Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti–topoisomerase I antibody

Abstract

Objective

To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs).

Methods

SSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined.

Results

Sixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10-year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS.

Conclusion

Anti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.

Systemic sclerosis (SSc; scleroderma) is a connective tissue disease characterized by fibrosis affecting the skin and internal organs (1). Almost all patients with SSc have serum antinuclear antibodies (ANAs), many of which are relatively specific for this disease. Anti–topoisomerase I (anti–topo I) antibody is present in ∼25% of SSc patients in the US and occurs rarely in other diseases (2). Beyond being disease specific, ANAs in SSc are correlated with clinical features. Anti–topo I antibody is associated with diffuse cutaneous SSc (dcSSc) and with interstitial lung disease (ILD) (2). However, nearly one-third of anti–topo I–positive patients have limited cutaneous SSc (lcSSc) and 40% have no ILD (3).

Does it make a difference to the patient or the managing physician of an anti–topo I–positive SSc patient how widespread the skin thickening is or how rapidly the skin thickening has progressed? The purpose of this study was to identify anti–topo I–positive patients with diffuse and limited cutaneous changes with varying skin thickness progression rates (STPRs) early in the course of the disease and to determine the association of skin thickness progression with clinical and laboratory features and the natural history of the disease.

PATIENTS AND METHODS

Patients.

The source of patients was the Pittsburgh Scleroderma Databank, a prospective cohort of >2,500 consecutive SSc patients seen at the University of Pittsburgh Medical Center (UPMC) since January 1, 1972. Patients with SSc first evaluated during the 22-year period from 1980 to 2001, either as inpatients or outpatients, were eligible for this study. All patients had SSc as their primary diagnosis, based on the evaluation of one of the senior clinicians (TAM or VDS). Patients were classified as having either dcSSc (skin thickening proximal to the elbows or knees at some time during the disease) or lcSSc (skin thickening only distal to the elbows and knees). Patients who had either dcSSc or lcSSc as well as another connective tissue disease were excluded. For dcSSc patients, the onset of skin thickening, determined by the patient's history or physician documentation, must have been within 2 years of the first visit to the UPMC. For patients with lcSSc at the first Pittsburgh visit, a minimum of 6 years of followup after the onset of skin thickening was required to observe for the evolution to dcSSc. Patients with both anti–topo I antibody and ≥1 other SSc-associated autoantibody, for example, anti–U1 RNP, were excluded.

Assessment of skin thickness.

Skin thickness was measured using the modified Rodnan skin thickness score (MRSS) (4). Skin thickness was graded from 0 (normal) to 3 (severe) at 17 different cutaneous sites, and these scores were summed to obtain the MRSS (maximum possible score 51). From 1980 to July 1993, we used the original Rodnan skin thickness score (26 cutaneous sites, graded on a scale of 0–4) (5). These scores were converted to the MRSS by eliminating 9 cutaneous sites and changing all scores of 4 to 3.

The onset of skin thickening was defined as the first time that the patient's fingers became swollen and never again returned to normal size. This definition was agreed upon in 1972 and has been used prospectively for all SSc patients since then. Only 3 physicians (TAM, VDS, and Gerald P. Rodnan [deceased]) assigned the skin onset date. The STPR was defined as the MRSS at the first Pittsburgh visit divided by the duration, in years, from when the patient reported or a physician judged or recorded the onset of skin thickening, in MRSS units per year. For example, if the MRSS was 12 at the first visit and the patient had noted skin thickening beginning 6 months previously, the STPR by extrapolation would be 24 in 1 year.

Laboratory methods.

Serum specimens from the first and subsequent visits were used. Anti–topo I antibodies in all sera were detected by double immunodiffusion, which was performed by the same senior laboratory technician (NF). Anti–topo 1 antibody–specific IgG levels were measured by enzyme-linked immunosorbent assay as previously described (6), which was performed by one investigator (PH).

Study design.

Patients were classified at the time of their initial Pittsburgh evaluation as having either dcSSc or lcSSc. Five anti–topo I antibody–positive SSc patient subgroups were created, as illustrated schematically in Figure 1. The dcSSc patients were divided into 3 subgroups based on their STPRs: rapid (dcSSc-r), with an STPR of ≥40 units per year; intermediate (dcSSc-i), with an STPR of 15–40 units per year; and slow (dcSSc-s), with an STPR of <15 units per year. The lcSSc patients were divided into 2 subgroups: those who had limited cutaneous skin changes at the first visit, which subsequently became diffuse during followup (lcSSc to dcSSc); and those who had limited cutaneous skin thickening that remained limited throughout followup (lcSSc to lcSSc). The demographic, clinical, and laboratory features, including survival rates and the involvement of 7 organ systems, of these 5 subgroups were compared.

