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Rheumatology 2001; 40: 615-622
© 2001 British Society for Rheumatology

Original Papers

Effects of the American College of Rheumatology systemic sclerosis trial guidelines on the nature of systemic sclerosis patients entering a clinical trial

D. E. Furst1,2,, P. J. Clements3, W. K. Wong4, M. D. Mayes5, F. Wigley6, B. White7, M. Weisman8, W. Barr9, L. Moreland10, R. Martin11, T. A. Medsger, Jr12, V. Steen13, D. Collier14, A. Weinstein15, E. Lally16, J. Varga17, S. R. Weiner3, B. Andrews18, M. Abeles19, J. B. Peter3 and J. R. Seibold20

1 Arthritis Clinical Research Unit, Virginia Mason Research Center,
2 Department of Medicine; University of Washington, WA,
3 UCLA School of Medicine,
4 Public Health–Biostatistics, UCLA,
5 Department of Rheumatology, Hutzel Hospital,
6 Department of Medicine, Johns Hopkins University, Baltimore, MD,
7 Department of Medicine, University of Maryland School of Medicine,
8 Department of Medicine, UCSD Medical Center,
9 Department of Medicine, Stritch School of Medicine, Loyola University,
10 Clinical Research, Department of Medicine, University of Alabama at Birmingham, AL,
11 Department of Medicine, Michigan State University College of Medicine,
12 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA,
13 Department of Medicine, Georgetown University Medical Center,
14 Department of Rheumatology, Denver Health Medical Center, University of Colorado,
15 Department of Medicine, George Washington University Medical Center,
16 Department of Medicine, Brown University School of Medicine,
17 Section of Rheumatology, University of Illinois at Chicago, Chicago, IL,
18 Department of Medicine, University of California at Irvine, CA,
19 Department of Medicine, University of Connecticut Health Center and
20 Scleroderma Program, UMDNJ–Robert Wood Johnson Medical School, NJ, USA


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. To compare the systemic sclerosis (SSc) patients entered into the d-penicillamine trial with SSc patients entered into previous controlled SSc trials. It was hypothesized that the d-penicillamine trial patients, who conformed to the American College of Rheumatology (ACR) guidelines for clinical trials in SSc were different from patients entered into previous trials.

Methods. Patients entering a double-blind, randomized trial of low- vs high-dose d-penicillamine were described carefully and completely. Their characteristics were then compared with previously published data on SSc and its treatment.

Results. One hundred and thirty-four patients had early [mean duration 9.5 (s.d. 4.2) months], diffuse [skin score 21 (8)] disease. Organ involvement in the patients was as follows: pulmonary 54%, cardiac 20%, joints 38%, muscular 20%. Thirty-three per cent had mild proteinuria and 13% were hypertensive when first seen. Compared with patients in most previous studies, these SSc patients had earlier disease and uniformly had diffuse disease. They had less muscular involvement, less dyspnoea, less abnormal pulmonary function and less cardiac and less renal involvement than patients in earlier studies.

Conclusions. The use of the new ACR guidelines for SSc trials may change the nature of patient populations entering future studies.

KEY WORDS: Systemic sclerosis, Scleroderma, Organ involvement, ACR guidelines for systemic sclerosis trials.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
A definition of disease modification in systemic sclerosis (SSc) has been advanced that requires a therapy to demonstrate decreased comorbidity (as measured by e.g. skin score), enhanced survival and/or reduced disability from the disease [1]. Disease modification implies the ability either to prevent new clinical complications or to stabilize and/or reverse previous organ disease. Prominent among the impediments to developing such a therapy is the remarkable heterogeneity of the disease course found in SSc. Differing levels of risk for progression of the disease or in accruing new features are thought to be heavily influenced by both duration and type of disease [1, 2]. Practical issues face the clinical research community as well. Access to homogeneous populations of subjects is limited, as are effective mechanisms for trial funding.

In 1995, the American College of Rheumatology (ACR) Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis (Scleroderma) published guidelines for disease-modifying interventions [3]. We had previously initiated a multicentre, prospective, dose comparison trial of D-penicillamine in the treatment of patients with early diffuse SSc, and these patients, and the study design, conformed closely to the ACR guidelines. This report describes the characteristics of the population as an example of the type of patient who would be recruited following the ACR guidelines.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
A portion of the patient descriptions, plus all inclusion and exclusion criteria and diagnostic tests used to describe this cohort of patients, has been published previously [4].

