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Autoantibodies in Systemic Sclerosis
Autoantibodies in Systemic Sclerosis Virginia D. Steen, MD OBJECTIVES To describe the clinical, laboratory, and prognostic features associated with the scleroderma-specific autoantibodies. METHODS Using the Pittsburgh Scleroderma Databank, all consecutive patients seen between 1980 and 1995 who had autoantibody studies performed were studied. Anticentromere antibodies (ACA), antitopoisomerase (TOPO), anti-U1-RNP (U1-RNP), anti-RNA Polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To), and anti-Pm/Scl (Pm/Scl) were determined according to previously described methods. The frequency of clinical features, organ system outcomes, and survival within the patients with a specific antibody were cumulative over the course of the disease. The frequency of a specific feature was compared across groups to identify significant manifestations and outcomes in patients with a specific antibody. RESULTS Some demographic, clinical, and organ system findings were associated with the specific antibody, and other features with the scleroderma subtype (limited cutaneous or diffuse cutaneous scleroderma). U3-RNP, U1-RNP, and TOPO were seen more commonly in African-American patients, and ACA was seen in older, female Caucasians. Muscle inflammation was seen in patients with U1-RNP and U3-RNP. Digital tip ulcers and digital tuft resorption were seen more frequently in those with ACA and TOPO. A vasculopathy causing pulmonary hypertension typically occurs with ACA and pulmonary fibrosis with TOPO; however, both types of lung disease were seen in patients with nucleolar antibodies, Th/To and U3-RNP. Importantly, severe interstitial fibrosis was rarely seen in cases with Pol 3. Renal crisis was strongly associated with Pol 3. Survival within limited scleroderma was decreased in the Th/To patients compared with ACA patients. Within the diffuse scleroderma group, patients with Pol 3 had the best survival. CONCLUSIONS Scleroderma autoantibodies are associated with very specific demographic, clinical, organ system, and survival features. RELEVANCE The determination of scleroderma autoantibodies may be helpful in assessing the prognosis, monitoring, and treatment of scleroderma patients. Semin Arthritis Rheum 35:35-42 © 2005 Elsevier Inc. All rights reserved. KEYWORDS scleroderma, autoantibodies, subsets, survival
A
ntinuclear antibodies are the hallmark of autoimmune diseases. In systemic sclerosis, autoantibodies are seen in more than 95% of patients. There are at least 7 sclerodermaspecific antibodies and others that are less frequent, nonspecific, unidentified, or without clinical significance. The scleroderma-specific antibodies are infrequently seen in other connective tissues diseases and are even less common in non-immune mediated processes. These antibodies are usually present at the onset of symptoms and do not change
Department of Medicine, Georgetown University, Washington, DC. Supported by the Arthritis Foundation Clinical Science Award. Address correspondence and reprint requests to: Virginia D. Steen, MD, Georgetown University, 3800 Reservoir Road, LL Gorman, Washington, DC, 20007. E-mail: [email protected]
0049-0172/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2005.03.005
from 1 antibody to a different 1 during the course of the disease. Patients rarely have multiple antibodies (1). Antibodies in scleroderma are not known to have any role in the pathogenesis of the disease but appear to be markers of clinical, genetic, and possibly etiologic patient subsets. The targets of the antibodies are specific components of the cell including kinetochore proteins, ribonuclear proteins, topoisomerase and RNA Polymerase enzymes. There is no known relationship of these cellular components to disease pathogenesis, but in the future, these antibodies may lead to important clues in understanding disease pathogenesis (2). Most of the scleroderma-specific antibodies are associated with distinctive clinical subsets with characteristic demographic, genetic, and clinical manifestations. This study uses the Pittsburgh Scleroderma Databank to describe the clinical 35
V.D. Steen
36 and prognostic features associated with the scleroderma-specific antibodies.
Methods Scleroderma patients from the Pittsburgh Scleroderma Databank whose initial visit was between July 1, 1980 and July 1, 1995 are included in this study. All patients had a standardized baseline evaluation (3) and are followed every 1 to 2 years as part of the Pittsburgh Scleroderma Outcome Study. As of 2000, 93% of these patients were accounted for. Deaths were confirmed through the Social Security Death Index and causes of death were determined from information obtained from our records, the patient’s family, physician, and the last hospitalization. We have previously validated our ability to determine the presence of severe organ involvement as well as the causes of death (4). Anticentromere antibodies (ACA), anti-Scl-70 or antitopoisomerase (TOPO), anti-U1-RNP (U1-RNP) (or antifibrillarin), anti-RNA Polymerase III (Pol 3), anti-U3-RNP (U3RNP), anti-Th/To (Th/To), and anti-Pm/Scl (Pm/Scl) antibodies were performed according to previously described methods (5-9). Varying numbers of antibody studies were performed depending on availability of the assay. In patients seen between 1980 and 1984, 95% had ACA, TOPO, and U1-RNP performed. Ninety-seven percent of consecutive patients seen between 1984 and 1989 had 6 or 7 of these scleroderma-specific antibodies determined. Of patients seen between 1989 and 1995 96% had ACA, TOPO, U1-RNP, and 30% had selective antibodies performed depending on the immunofluorescent patterns. Only patients with a single scleroderma-specific antibody are included in the study. Ten patients with more than 1 antibody were excluded from the study. Patients with a positive antinuclear antibody but whose scleroderma-specific antibody was not identified in the studies performed at the time of their evaluation (n ⫽ 410, 25%) and those with a negative antinuclear antibody (n ⫽ 75, 5%) were not included in this study. The comparison of the frequency of the individual antibodies within the entire population may not be accurate, since all patients did not have all antibodies assays performed and our population has a high referral population. However, the frequencies of the specific antibodies in patients seen during this extensive time period are similar to other studies and to the studies performed between 1984 and 1989 when all patients had all antibodies tested (6-8). In diffuse scleroderma patients, ACA was present 2%, TOPO 31%, U1-RNP 11%, Th/To 2%, U3-RNP 14%, Pm/Scl 2%, and Pol 3 was present in 45%. In limited scleroderma, again the frequencies were as expected, ACA 38%, TOPO 13%, U1-RNP 10%, Th/To 24%, U3-RNP 8%, Pm/Scl 7%, and Pol 3 in 6%. This study focuses primarily on the frequency of clinical features, outcomes, and survival in patients with a specific antibody. The features and survival described are cumulative over the course of the disease up to the time of the 2000 Outcome Study. Survival was measured from the time of diagnosis of scleroderma and was determined using Kaplan– Meier survival curves and log rank analysis.