Figure 1. Modified Rodnan skin thickness score (MRSS) in subgroups of anti–topoisomerase I antibody–positive patients, according to the skin thickness progression rate. dc-r = diffuse cutaneous systemic sclerosis (dcSSc) with rapid progression; dc-i = dcSSc with intermediate progression; dc-s = dcSSc with slow progression; lc to dc = limited cutaneous SSc (lcSSc) progressing to dcSSc; lc to lc = lcSSc remaining as lcSSc.

Definitions of organ system involvement.

SSc organ involvement was considered to be present if predefined clinical features in the following 7 organ systems (excluding skin) were observed during the course of the illness and were not attributable to other diseases: 1) peripheral vascular (Raynaud's phenomenon or 1 of the following: digital pitting scars, digital tip ulceration, or digital gangrene); 2) articular (any 1 of the following: polyarthritis or finger joint contractures, carpal tunnel syndrome, palpable tendon friction rubs, or either joint space narrowing or erosions on radiography); 3) muscular (proximal muscle weakness on physical examination plus either elevated serum creatine kinase levels or myopathic changes on electromyography); 4) gastrointestinal (any 1 of the following: distal esophageal dysmotility, by esophagraphy or motility study; hypomotility of the duodenum or small intestine; malabsorption syndrome based on the physician's judgment; or colonic sacculations); 5) pulmonary (any 1 of the following: restrictive lung disease without obstructive lung disease [forced vital capacity (FVC) <70% predicted plus forced expiratory volume in 1 second (FEV₁)/FVC >80% predicted]; diffusing capacity for carbon monoxide <65% predicted; pulmonary fibrosis seen on chest radiography or high-resolution computed tomography [CT]; elevated mean pulmonary artery pressure of >30 mm Hg on right heart catheterization or estimated pulmonary artery or right ventricular systolic pressure >40 mm Hg by echocardiography, not believed to be secondary to ILD; or pleuritis, defined as pleuritic chest pain plus a pleural friction rub or pleural effusion. Two subgroups of pulmonary involvement were defined as follows: “intrinsic” pulmonary hypertension, which is elevated pulmonary artery pressure as defined above; and ILD, defined as FVC <70% predicted plus FEV₁/FVC >80% predicted or pulmonary fibrosis by chest radiography or high-resolution CT); 6) cardiac (any one of the following: estimated left ventricular ejection fraction <45% or left-sided congestive heart failure, pericarditis [pericardial pain and either a pericardial friction rub or pericardial effusion], arrhythmia requiring treatment, or complete heart block); and 7) renal (clinical evidence of scleroderma renal crisis, defined as the abrupt onset of accelerated arterial hypertension or rapidly progressive oliguric renal failure).

Statistical analysis.

Differences were detected using Student's t-test for continuous data, chi-square tests for categorical data, and nonparametric analysis of variance for non-normally distributed data. Continuous and ordinal data were compared using Spearman's correlation. Fisher's exact test was used for categorical data when appropriate. Survival was calculated from the first physician diagnosis of SSc using log rank tests. Followup data were ascertained through December 2002. Causes of death were determined from medical records when available. P values less than 0.05 were considered significant.

RESULTS

From 1980 to 2001, a total of 2,057 SSc patients who did not also have other connective tissue diseases were evaluated. Of these, 212 (10.3%) were found to have serum anti–topo I antibody with no other SSc-associated autoantibody and to have appropriate disease duration and followup as described above. According to the above criteria, these patients were divided into subgroups as follows: dcSSc with rapid STPR (n = 60), dcSSc with intermediate STPR (n = 82), dcSSc with slow STPR (n = 29), lcSSc that became dcSSc during followup (n = 14), and lcSSc that did not change during followup (n = 27).

Demographic features.