In brief, patients in this trial had diffuse cutaneous SSc of duration <=18 months. They had met predefined criteria for pulmonary, cardiac, renal, gastrointestinal, skin and musculoskeletal involvement. The exclusion criteria required that the patient should not be taking medications that could interfere with the effects of D-penicillamine (e.g. immunosuppressives), although low-dose prednisone or equivalent (less than or equal to 10 mg/day) and non-steroidal anti-inflammatory drugs (NSAIDs) were allowed. Diagnostic tests included history, physical examination with Rodnan skin score and related examinations, biochemical tests, complete blood counts, appropriate serological tests, 24-h urine collection, pulmonary function tests and chest radiographs. For a complete description, see [4].

Assessment of visceral involvement
Pulmonary involvement was considered present if the carbon monoxide diffusing capacity (DLCO) was <=70% of the predicted value, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) or total lung capacity (TLC) was <=75% of the predicted value, or definite chronic interstitial changes were noted on chest X-ray [5–7]. Renal involvement was considered present if the serum creatinine concentration was equal to or greater than the upper limit of normal (ULN) (usually 1.4 mg/dl) or creatinine clearance was <=70 ml/min (after standardizing the clearance to 1.73 m2 body surface area). Because patients might have used D-penicillamine previously, proteinuria could not be used as a reliable indicator of renal involvement, although the data were collected. Muscle involvement was considered present if the creatine kinase (CK) concentration was >=200% of the ULN or muscle strength was <=4 out of 5 in the proximal muscles. Joint involvement was considered present if the joint tenderness count was >=1. Cardiac involvement was considered to be present if the patient reported a history of, or currently had, congestive heart failure, cardiac arrhythmia requiring medication, pericarditis, moderate to large pericardial effusion, cardiomegaly on chest X-ray read by an independent radiologist, or a cardiothoracic ratio >0.5 on chest X-ray, not related to causes other than SSc.

Seventeen centres from all over the USA (locations available by request) required 45 months to accrue 143 patients for potential entry into the trial. Of these, nine patients never took any study medication and had incomplete data, so were excluded, leaving 134 patients, who are described below.

Literature comparison
Baseline patient demographics and clinical/laboratory data were abstracted from published, controlled trials of treatments for SSc and (separately) collected patient series of SSc patients. The data from the literature-based studies and patient series were then compared with the data from the present study. Qualitative comparisons between the literature data and the present study were made with visceral involvement defined as above, as far as possible. No formal statistical comparison was appropriate as data were not obtained concurrently and the methods used were often not well defined. The use of comparative ranges and qualitative comparisons was felt to be more useful.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Demographics (Table 1Go)
The ratio of females to males was approximately 4:1 in the study cohort. Mean disease duration was short (mean 9.5 months). Sixty-eight per cent of the patients were Caucasian and nearly one-third of the patients were African–American (19%) or Hispanic (8%) or from other ethnic groups (4%). Among the 17 centres, recruitment ranged from one to 21 patients, with an average of 7.9 patients per centre. Corticosteroid use (>=10 mg prednisone or equivalent) was common, occurring in 30% of the patients. NSAIDs and calcium channel blockers were used in 38 and 34% respectively, while diuretics were used by 16% of the patients. Seven patients had received small amounts of D-penicillamine previously (dose 11.8 ± 7.9 g) and five had received methotrexate (total dose 37 ± 21 mg), but other immunosuppressive or immunomodulatory drugs had not been used.


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  		TABLE 1. Demographics of the 134 participants at baseline

 

Organ involvement (Tables 2 and 3; Fig. 1Go)
Table 2Go reviews the prevalence of the discrete variables and Table 3Go displays the continuous variables. Most patients had recent worsening of their skin involvement (85%), although active skin ulcers were not common. Skin involvement was substantial, with a mean skin thickness score of 21 out of a maximum of 51 (range 10–43) (Fig. 1Go). As expected, most patients had some trunk involvement (85%). Although no normal values are available for hand extension in the literature, the values in Table 3Go can serve as the basis for future studies. There was some correlation between total skin score and hand extension (right and left hand vs total skin score, r = -0.536 and -0.492 respectively, P < 0.05). Some degree of joint involvement (tender or swollen joints or both) occurred in 52% of patients, although only 38% of the joints were tender on examination. Muscle weakness was uncommon (10%) and moderate CK elevations (>=200% of ULN) were also uncommon (8%). However, mild CK elevations (greater than normal but < 200% above the ULN) occurred in another 12% of patients, so that the CK concentration was abnormal to some degree in one-fifth of patients. One patient had a marked CK elevation, of >500% ULN, but did not have myositis (muscle biopsy failed to show inflammatory infiltrates). These patients probably did not have polymyositis despite the possibility that the biopsy had missed active lesions. Although baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were mildly elevated in 3 and 6% of the patients respectively, 38% of the patients were taking NSAIDs at baseline, confounding the meanings of the AST and ALT values. Antinuclear antibodies (ANA) were positive in 91.6%, antitopoisomerase antibodies in 27.4% and anticentromere antibodies in 2.1% of the 95 sera available.