The onset of disease was the time of the very first symptom attributed to scleroderma whether it was Raynaud’s, swollen fingers, or renal crisis. Patients were classified as limited cutaneous or diffuse cutaneous scleroderma according to Leroy and coworkers (10). Joint involvement was defined as inflammatory arthralgias, arthritis, or carpal tunnel symptoms. Calcinosis was identified on hand radiographs at the initial visit or when it was clinically obvious. Muscle inflammation was defined as muscle weakness along with an increased creatinine phosphokinase, electromyogram (EMG), or muscle biopsy consistent with inflammation (3). Noninflammatory myopathy and nonspecific weakness were not classified as muscle involvement in this study. Digital tip ulcers were based on physical observation but digital tuft resorption was determined by radiographic changes. Organ system involvement was defined as we have done previously with some modifications (3). Fibrosis on chest radiographs (not just increased markings) and/or a forced vital capacity of less than 75% predicted on pulmonary function tests (restrictive lung disease pattern) were used to define interstitial fibrosis. Highresolution computerized tomography (CT) scans and bronchoalveolar lavages were not uniformly performed and thus are not included in the criteria. Isolated pulmonary hypertension (PHT), primarily from vasculopathy, was defined as the development of markedly increased pulmonary artery systolic pressures (⬎50 mm Hg) in patients without severe hypoxic interstitial fibrosis (11). Increased systolic pulmonary artery pressure (between 30 and 50 mm Hg) on echocardiogram without other objective evidence of PHT was not defined as PHT. Severe heart involvement, cardiomyopathy, symptomatic pericarditis, arrhythmias requiring treatment, and renal crisis criteria were as previously described (3,4). The frequency of specific clinical features within patients with a specific antibody was based on the number of those with a specific feature present divided by those who had the feature evaluated. Comparisons of the percentages of a specific feature were compared across groups to identify manifestations and outcomes of patients with a specific antibody.
Results There were 1432 patients who had autoantibody assays performed during the above time period: Of these, 291 patients had ACA, 318 had TOPO, 71 had U1-RNP, 120 had Pol 3, 55 had U3-RNP, 72 had Th/To, and 36 had Pm/Scl. Table 1 summarizes the demographic features in these patients. Only 8% of ACA patients were male compared with 19 to 26% in the other groups (P ⬍ 0.01). Only 3% of ACA, 4% of Th/To, and 4% of Pol 3 patients were African-Americans compared with 32% of U3-RNP, 17% of TOPO, and 13% of U1-RNPpositive patients (P ⬍ 0.01). African-Americans account for 8% of our patient population and 76% of these 114 patients had U3-RNP, TOPO, or U1-RNP. Patients with Pm/Scl, U1-RNP, and U3-RNP were younger at the onset of symptoms compared with the other groups. Diffuse scleroderma occurred most frequently in patients with U3-RNP, TOPO and Pol 3; 64, 71 and 85%, respectively. Only 5% ACA and 7% Th/To patient subgroups had
Autoantibodies in systemic sclerosis
37
Table 1 Demographic Features of Patients with Scleroderma-Specific Autoantibodies Present Antibody Number of patients Male sex (%)* African African (%)* Age of onset years* Diffuse SSc (%)* Disease duration (years) At diagnosis* At last visit
ACA
Th/To
291 8 3 42 5 8.7 20
PmScl
U1RNP
U3RNP
TOPO
72 19 4 40 7
36 19 3 38 22
71 21 13 33 20
55 29 29 35 64
318 27 17 43 71
7.9 16.3
3.2 14.3
3.2 16.5
2.9 12.0
2.2 16.3
Pol3 120 19 3 44 85 1.5 11.3
*P < 0.001 by ANOVA. Major differences in bold.