There were no significant differences among all anti–topo I antibody–positive patients with dcSSc and lcSSc combined or between any of the dcSSc or lcSSc subgroups with regard to sex or ethnicity (Table 1). Age at disease onset (date of first symptom attributable to SSc) and age at first physician diagnosis of SSc were significantly lower in lcSSc than in dcSSc patients (P < 0.001). The first physician diagnosis of SSc was prompt in the dcSSc patients with rapid STPR (mean 1 year after the date the first symptom occurred) and delayed in both lcSSc subgroups (mean 6–8 years) (data not shown). There were similar trends for mean duration from the onset of skin thickening to the first Pittsburgh visit (Table 1). The duration differed significantly in the rapid versus intermediate STPR subgroup (0.5 versus 1.0 years; P < 0.001) and in the rapid versus slow STPR group (0.5 versus 1.3 years; P < 0.001). Patients with intermediate and slow STPR were also significantly different from one another in this regard (P < 0.002). Thus, anti–topo I antibody–positive patients with lcSSc tended to be younger at disease onset and to have a longer disease duration at diagnosis, consistent with their having a milder, more slowly progressing disease.

Table 1. Demographic features of the anti–topoisomerase antibody–positive patients with SSc, according to the skin thickness progression rate*

	Patients with dcSSc at first visit			Patients with lcSSc at first visit		All patients
	dc-r (n = 60)	dc-i (n = 82)	dc-s (n = 29)	lc to dc (n = 14)	lc to lc (n = 27)	dcSSc (n = 171)	lcSSc (n = 41)
* SSc = systemic sclerosis; dcSSc = diffuse cutaneous SSc; dc-r = dcSSc with rapid skin thickness progression; dc-i = dcSSc with intermediate skin thickness progression; dc-s = dcSSc with slow skin thickness progression; lcSSc = limited cutaneous SSc; lc to dc = lcSSc progressing to dcSSc; lc to lc = lcSSc remaining as lcSSc. † P < 0.001 versus all patients with dcSSc. ‡ P < 0.013 versus lc to dc group. § P < 0.001 versus dc-i and dc-s groups. ¶ P < 0.002 versus dc-s group.
Female, no. (%)	40 (67)	62 (76)	24 (83)	10 (71)	23 (85)	126 (74)	33 (80)
White, no. (%)	53 (88)	70 (85)	26 (90)	12 (86)	26 (96)	149 (87)	38 (95)
Age at disease onset, mean (range) years	48 (11–73)	47 (3–79)	44 (12–65)	30 (5–52)	39 (18–71)	47 (3–79)	36 (5–71)†
Age at SSc diagnosis, mean (range) years	49 (11–76)	49 (6–81)	46 (13–67)	36 (8–71)	47 (27–73)‡	48 (6–81)	43 (8–73)
Time from onset of skin thickening to first Pittsburgh visit, mean (range) years	0.5 (0.1–1.2)§	1.0 (0.2–2.0)¶	1.3 (0.4–2.0)	2.2 (1.0–18.0)	4.2 (0.1–31.0)	0.9 (0.1–2.0)	3.6 (−1 to 31)†

Skin thickness scores.

The mean ± SD MRSS at the first visit for the 5 subgroups were as follows: rapid = 30.7 ± 11.0, intermediate = 24.9 ± 10.1, slow = 13.4 ± 5.9, lcSSc to dcSSc = 6.3 ± 4.6, and lcSSc to lcSSc = 7.0 ± 3.6. The highest mean ± SD maximum MRSS recorded for the subgroups at any time during followup were as follows: rapid = 33.3 ± 10.9, intermediate = 28.6 ± 10.9, slow = 19.1 ± 8.1, lcSSc to dcSSc = 21.6 ± 10.0, and lcSSc to lcSSc = 8.3 ± 4.5. The MRSS in all subgroups were significantly different from one another at the first visit, except for those of the 2 lcSSc groups. In the lcSSc to dcSSc subgroup, the mean time from the onset of skin thickening to the confirmation of diffuse skin changes was 5.6 years. Because the dcSSc subgroups were defined according to progression rate, there was an inverse relationship between the MRSS at the first visit and the duration from onset of skin thickening to the first visit, as shown schematically in Figure 1. In other words, dcSSc patients with the shortest duration between the onset of SSc and their first Pittsburgh visit had the highest mean MRSS.

Organ system involvement.

Table 2 summarizes organ system involvement by anti–topo I antibody subgroup. There were no differences between the dsSSc and lcSSc groups or any of the subgroups with regard to peripheral vascular involvement (nearly 100%), gastrointestinal involvement (67–88%), or ILD (53–69%). When the severity of ILD was examined using the modified SSc severity index (7), there was no apparent gradient according to dcSSc or lcSSc classification or to STPR (data not shown). Thus, moderate or severe lung involvement occurred regardless of the extent of skin thickness or the STPR. There were only 2 cases of “intrinsic” pulmonary arterial hypertension.

