Africa); T. Tinturé (Pamplona, Spain); H.-P. Tony (Wurzburg, Germany); S. Transö (Jönköping, Sweden); H. van der Leeden (Dordrecht, The Netherlands); H. van der Tempel (Heerlen, The Netherlands); D. van Zeben (The Hague, The Netherlands); B. Volck (Hvidovre, Denmark); F. W. S. Webb (Ipswich, UK); M. Webley (Aylesbury, UK); G. Wessel (Kötzting, Germany); T. Woolf (Truro, UK); A. Young (St Albans, UK).
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Notes
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Correspondence to: D. L. Scott. 
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Submitted 10 December 2001;
Accepted 28 February 2002