diffuse scleroderma. Disease duration at the time of diagnosis was longest in ACA patients and shortest in Pol 3 patients. The disease duration at the time of last follow-up ranged from 9 to 20 years. Many of the clinical features described in Table 2 were primarily associated with the predominant disease subtype, diffuse scleroderma, or limited scleroderma, rather than antibody subgroup. This is the case for joint involvement and tendon friction rubs that were most commonly found in diffuse scleroderma patients, and those with Pol-3, U3-RNP, and TOPO. Digital tip ulcers were seen frequently in all subgroups, but digital tip gangrene and digital tuft resorption was higher in the ACA and TOPO groups. This finding suggests that more severe peripheral vascular disease was more closely related to the specific autoantibody than to the scleroderma subset (P ⬍ 0.01). Muscle involvement (inflammation) was most common in the 2 subsets which included patients with overlap disease, Pm/Scl, a nucleolar antibody, and U1-RNP, but it was also frequent in 1 of the other nucleolar antibody groups, U3-RNP. Muscle involvement was conspicuously infrequent in the Pol 3 (4%) (diffuse scleroderma) and ACA (2%) (limited scleroderma) groups, showing that this feature is more closely related to the antibody than to the disease subtype. Organ involvement was also highly associated with antibody specificity (Table 3). Subjective gastrointestinal (GI) involvement occurred in more than 80% of all groups without relationship to specific antibodies, but severe GI involvement (malabsorption, pseudoobstruction, or hyperalimenta-
tion) (4) was significantly greater in patients with U3-RNP. Twenty percent of the U3-RNP patients had malabsorption, pseudoobstruction, or required hyperalimentation. The other nucleolar antibody, Th/To, as well as U1-RNP were significantly increased in severe GI disease (13 and 14% compared to 5-8% in the other groups). Lung involvement, both pulmonary fibrosis and PHT, was very closely associated with specific antibody. Pulmonary interstitial fibrosis was very infrequent in patients with ACA and very common with TOPO, as previously shown (5). However, Pol-3 patients, the largest number with diffuse scleroderma, had an impressive lack of severe interstitial disease. Only 7% of Pol 3 patients had a FVC ⬍ 55% predicted, severe fibrosis (4), and the mean lowest FVC was 81% predicted. This low frequency of severe interstitial fibrosis was similar to that seen in limited scleroderma patients with ACA. In contrast, 25% of the TOPO group had severe fibrosis and their mean lowest FVC was 68% of predicted. Patients with the nucleolar antibodies, U3-RNP and Th/To, also had an increased frequency of severe fibrosis, 24 and 16%, respectively, and lower mean FVCs. Patients with ACA had the highest frequency of isolated or vasculopathy type of PHT, but patients with U3-RNP and Th/To also had an increased frequency of this type of PHT. In contrast to ACA patients with PHT who usually have minimal evidence of interstitial disease and a near normal FVC, patients with PHT and a nucleolar antibody had some degree of pulmonary fibrosis. The mean FVC in these patients was 69% of predicted, which was not associated with significant hyp-
Table 2 Clinical Findings in Patients with Scleroderma-Specific Antibodies Antibody
ACA
Th/To
PmScl
U1RNP
U3RNP
TOPO
Pol 3
Number Joints (%)* Carpal tunnel (%) Tendon rubs (%)* Digital ulcers (%)* Gangrene (%)* Digital tuft resorption (%)* (X-ray numbers actually performed) Calcinosis (%)* Muscle inflammation (%)*
291 60 22 3 61 18
72 60 26 4 29 5
36 75 25 25 47 5
71 94 29 16 49 11
55 89 27 42 58 9
318 86 28 50 63 13
120 88 43 61 42 3
27 (41/151) 46 1
7 (2/28) 22 6
32 (7/22) 39 58
17 (5/29) 14 27
9 (2/22) 22 18
28 (49/173) 17 9
5 (3/54) 14 4
*P < 0.001 by ANOVA. Major differences in bold.
V.D. Steen
38 Table 3 Organ Involvement in Patients with Scleroderma-Specific Antibodies Antibody
ACA
Th/To
PmScl
U1RNP
U3RNP
TOPO
Pol 3
Number of Patients Any GI (%) Severe GI (%)* Number with PFTs Any Lung (%) Severe fibrosis (%)* Lowest FVC* (% predicted) Isolated PHT (%) Severe heart disease (%)* Renal crisis (%)*
291 57 8 (184) 45 6 87 19* 4 1
72 33 13 (49) 62 16 70 32* 7 4
36 39 0 (22) 58 27 74 3 6 4
71 39 14 (40) 53 22 75 14 11 7
55 59 25 (37) 67 24 68 24* 18 7
318 56 8 (235) 73 23 67 2 16 10
120 37 5 (74) 49 7 81 6 7 28
*P < 0.01 by ANOVA. Major differences in bold.
oxia. Thus, it is unlikely that the fibrosis causes secondary increases in the pulmonary artery pressure. In PHT patients, the mean pulmonary artery systolic pressure by echocardiogram on right heart catheterization was 84 mm Hg in the nucleolar patients, the same as that seen in ACA PHT patients. Thus, the severity of the PHT was out of proportion to the degree of fibrosis and primarily from vasculopathy. Most of these patients developed moderate fibrosis early in their illness, which then stabilized for several years, but was followed by the development of severe PHT, rapid deterioration, and death. One other helpful way of determining whether the primary process is vasculopathy or not is the ratio of the FVC/DLCO (12,13). In patients with PHT who had ACA or U3-RNP this ratio was greater than 1.6 in 85% of patients, consistent with vasculopathy. This increased ratio and this type of vasculopathy causing PHT was not seen in the Pm/Scl, TOPO groups and was infrequent in the Pol 3 group. Heart and kidney involvement were seen most often in the diffuse scleroderma subgroups, U3-RNP, TOPO, and Pol 3. There was a particular propensity for renal crisis to occur in Pol 3 patients of whom 25% had scleroderma renal crisis in comparison to only 12% in other patients with diffuse cutaneous disease. Severe heart disease was seen infrequently in Pol 3 patients despite a high frequency of diffuse scleroderma and renal crisis. Severe heart disease and renal crisis were very infrequent in the limited scleroderma patient subsets. It is difficult to compare the survival of scleroderma patients with limited cutaneous and diffuse cutaneous disease because of the differences in disease duration at the time of diagnosis. Patients with ACA had a longer survival from the date of the diagnosis of scleroderma compared with patients in the TOPO subgroup (5). However, the disease duration in the ACA patients was significantly longer at the time of diagnosis than in the TOPO patients. To better compare the survival of patients in specific scleroderma antibody subgroups, we focused on antibody subgroups that predominantly included limited scleroderma patients and those that predominantly included diffuse scleroderma patients. Comparing similar groups makes it easier to determine whether there are differences in survival that are specifically associated with the antibody as opposed to the scleroderma subtype. Figure 1
shows the survival from diagnosis in these limited scleroderma subgroups. The best survival was in the patients with U1-RNP who were some of the youngest patients. Patients with Th/To had the worst survival perhaps because they had an increased frequency of both fibrotic and vascular types of lung disease. The ACA patients’ 5- and 10-year cumulative survival rate, 84 and 76%, was significantly better than the Th/To patients, 76% versus 58%, P ⬍ 0.03. Most patients with TOPO, U3-RNP, and Pol 3 have diffuse scleroderma. Their disease duration at the time of diagnosis was similar, ranging from 1.9 to 3.4 years. However, the 5and 10-year cumulative survival rates from the time of diagnosis were significantly better in the Pol 3 patients despite having more severe skin thickening and a higher frequency of renal crisis (P ⬍ 0.01) (Fig. 2). The lower frequency of severe interstitial lung disease in the Pol 3 group compared with the TOPO and U3-RNP groups likely accounted for their improved survival.