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  		TABLE 2. Frequency of baseline characteristics (discrete variables) of the 134 participants

 

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  		TABLE 3. Baseline characteristics (continuous variables) of the 134 participants

 


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  		FIG. 1. Distribution of modified Rodnan skin scores among 134 SSc patients (%).

 
Mean pulmonary function test values were normal (Tables 2 and 3), but 32% of the patients had dyspnoea and 54% had some lung involvement, as defined above. Chest radiographs were not sensitive for discerning pulmonary involvement, being abnormal in only 11% of the patients. The most frequent abnormal pulmonary function test was DLCO, which was <70% of predicted value in 40% of the patients at baseline. It was <45% of the predicted value in three patients (2.2%).

Cardiovascular measurements showed some abnormality 20% of the time (Tables 2 and 3). Cardiomegaly, as judged by a radiologist, occurred in 12% and an elevated cardiothoracic ratio (measured by the investigators on the chest X-ray film as a cardiothoracic ratio >0.5) occurred in 18%. These two measures of cardiomegaly do not necessarily represent the same patients, as the correlation coefficient between the two ways of measuring cardiomegaly was only 0.465 (P < 0.05). Thirteen per cent of the patients had hypertension (blood pressure > 140/90) at the beginning of the trial, although the mean systolic and diastolic measurements for the group as a whole were within the normal limits.

Although no patients had a serum creatinine concentration greater than the ULN value of 1.4 mg/dl and the mean creatinine clearance was 93 ml/min, 33% of the patients had some proteinuria and four patients (2%) had an apparent creatinine clearance between 34 and 50 ml/min.

Literature data
Of 23 controlled studies reviewed (all that were available in the published literature) (Table 4Go ), six did not define disease duration and 16 used patients with disease duration of at least 29 months [8–30]. Only one study used patients whose mean disease duration was 18 months [24]. Most earlier studies used either a mix of patients with limited and diffuse SSc or did not define their patient groups at all (Table 4). Of the same 23 studies, 12 defined the disease type while the other 11 did not. Five of the 11 studies in which disease type was described entered patients with both limited and diffuse disease [10, 15, 19, 20, 23] and six studies entered patients with only diffuse disease [14, 18, 22, 25, 26, 29]. Table 4 demonstrates that the populations that had been entered into previous studies were relatively heterogeneous or undefined, making comparisons of the present data with those studies problematical.


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  		TABLE 4. Characteristics of controlled trials in SSc (modified from [30] with permission)

 
Table 5 shows the visceral involvement found in patients from other literature series [31–46] and compares that literature with our SSc patients.


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  		TABLE 5. Comparison of organ involvement in SSc (defined by the measures outlined) in the literature and in the present study

 
One can see from Table 5Go that previously published patient populations generally had more muscle, lung and renal involvement and probably more cardiac involvement than the present group. The percentages of abnormal values for the measured parameters in our population are frequently below the previously published ranges (e.g. hypertension 13%, cardiomegaly 18%, low FVC 27%, elevated creatinine or blood urea nitrogen 0%) [31–35, 38–45]. If not below, they are generally at the lower end of these ranges (e.g. joint pain 52%, DLCO 40%) [36–44]. Only a few measures were clearly well within previously published ranges (e.g. congestive heart failure, proteinuria) [31, 32, 34, 35, 45].


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The ACR guidelines for clinical trials in SSc were published in 1995 and the present study is the first to follow these guidelines [3].

One might say that differences between studies and series before the publication of these guidelines are to be expected. Nevertheless, this description serves three purposes: (i) to supply others with a more detailed and complete description of the patients in this study than has been presented in the study results paper [4], thus allowing others to make more complete comparisons with the D-penicillamine results in the future; (ii) to demonstrate that the new guidelines select for a group of patients who are different from those of previous data, so that comparisons of the D-penicillamine study with previous work and series are done with appropriate caution; and (iii) to highlight the type of patients who are most likely to enter into, and most likely to allow definition of, effective disease-modifying therapy aimed at the early immunological (and perhaps early fibrotic) pathogenic aspects of SSc.

The description presented here is somewhat different from that in the study published previously [4], although there is overlap. For example, the present paper gives more detail regarding the distribution of skin scores, combines the data from the separate groups for a better overall view of what these patients were like, and gives ranges of results, details of concomitant medications and patient recruitment per centre. These and the other data not available in previous publications are presented both to describe carefully a large cohort of diffuse SSc patients and to allow others to make clearer comparisons with the D-penicillamine study in future studies.

The background medications in this study were well documented, the reports showing that patients used certain classes of medications frequently. The use of NSAIDs in 38% and diuretics in 16% of the patients is not surprising. Thirty per cent of the patients used low-dose corticosteroids (mean dose of 1.5 mg per day; all <=10 mg per day), which is a surprising finding and one that needs to be considered as a possible confounding variable in future studies.