Table 2. Organ system involvement in anti–topoisomerase I–positive patients with SSc at any time during the disease course*

Organ system	Patients with dcSSc at first visit			Patients with lcSSc at first visit		All patients
	dc-r (n = 60)	dc-i (n = 82)	dc-s (n = 29)	lc to dc (n = 14)	lc to lc (n = 27)	dcSSc (n = 171)	lcSSc (n = 41)
* Values are the number (%) of patients with involvement. See Table 1 for definitions. † P < 0.003 versus all patients with dcSSc. ‡ P = 0.051 versus dc-i group. § P = 0.018 versus lc to dc group. ¶ P < 0.001 versus all patients with dcSSc. # P < 0.015 versus all patients with dcSSc. ** P = 0.006 versus dc-r group, and P = 0.043 versus dc-i group. †† P < 0.012 versus all patients with dcSSc.
Peripheral blood vessels	58 (97)	82 (100)	29 (100)	14 (100)	27 (100)	169 (99)	41 (100)
Joints/tendons	59 (98)	81 (99)	29 (100)	14 (100)	22 (81)	169 (99)	36 (88)†
Tendon friction rubs	41 (68)	58 (71)	14 (48)‡	7 (50)	3 (11)§	113 (66)	10 (24)¶
Skeletal muscle	17 (28)	18 (22)	5 (17)	1 (7)	1 (4)	40 (23)	2 (5)#
Gastrointestinal tract	45/51 (88)	54/66 (82)	20/27 (74)	9/11 (82)	14/21 (67)	119/144 (83)	23/32 (72)
Lung	44 (73)	61 (74)	20 (69)	9 (64)	20 (74)	125 (73)	29 (71)
Interstitial fibrosis	31/56 (55)	43/81 (53)	16/29 (55)	9/13 (69)	15/26 (58)	90/166 (54)	24/39 (61)
Pulmonary arterial hypertension	0	1 (1)	1 (3)	0	0	2 (1)	0
Heart	21/51 (41)	21/71 (30)	2/23 (9)**	2/11 (18)	4/22 (18)	44/145 (30)	6/33 (18)
Kidney	13 (22)	12 (15)	3 (10)	0	0	28 (16)	0††

Joint and tendon involvement was significantly more frequent in dcSSc versus lcSSc patients, but the proportions in both subgroups were high. Palpable tendon or bursal friction rubs were significantly more frequent in dcSSc versus lcSSc patients (66% versus 24%; P < 0.001). At the first visit, only 1 patient in the lcSSc to dcSSc group (7%) and 2 patients in the lcSSc to lcSSc group (7%) had friction rubs. Thus, these 2 subgroups could not be distinguished from one another on this basis at first visit. However, 7 of the patients in the lcSSc to dcSSc group (50%) ultimately had friction rubs detected. Skeletal muscle involvement was significantly more frequent in all dcSSc patients compared with all lcSSc patients combined (23% versus 5%; P < 0.015).

The rapid STPR subgroup had the highest frequency of cardiac involvement (41%), and SSc cardiac disease was found significantly more often in patients with rapid versus slow STPR (P = 0.006) and in patients with intermediate versus slow STPR (P = 0.043). Patients who developed scleroderma renal crisis were exclusively in the dcSSc subgroups (28 versus 0 among all dcSSc versus all lcSSc patients; P < 0.012). Within the dcSSc subgroups, both cardiac disease and renal crisis occurred in direct proportion to the STPR.

Of the 28 patients with renal crisis, 22 (79%) developed this complication within 2.5 years of the onset of skin thickening. Similarly, of the 50 patients with documented cardiac involvement, we were able to determine the date of onset of that complication in 40 of them. Thirty of the 40 patients (75%) developed scleroderma cardiac disease within 3 years of the onset of skin thickening. Thus anti–topo I antibody–positive patients with rapid or intermediate STPRs are at considerable early risk for the occurrence of SSc-associated renal and cardiac problems.

Anti–topo I antibody levels.