Discussion Autoantibodies have been associated with systemic sclerosis since the 1960s when they were first identified (14). The observation that the ACA and TOPO antibodies were closely
Figure 1 Survival from time of diagnosis for patients with specific autoantibodies that are most frequently associated with limited cutaneous scleroderma.
Autoantibodies in systemic sclerosis
39
Figure 2 Survival from the time of diagnosis for patients with specific autoantibodies that are most frequently associated with diffuse cutaneous scleroderma.
related to the classical manifestations of the 2 major subsets of scleroderma, limited (CREST syndrome) and diffuse scleroderma, led to a better understanding of these distinct clinical subsets (5,10,15). Since then, at least 7 sclerodermaspecific antibodies have been identified, each with unique clinical associations. The presence of antibodies associated with specific clinical manifestations raises questions as to what role these antibodies have in scleroderma. There is little evidence that these antibodies actually cause any pathologic abnormalities. Theories of the relationship of autoantibodies to the pathogenesis of scleroderma include the possibilities that antibodies may be biologic markers of tissue injury, or they could cause epitope spreading (16) or could be receptors that mediate contractions in muscles (17). None of these theories have adequate data to account for the entire disease process and most importantly they have little to no correlation with the clinical manifestations of the disease (18). Patients with a specific genetic makeup may respond in a certain manner to an antigen resulting in a specific set of disease manifestations and a specific antibody. Reproducible genetic associations have been identified with most of the antibodies (19). However, only 1.6% of patients have a firstdegree relative with scleroderma. Recent twin studies did not
show an increase in frequency of scleroderma in identical twins compared with fraternal twins, although a positive antinuclear antibody was seen more frequently in the nonaffected identical twin (20). Clinical and genetic features differ from country to country supporting the importance of genetic background in the pathogenesis of systemic sclerosis. In England the ratio of limited to diffuse scleroderma is 4.7:1; in the US it is closer to 1.5:1 (21,22). Italian patients have a high percentage of antiTOPO (23,24), but only 8% of Italian patients have anti-RNA Pol 3 compared with 25 to 33% of patients in other studies (6,25). In Thailand, 100% of patients had diffuse scleroderma; anti-TOPO was present in 76% and many others had a nucleolar pattern. This is in contrast to Australians where the majority of patients have limited scleroderma (6:1) and 50% have anticentromere antibody. The prevalence of scleroderma is markedly increased in the Choctaw Indians. These patients have the anti-TOPO antibody; this has led to intensive studies looking for the gene related to scleroderma in this population (26). Tan and coworkers using microsatellite arrays have demonstrated that the fibrillin 1 gene or 1 nearby on chromosome 15q gives an increased susceptibility in the Choctaw Indians with antiTOPO (27). Autoantibodies have been noted before any manifestations of the disease, are present at the time of diagnosis of scleroderma, and remain throughout the course of the disease (28). Antibodies, as in this study, are usually mutually exclusive and do not change from 1 antibody to a different antibody during the illness (29-31). In this study we have shown that these scleroderma-specific antibodies are strongly associated with clinical subsets of scleroderma. They are very good prognostic indicators which can guide the diagnosis, monitoring, treatment, and outcome of individual patients. Several of the antibodies are not commercially available, but based on the pattern of ANA and other typical findings, 1 can determine what the patient’s antibody is with a reasonable degree of certainty (Table 4). Anticentromere is associated with the classic description of limited scleroderma or the old “CREST” syndrome (1,5). These patients have limited cutaneous disease, without cardiac and renal involvement and rarely severe interstitial fibrosis. However, more than half of these patients who die
Table 4 Predominant Features Associated with Scleroderma-Specific Autoantibodies* ACA Demographics SSc subset Joint, skin Muscle Calcinosis Vascular changes Lung Kidney
Female Limited 2Joint 22Muscles 1Calcinosis 1Tuft resorption Dig ulcers 11PHT
Th/To
U1-RNP
Limited 2Joints
MCTD Limited 1Joints Overlap
PF ⴙ PHT
*Modified from previous chart in Rheumatology (51).