By design, these study patients had very early disease, with a mean duration of 9.5 months and a maximum duration of 19.2 months from the first non-Raynaud's sign or symptom clearly ascribable to SSc. Previous studies used patients with longer disease duration, most often with disease duration of at least 29 months (Table 4Go).

In comparing the present data with the literature, formal statistical comparisons would have been ideal. However, the literature data and the present data were not obtained concurrently and, importantly, the methods used in the literature were often not well defined. In these circumstances, we felt that simple qualitative comparisons of the presence or absence of involvement and comparisons of ranges of involvement without formal statistical analyses were the best comparisons possible.

We compared our methods as closely as we could with similar methods in the literature (e.g. cardiomegaly by chest X-ray, not by comparing the echocardiogram in one study with the chest X-ray) so comparisons could be relatively unambiguous. Therefore, the differences found for skin, muscle, renal and pulmonary involvement are likely to be real, although not formally tested statistically. This is particularly true when percentage involvements were below the lower value of the range documented in the literature series.

Kidney involvement was present in our group despite all serum creatinine values being less than 1.4 mg/dl. Proteinuria, a common finding in other studies, was also present here, as 33% of patients had mild proteinuria. Previous studies documented hypertension, proteinuria, azotaemia or some evidence of renal involvement in 45–60% of patients with diffuse SSc [31–35, 45]. These studies may have had a higher incidence of involvement because the patients had longer disease duration and the studies often included patients who were already taking D-penicillamine [45]. Two per cent of our patients had creatinine clearance between 34 and 50 ml/min. Because their serum creatinine concentrations were <=1.1 mg/dl, these apparently low creatinine clearance values are most probably due to incomplete urine collection. Another possibility was that patient muscle mass was very low; the patients with low creatinine clearances weighed more than 70 kg, so this is not a likely explanation.

It is possible that the patients who did not enter the trial because they refused for some reason or were excluded for some reason might have been more like those in the literature, but unfortunately we do not have complete data on those patients. Furthermore, a similar statement could be made for the comparator studies as they also did not describe the patients not entering the trials or not included in the series.

The measures of cardiac involvement were relatively insensitive (e.g. cardiomegaly on radiograph, electrocardiogram or clinical congestive heart failure) but were chosen because more sensitive measures were too expensive to use in this study.

The percentages of patients with positive ANA, antitopoisomerase antibodies and anticentromere antibodies were as expected in a group of patients with diffuse SSc.

The patients described in this paper were those recruited for a study of D-penicillamine. Their visceral involvement was somewhat different from that of the patients described in the previous literature, although the recruitment in our study was specifically oriented towards early diffuse disease, i.e. patients who were predicted to eventually develop more severe involvement. The relatively high mean skin score (21) and early disease (mean duration 9.5 months) bespeaks successful recruitment and the degree of visceral involvement probably means we captured the patients before too much severe internal damage had occurred. Previous studies included less homogeneous populations and tended to include patients with later disease and mixed limited and diffuse disease, or incompletely defined disease (Table 4Go). This is important, as it means that the patients in this study may reflect a different population of patients than those studied previously.

This study is the first demonstration of the type of patient to be expected in studies when using the ACR scleroderma clinical trials guidelines to study diffuse SSc and treatments with drugs aimed at overall disease modification. Our study is also relatively representative of the general population of SSc patients who fit these guidelines, because they were recruited from 17 centres, a larger sample than in most previous studies (in which the patients were usually from one to three centres). Parenthetically, the study requirements made accrual difficult and subjects entered the protocol at a rate of about three per month, despite the participation of many of the major US clinical centres interested in SSc.

We believe these data exemplify the spectrum of early diffuse SSc found in the general population of patients attending SSc clinics and define the baseline characteristics that are likely to be found in future clinical trials using the ACR guidelines.


   Acknowledgments
 
We acknowledge the help of Debbie Granner and Jane Lopez for excellent secretarial assistance in the preparation of this manuscript. The study was supported by The Scleroderma Foundation (the predecessor organizations were the United Scleroderma Foundation, Watsonville, CA and the Scleroderma Federation, Peabody, MA), the W. H. Conzen Endowment of the Schering–Plough Foundation, the Orphan Drug Program at the FDA, the Arthritis Foundation, PHS Grant MO RR 00065, the Rasmuson Center for Arthritis, Orthopedics and Musculoskeletal Diseases and the Richard Barnett Meurck Scleroderma Endowment.


   Notes
 
Correspondence to: D. E. Furst, Virginia Mason Research Center, 1000 Seneca Street, Seattle, WA 98101, USA. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 6 April 2000; Accepted 11 December 2000


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