The median IgG anti–topo I antibody levels and median STPRs of 184 of the 212 patients at the first Pittsburgh visit are shown in Figure 2. Two patients had extremely elevated levels of anti–topo I antibody and were omitted from the analysis; those results are not shown in Figure 2. Both of these patients had intermediate skin thickness progression; 1 developed renal crisis 2 months after the serum specimen was obtained. The IgG anti–topo I antibody levels were positively correlated with the STPRs (ρ = 0.41, P < 0.0001). Median IgG anti–topo I antibody levels were significantly higher in all dcSSc patients combined compared with patients in both lcSSc subgroups combined (P < 0.0001). Anti–topo I antibody levels were also significantly higher in patients with rapid versus slow STPR (P = 0.03).

Figure 2. Median serum levels of IgG anti–topoisomerase I (anti–topo I) and median skin thickness progression rates (STPRs; in MRSS units per year). See Figure 1 for SSc subgroup definitions.

Six of the 14 patients in the lcSSc to dcSSc subgroup had serial serum specimens available for study. IgG anti–topo I antibody levels correlated positively with the MRSS, reaching a peak when the MRSS was highest and declining thereafter (data not shown).

Survival.

The 10-year cumulative survival rate from first physician diagnosis of SSc was significantly decreased for anti–topo I antibody–positive patients with dcSSc versus patients with lcSSc (40% versus 86%; P < 0.001) (Figure 3). The 10-year cumulative survival rates for the various groups were as follows: dcSSc with rapid STPR 36%, dcSSc with intermediate STPR 32%, dcSSc with slow STPR 70%, lcSSc to dcSSc 88%, and lcSSc to lcSSc 86%. The cumulative survival rate was inversely related to the STPR, i.e., patients with rapid STPR had the worst survival rate and patients in both lcSSc subgroups had the best survival rate.

Figure 3. Cumulative survival rate of anti–topoisomerase I antibody–positive patients with SSc, according to the skin thickness progression rate. See Figure 1 for SSc subgroup definitions.

The primary reason for poor survival in dcSSc patients was a disproportionate number of deaths due to cardiac disease. In the rapid and intermediate STPR subgroups combined, there were 17 deaths attributed to scleroderma cardiac disease out of 79 total deaths versus 0 of 23 in all other groups combined (P = 0.01, odds ratio 1.4, 95% confidence interval 1.2–1.6). There was a similar trend for renal crisis (13 of 79 deaths versus 2 of 23 deaths; P not significant). Renal crisis was also more severe than expected, because the proportion of patients with renal crisis who died was high (15 of 28 patients; 54%).

DISCUSSION

Among dcSSc patients, ∼30–70% have anti–topo I antibody, depending on ethnicity and geographic location (3, 8). In contrast, among lcSSc patients, anti–topo I antibody is found in only 10–20% (9). Most studies to date have examined the prognostic implications of anti–topo I antibody in dcSSc and lcSSc patients combined, but none has considered differences in skin thickening in a pure anti–topo I antibody–positive group of SSc patients (3, 9–14). The question addressed in this study is whether, in anti–topo I antibody–positive patients with SSc, the STPR and the ultimate classification of patients by degree and extent of skin thickening are important in predicting outcome.

In this study, the STPR for dcSSc patients was determined by the MRSS at the first visit divided by the number of years since the initial skin involvement based on the patient's history or physician documentation. This starting point is admittedly “soft,” but in our patient series, there was internal consistency in making this determination, since only 3 experienced physicians elicited the history and estimated the time of onset of skin thickening in all patients using the same definition of onset prospectively for the entire study period.

The STPR is a new concept that we believe will be helpful in the evaluation of dcSSc patients. Performing a careful medical history and physical examination can provide important insights into the pace of disease in anti–topo I antibody–positive patients with SSc and the likelihood of subsequent serious visceral complications. The STPR is most reliable early in the disease, before skin thickness has reached its peak. In our clinical experience, increase in skin thickness tends to be linear in this early phase of disease. We have also measured the STPR in dcSSc patients with anti–RNA polymerase III and anti–U3 RNP antibodies (15). In both cases, rapid STPR was associated with increased frequency of internal organ involvement early in the disease and reduced survival rates.

We recognize that patients with lcSSc at their first Pittsburgh visit initially may have had dcSSc, which subsequently regressed to lcSSc. Typically, such improvement occurs over the course of 5–10 years. In an attempt to minimize this possibility, all patients included in this study were first evaluated within 2 years of the onset of skin thickening.