PHT
PmScl Limited Overlap 1Calcinosis
U3-RNP AfroAmer Diffuse
Topo Diffuse
Muscles
PF ⴙ PHT Kidney
1Tuft resorption Dig ulcers 11PF Kidney
Pol 3 Diffuse 11Skin 2Muscles
22PF 1Kidney
40 from scleroderma-related causes die from PHT late in their illness (32-34). Patients with an anticentromere can be reassured that they will not develop diffuse cutaneous disease. They do not need to be closely monitored for renal crisis or interstitial fibrosis. However, since PHT is the major cause of death in these patients, careful monitoring of the DLCO and Echo sPAP are necessary. An isolated decrease in the diffusing capacity, a FVC/DLCO ratio ⬎1.8, or a low-level increase in the pulmonary artery systolic pressures on echocardiogram often occur before the diagnosis of PHT (12,33,35). Symptomatic PHT can be treated aggressively with newer agents (36,37) and hopefully in the future we will be able to determine whether early treatment can prevent the deadly form of PHT. A nucleolar pattern for antinuclear antibodies in connective tissue diseases includes anti-Th/To, anti-U3-RNP, and anti-Pm-Scl and is fairly specific for scleroderma (38-40), although it does occur in liver disease, hepatocellular cancer, and other malignancies (41,42). One of the 3 nucleolar antibodies seen in scleroderma, anti-Th/To, occurs in limited scleroderma patients (8,43) who have a shorter duration between the onset of Raynaud’s and swollen hands compared with the ACA patients (8,44). Although the close proximity of the onset of swollen hands to Raynaud’s suggests diffuse scleroderma, Th/To patients (Caucasians with a nucleolar antibody) do not get diffuse cutaneous disease or renal crisis (8). Like the other nucleolar antibodies, inflammatory muscle disease occurs (45). The major difference between the 2 limited scleroderma patient groups, ACA and the nucleolar antibody, Th/To, is that Th/To patients can get both interstitial and vascular pulmonary disease (13,44). Usually the fibrosis occurs early in the disease (similar to the TOPO patients) and PHT develops later. However, the degree of PHT is out of proportion to the degree of fibrosis and restrictive lung disease. The increased frequency and severity of lung disease results in decreased survival compared with other limited scleroderma patients. Patients with overlap syndromes, including those with anti-U1RNP and Pm/Scl antibodies, also usually have limited cutaneous disease (9,46). Pm/Scl patients have increased calcinosis in the distribution seen in dermatomyositis. Anti-U1RNP is associated with a high-titer speckled ANA and classic mixed connective tissue disease. Another group of patients who have limited scleroderma are those with anti-TOPO antibody, 24% of patients with TOPO have limited scleroderma. Although they have a shorter duration between onset of Raynaud’s and swollen hands (rather than just fingers), they rarely develop diffuse cutaneous disease. They have a high frequency of interstitial fibrosis, similar to the anti-TOPO diffuse cutaneous scleroderma patients and an increased frequency of PHT similar to limited scleroderma patients. Like other limited scleroderma patients, they rarely have renal crisis (47). The survival of patients with limited scleroderma with anti-TOPO was similar to those with anti-Th/To. There is a high frequency of pulmonary hypertension in ACA patients. However, their overall survival is better compared with the limited Th/To
V.D. Steen patients. This may be because Th/To patients also have a significant frequency of interstitial disease. The autoantibodies in patients with diffuse cutaneous scleroderma are associated with distinctive and discriminating features. Patients with anti-TOPO have classic “diffuse” scleroderma. They can have renal crisis, severe GI, and heart involvement, but the most characteristic organ involvement is severe interstitial fibrosis (48,49). Alveolitis occurs early in the disease so careful monitoring is particularly important in the first 3 to 4 years of disease (50). PFTs and HRCTs should be performed every 3 to 6 months until they are stable. During this time, patients may not have any or only mild respiratory symptoms. With time, many develop progressive disease and die of lung-related problems an average of 10 years after the onset of scleroderma symptoms. Fortunately, not all TOPO patients have this severe course and many have stable moderate fibrosis and function quite normally. Diffuse scleroderma patients with anti-RNA POL3 have the most severe cutaneous thickening and the highest frequency of renal crisis but they do not have severe interstitial fibrosis. Patients with this antibody can often be identified even without the availability of commercialized antibody testing using the following combination of features: a speckled antibody (although some are nucleolar), a negative antiTOPO, extensive skin and tendon involvement early in their disease, and a FVC that is close to normal despite the severe skin disease. This group of patients has an increased likelihood of having Pol 3 and thus should be monitored very closely for renal crisis. Patients at high risk for renal crisis should take their blood pressure at home regularly and be told what level of blood pressure should be reported to their physicians. Then, they can take their blood pressure any time they have symptoms and know when to contact their physician. Early in the illness, as soon as diagnosis of scleroderma is made, these patients need aggressive physical and occupational therapy. They rarely have severe pulmonary fibrosis and often have normal PFTs. Aggressive treatment of lung disease is generally not necessary. Survival in patients with RNA-Pol 3 is better than those with anti-TOPO since renal crisis is now more easily treated than pulmonary fibrosis. These well-established outcomes should be considered in future therapeutic trials. Clinical management focusing on these differences, particularly when an assay for Pol 3 is commercially available, could be lifesaving. Patients with the nucleolar antibody, U3-RNP, also have classic diffuse scleroderma with multiorgan involvement. More than half the patients with this antibody are black. Twenty-five percent of my Georgetown scleroderma patients are African-Americans and more than half have a nucleolar antibody. This is most likely U3-RNP. I have been impressed with the severity of disease in these patients. They have severe lung disease, both fibrosis and PTH similar to the other nucleolar antibody Th/To, severe small bowel involvement, and severe peripheral neuropathies which are uncommon in other scleroderma populations. With a similar type of lung disease as patients with the nucleolar antibody Th/To, 1 can use that pattern to anticipate the problems these patients will have. They need to be monitored early for alveolitis and
Autoantibodies in systemic sclerosis development of fibrosis, and later, 1 must anticipate the development of severe vascular PHT. This often has an acute onset and is out of proportion to the severity of fibrosis. Diagnosis is very important since treatment approaches are very different. Since African-Americans also commonly have anti-TOPO, all African-Americans should be aggressively monitored and treated for pulmonary fibrosis early in the disease. Patient survival is closely related to both the subset, limited and diffuse, and the antibody present. This, rather than socioeconomic reasons, is probably why African-Americans have such severe disease. Anti-Th/To has the worst survival in limited scleroderma patients and Pol 3 patients have the best prognosis among the diffuse scleroderma patients. In summary, scleroderma autoantibodies are very specific and associated with meaningful clinical manifestations. They should be considered in developing clinical trials, patient monitoring, treatment, and prognosis. Hopefully, the specificity of the antibodies to scleroderma and their associated specific and quite different clinical patterns will lead to a better understanding of the pathogenesis of scleroderma.
References 1. Reveille JD, Solomon DH. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 2003;49(3):399-12. 2. Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am 1996;22(4):709-35. 3. Steen VD, Medsger Jr TA, Rodnan GP. D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med 1982;97(5):652-9. 4. Steen VD, Medsger Jr TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000;43(11):2437-44. 5. Steen VD, Powell DL, Medsger Jr TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988;31(2):196-203. 6. Okano Y, Steen VD, Medsger Jr TA. Autoantibody reactive with RNA polymerase III in systemic sclerosis. Ann Intern Med 1993;119(10): 1005-13. 7. Okano Y, Steen VD, Medsger Jr TA. Autoantibody to U3 nucleolar ribonucleoprotein (fibrillarin) in patients with systemic sclerosis. Arthritis Rheum 1992;35(1):95-100. 8. Okano Y, Medsger Jr TA. Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis. Arthritis Rheum 1990;33(12):1822-8. 9. Oddis CV, Okano Y, Rudert WA, Trucco M, Duquesnoy RJ, Medsger Jr TA. Serum autoantibody to the nucleolar antigen PM-Scl. Clinical and immunogenetic associations. Arthritis Rheum 1992;35(10):1211-7. 10. Leroy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15(2):202-5. 11. Steen VD, Mayes MD, Merkel PA. Assessment of kidney involvement. Clin Exp Rheumatol 2003;21(3 Suppl 29):S29-S31. 12. Steen VD, Graham G, Conte C, Owens G, Medsger Jr TA. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992;35(7):765-70. 13. Steen V. Predictors of end stage lung disease in systemic sclerosis. Ann Rheum Dis 2003;62(2):97-9. 14. Rothfield NF, Rodnan GP. Serum antinuclear antibodies in progressive systemic sclerosis (scleroderma). Arthritis Rheum 1968;11(5):607-17. 15. Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler MJ, Peebles C. Diversity of antinuclear antibodies in progressive systemic sclerosis. Anti-centromere antibody and its relationship to CREST syndrome. Arthritis Rheum 1980;23(6):617-25.
41 16. Brouwer R, Vree Egberts WT, Hengstman GJ, Raijmakers R, van Engelen BG, Seelig HP, et al. Autoantibodies directed to novel components of the PM/Scl complex, the human exosome. Arthritis Res 2002;4(2): 134-8. 17. Goldblatt F, Gordon TP, Waterman SA. Antibody-mediated gastrointestinal dysmotility in scleroderma. Gastroenterology 2002;123(4):1144-50. 18. Harris ML, Rosen A. Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies. Curr Opin Rheumatol 2003;15(6):778-4. 19. Johnson RW, Tew MB, Arnett FC. The genetics of systemic sclerosis. Curr Rheumatol Rep 2002;4(2):99-107. 20. Feghali-Bostwick C, Medsger Jr TA, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003;48(7):1956-63. 21. Mayes MD, Lacey Jr JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48(8):2246-55.2003 22. Allcock RJ, Forrest I, Corris PA, Crook PR, Griffiths ID. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology (Oxford) 2004;43(5):596-602. 23. Picillo U, Migliaresi S, Marcialis MR, Ferruzzi AM, Tirri G. Clinical setting of patients with systemic sclerosis by serum autoantibodies. Clin Rheumatol 1997;16(4):378-83. 24. Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Montagna G, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002; 81(2):139-53. 25. Bunn CC, Denton CP, Shi-wen X, Knight C, Black CM. Anti-RNA polymerases and other autoantibody specificities in systemic sclerosis. Br J Rheumatol 1998;37(1):15-20. 26. Zhou X, Tan FK, Wang N, Xiong M, Maghidman S, Reveille JD, et al. Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum 2003;48(9):2585-92. 27. Tan FK, Wang N, Kuwana M, Chakraborty R, Bona CA, Milewicz DM, et al. Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum 2001;44(4):893-901. 28. Tramposch HD, Smith CD, Senecal JL, Rothfield N. A long-term longitudinal study of anticentromere antibodies. Arthritis Rheum 1984;27(2): 121-4. 29. Hildebrandt S, Jackh G, Weber S, Peter HH. A long-term longitudinal isotypic study of anti-topoisomerase I autoantibodies. Rheumatol Int 1993;12(6):231-4. 30. Ruffatti A, Calligaro A, Ferri C, Bombardieri S, Gambari PF, Todesco S. Association of anti-centromere and anti-Scl 70 antibodies in scleroderma. Report of two cases. J Clin Lab Immunol 1985;16(4):227-9. 31. Dick T, Mierau R, Bartz-Bazzanella P, Alavi M, Stoyanova-Scholz M, Kindler J, et al. Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis. Ann Rheum Dis 2002; 61(2):121-7. 32. Kane GC, Varga J, Conant EF, Spirn PW, Jimenez S, Fish JE. Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status. Respir Med 1996;90(4):223-30. 33. Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003;48(2):516-22. 34. Morelli S, Barbieri C, Sgreccia A, Ferrante L, Pittoni V, Conti F, et al. Relationship between cutaneous and pulmonary involvement in systemic sclerosis. J Rheumatol 1997;24(1):81-5. 35. Macgregor AJ, Canavan R, Knight C, Denton CP, Davar J, Coghlan J, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001; 40(4):453-9. 36. Klings ES, Hill NS, Ieong MH, Simms RW, Korn JH, Farber HW. Systemic sclerosis-associated pulmonary hypertension: short- and
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long-term effects of epoprostenol (prostacyclin). Arthritis Rheum 1999;42(12):2638-45. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;2002;346(12):896-903. Harvey G, Black C, Maddison P, McHugh N. Characterization of antinucleolar antibody reactivity in patients with systemic sclerosis and their relatives. J Rheumatol 1997;24(3):477-84. Van Eenennaam H, Vogelzangs JH, Lugtenberg D, van den Hoogen FH, van Venrooij WJ, Pruijn GJ. Identity of the RNase MRP- and RNase Passociated Th/To autoantigen. Arthritis Rheum 2002;46(12):3266-72. Van Eenennaam H, Vogelzangs JH, Bisschops L, Te Boome LC, Seelig HP, Renz M, et al. Autoantibodies against small nucleolar ribonucleoprotein complexes and their clinical associations. Clin Exp Immunol 2002;130(3):532-40. Strassburg CP, Manns MP. Antinuclear antibody (ANA) patterns in hepatic and extrahepatic autoimmune disease. J Hepatol 1999;31(4): 751. Imai H, Ochs RL, Kiyosawa K, Furuta S, Nakamura RM, Tan EM. Nucleolar antigens and autoantibodies in hepatocellular carcinoma and other malignancies. Am J Pathol 1992;140(4):859-70. Kipnis RJ, Craft J, Hardin JA. The analysis of antinuclear and antinucleolar autoantibodies of scleroderma by radioimmunoprecipitation assays. Arthritis Rheum 1990;33(9):1431-7.