The demographic features of patients in the 5 subgroups were similar. Nearly all patients were white. It was not surprising to find that patients with a more rapid STPR had a decreased length of time from onset of skin thickening to the diagnosis of SSc and to the first Pittsburgh visit. It is likely that the STPR was alarming to both the patients and their physicians, prompting an early referral.

As expected, there was an increased frequency of internal organ involvement in the dcSSc subgroups. Skeletal muscle involvement, cardiac disease, and renal disease were more often detected in patients with rapid compared with slow skin thickness progression. In the lcSSc to dcSSc subgroup, gastrointestinal and joint involvement were more frequent compared with patients in the lcSSc to lcSSc group. ILD was encountered with equal frequency among the SSc subgroups, and “intrinsic” pulmonary arterial hypertension was rare.

The 10-year cumulative survival rate of the 41 lcSSc patients combined was better than that of the 171 dcSSc patients combined (Figure 3). This result is similar to those reported from other geographic areas. Survival was improved in dcSSc patients with slow STPR compared with rapid STPR. The 5-year cumulative survival rate of all 212 SSc patients combined was 70% (not shown in Figure 3), and 67% if calculated from the time of the first Pittsburgh visit. The latter 5-year cumulative survival rate is lower than the 75% from the first Pittsburgh visit, which we published in 1988 for a group of 102 anti–topo I antibody–positive patients with SSc (3). The reason for this discrepancy is that we excluded from the present study many dcSSc patients who have a better survival rate, particularly those with a duration of skin thickening of >2 years before the first Pittsburgh visit, who would have been classified in the slow STPR subgroup or one of the lcSSc subgroups. Exclusions were made so that we could assemble homogeneous dcSSc subsets of patients most often seen early in their disease course.

The most frequent known cause of death in patients in the dcSSc subgroup was not ILD, as might be expected, but rather, cardiac involvement. Furthermore, the 54% mortality rate from renal crisis was much greater in the anti–topo I antibody–positive patients with dcSSc than we have reported previously for all renal crisis patients (15 of 55 patients; 27%) (16). This comparison is not flawed by differential use of angiotensin-converting enzyme inhibitor therapy since both studies included only patients evaluated after the availability of this therapy. It is thus very important for managing physicians to have a high index of suspicion for both cardiac and renal involvement in dcSSc patients with anti–topo I antibody who have a rapid STPR.

We previously reported a correlation between the MRSS and the IgG anti–topo I antibody level in 59 patients with SSc, including 11 patients with serial evaluations (5). Twenty-eight of those 59 SSc patients were also included in this study. A positive correlation of skin thickness with anti–topo I antibody level (17) and loss of anti–topo I reactivity late in disease (18) has been reported by others. In the present study, patients in whom serial serum specimens were available were noted to have elevated IgG anti–topo I antibody levels that paralleled the MRSS during followup, as we have previously determined (6).

A significant proportion of patients who are entered into clinical trials for treatment of early dcSSc have a disease duration of <2 years and are anti–topo I antibody positive. Because these patients differ considerably from one another with regard to the STPR, frequency of internal organ involvement, and survival, consideration should be given to stratifying anti–topo I antibody–positive patients according to STPR at the time of trial enrollment.

The STPR is a simple bedside method of obtaining important information on the pace and potential complications of dcSSc. Anti–topo I antibody–positive patients with dcSSc with a rapid STPR are at greatest risk for early fatal cardiac and renal involvement. In contrast, anti–topo I antibody–positive patients with the best prognosis are those with limited skin thickening that persists indefinitely or for a prolonged period of time without becoming widespread. Anti–topo I antibody–positive patients with lcSSc have a reduced frequency of renal crisis and other organ system involvement and an overall better prognosis. However, the occurrence and severity of ILD appears to be independent of the STPR. Therefore, surveillance for the development and progression of ILD is important in all anti–topo I antibody–positive patients with SSc. This study is consistent with previous work demonstrating that higher levels of serum anti–topoisomerase I antibody are associated with more severe SSc.

AUTHOR CONTRIBUTIONS

Dr. Perera had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Perera, Steen, Medsger.

Acquisition of data. Perera, Fertig, Lucas, Hu, Steen, Medsger.

Analysis and interpretation of data. Perera, Fertig, Lucas, Rodriguez-Reyna, Medsger.

Manuscript preparation. Perera, Rodriguez-Reyna, Steen, Medsger.

Statistical analysis. Rodriguez-Reyna, Medsger.