44. Mitri GM, Lucas M, Fertig N, Steen VD, Medsger Jr TA. A comparison between anti-Th/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement. Arthritis Rheum 2003;48(1):203-9. 45. Reimer G, Steen VD, Penning CA, Medsger Jr TA, Tan EM. Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma). Arthritis Rheum 1988;31(4):525-2. 46. Maddison PJ. Mixed connective tissue disease: overlap syndromes. Baillieres Best Pract Res Clin Rheumatol 2000;14(1):111-24. 47. Steen VD, Medsger Jr TA. Epidemiology and natural history of systemic sclerosis. Rheum Dis Clin North Am 1990;16(1):1-10. 48. Greidinger EL, Flaherty KT, White B, Rosen A, Wigley FM, Wise RA. African-American race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998; 114(3):801-7. 49. Ho KT, Reveille JD. The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 2003;5(2):80-93. 50. Steen VD, Conte C, Owens GR, Medsger Jr TA. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994;37(9):1283-9. 51. Steen V: Epidemiology of Systemic Sclerosis, in Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (eds): Rheumatology. London, Elsevier Limited, 2005;1455-1462.
A
ntinuclear antibodies are the hallmark of autoimmune diseases. In systemic sclerosis, autoantibodies are seen in more than 95% of patients. There are at least 7 sclerodermaspecific antibodies and others that are less frequent, nonspecific, unidentified, or without clinical significance. The scleroderma-specific antibodies are infrequently seen in other connective tissues diseases and are even less common in non-immune mediated processes. These antibodies are usually present at the onset of symptoms and do not change
Department of Medicine, Georgetown University, Washington, DC. Supported by the Arthritis Foundation Clinical Science Award. Address correspondence and reprint requests to: Virginia D. Steen, MD, Georgetown University, 3800 Reservoir Road, LL Gorman, Washington, DC, 20007. E-mail: [email protected]
0049-0172/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2005.03.005
from 1 antibody to a different 1 during the course of the disease. Patients rarely have multiple antibodies (1). Antibodies in scleroderma are not known to have any role in the pathogenesis of the disease but appear to be markers of clinical, genetic, and possibly etiologic patient subsets. The targets of the antibodies are specific components of the cell including kinetochore proteins, ribonuclear proteins, topoisomerase and RNA Polymerase enzymes. There is no known relationship of these cellular components to disease pathogenesis, but in the future, these antibodies may lead to important clues in understanding disease pathogenesis (2). Most of the scleroderma-specific antibodies are associated with distinctive clinical subsets with characteristic demographic, genetic, and clinical manifestations. This study uses the Pittsburgh Scleroderma Databank to describe the clinical 35
V.D. Steen
36 and prognostic features associated with the scleroderma-specific antibodies.
Methods Scleroderma patients from the Pittsburgh Scleroderma Databank whose initial visit was between July 1, 1980 and July 1, 1995 are included in this study. All patients had a standardized baseline evaluation (3) and are followed every 1 to 2 years as part of the Pittsburgh Scleroderma Outcome Study. As of 2000, 93% of these patients were accounted for. Deaths were confirmed through the Social Security Death Index and causes of death were determined from information obtained from our records, the patient’s family, physician, and the last hospitalization. We have previously validated our ability to determine the presence of severe organ involvement as well as the causes of death (4). Anticentromere antibodies (ACA), anti-Scl-70 or antitopoisomerase (TOPO), anti-U1-RNP (U1-RNP) (or antifibrillarin), anti-RNA Polymerase III (Pol 3), anti-U3-RNP (U3RNP), anti-Th/To (Th/To), and anti-Pm/Scl (Pm/Scl) antibodies were performed according to previously described methods (5-9). Varying numbers of antibody studies were performed depending on availability of the assay. In patients seen between 1980 and 1984, 95% had ACA, TOPO, and U1-RNP performed. Ninety-seven percent of consecutive patients seen between 1984 and 1989 had 6 or 7 of these scleroderma-specific antibodies determined. Of patients seen between 1989 and 1995 96% had ACA, TOPO, U1-RNP, and 30% had selective antibodies performed depending on the immunofluorescent patterns. Only patients with a single scleroderma-specific antibody are included in the study. Ten patients with more than 1 antibody were excluded from the study. Patients with a positive antinuclear antibody but whose scleroderma-specific antibody was not identified in the studies performed at the time of their evaluation (n ⫽ 410, 25%) and those with a negative antinuclear antibody (n ⫽ 75, 5%) were not included in this study. The comparison of the frequency of the individual antibodies within the entire population may not be accurate, since all patients did not have all antibodies assays performed and our population has a high referral population. However, the frequencies of the specific antibodies in patients seen during this extensive time period are similar to other studies and to the studies performed between 1984 and 1989 when all patients had all antibodies tested (6-8). In diffuse scleroderma patients, ACA was present 2%, TOPO 31%, U1-RNP 11%, Th/To 2%, U3-RNP 14%, Pm/Scl 2%, and Pol 3 was present in 45%. In limited scleroderma, again the frequencies were as expected, ACA 38%, TOPO 13%, U1-RNP 10%, Th/To 24%, U3-RNP 8%, Pm/Scl 7%, and Pol 3 in 6%. This study focuses primarily on the frequency of clinical features, outcomes, and survival in patients with a specific antibody. The features and survival described are cumulative over the course of the disease up to the time of the 2000 Outcome Study. Survival was measured from the time of diagnosis of scleroderma and was determined using Kaplan– Meier survival curves and log rank analysis.
The onset of disease was the time of the very first symptom attributed to scleroderma whether it was Raynaud’s, swollen fingers, or renal crisis. Patients were classified as limited cutaneous or diffuse cutaneous scleroderma according to Leroy and coworkers (10). Joint involvement was defined as inflammatory arthralgias, arthritis, or carpal tunnel symptoms. Calcinosis was identified on hand radiographs at the initial visit or when it was clinically obvious. Muscle inflammation was defined as muscle weakness along with an increased creatinine phosphokinase, electromyogram (EMG), or muscle biopsy consistent with inflammation (3). Noninflammatory myopathy and nonspecific weakness were not classified as muscle involvement in this study. Digital tip ulcers were based on physical observation but digital tuft resorption was determined by radiographic changes. Organ system involvement was defined as we have done previously with some modifications (3). Fibrosis on chest radiographs (not just increased markings) and/or a forced vital capacity of less than 75% predicted on pulmonary function tests (restrictive lung disease pattern) were used to define interstitial fibrosis. Highresolution computerized tomography (CT) scans and bronchoalveolar lavages were not uniformly performed and thus are not included in the criteria. Isolated pulmonary hypertension (PHT), primarily from vasculopathy, was defined as the development of markedly increased pulmonary artery systolic pressures (⬎50 mm Hg) in patients without severe hypoxic interstitial fibrosis (11). Increased systolic pulmonary artery pressure (between 30 and 50 mm Hg) on echocardiogram without other objective evidence of PHT was not defined as PHT. Severe heart involvement, cardiomyopathy, symptomatic pericarditis, arrhythmias requiring treatment, and renal crisis criteria were as previously described (3,4). The frequency of specific clinical features within patients with a specific antibody was based on the number of those with a specific feature present divided by those who had the feature evaluated. Comparisons of the percentages of a specific feature were compared across groups to identify manifestations and outcomes of patients with a specific antibody.
Results There were 1432 patients who had autoantibody assays performed during the above time period: Of these, 291 patients had ACA, 318 had TOPO, 71 had U1-RNP, 120 had Pol 3, 55 had U3-RNP, 72 had Th/To, and 36 had Pm/Scl. Table 1 summarizes the demographic features in these patients. Only 8% of ACA patients were male compared with 19 to 26% in the other groups (P ⬍ 0.01). Only 3% of ACA, 4% of Th/To, and 4% of Pol 3 patients were African-Americans compared with 32% of U3-RNP, 17% of TOPO, and 13% of U1-RNPpositive patients (P ⬍ 0.01). African-Americans account for 8% of our patient population and 76% of these 114 patients had U3-RNP, TOPO, or U1-RNP. Patients with Pm/Scl, U1-RNP, and U3-RNP were younger at the onset of symptoms compared with the other groups. Diffuse scleroderma occurred most frequently in patients with U3-RNP, TOPO and Pol 3; 64, 71 and 85%, respectively. Only 5% ACA and 7% Th/To patient subgroups had
Autoantibodies in systemic sclerosis
37
Table 1 Demographic Features of Patients with Scleroderma-Specific Autoantibodies Present Antibody Number of patients Male sex (%)* African African (%)* Age of onset years* Diffuse SSc (%)* Disease duration (years) At diagnosis* At last visit
ACA
Th/To
291 8 3 42 5 8.7 20
PmScl
U1RNP
U3RNP
TOPO
72 19 4 40 7
36 19 3 38 22
71 21 13 33 20
55 29 29 35 64
318 27 17 43 71
7.9 16.3
3.2 14.3
3.2 16.5
2.9 12.0
2.2 16.3
Pol3 120 19 3 44 85 1.5 11.3
*P < 0.001 by ANOVA. Major differences in bold.
diffuse scleroderma. Disease duration at the time of diagnosis was longest in ACA patients and shortest in Pol 3 patients. The disease duration at the time of last follow-up ranged from 9 to 20 years. Many of the clinical features described in Table 2 were primarily associated with the predominant disease subtype, diffuse scleroderma, or limited scleroderma, rather than antibody subgroup. This is the case for joint involvement and tendon friction rubs that were most commonly found in diffuse scleroderma patients, and those with Pol-3, U3-RNP, and TOPO. Digital tip ulcers were seen frequently in all subgroups, but digital tip gangrene and digital tuft resorption was higher in the ACA and TOPO groups. This finding suggests that more severe peripheral vascular disease was more closely related to the specific autoantibody than to the scleroderma subset (P ⬍ 0.01). Muscle involvement (inflammation) was most common in the 2 subsets which included patients with overlap disease, Pm/Scl, a nucleolar antibody, and U1-RNP, but it was also frequent in 1 of the other nucleolar antibody groups, U3-RNP. Muscle involvement was conspicuously infrequent in the Pol 3 (4%) (diffuse scleroderma) and ACA (2%) (limited scleroderma) groups, showing that this feature is more closely related to the antibody than to the disease subtype. Organ involvement was also highly associated with antibody specificity (Table 3). Subjective gastrointestinal (GI) involvement occurred in more than 80% of all groups without relationship to specific antibodies, but severe GI involvement (malabsorption, pseudoobstruction, or hyperalimenta-
tion) (4) was significantly greater in patients with U3-RNP. Twenty percent of the U3-RNP patients had malabsorption, pseudoobstruction, or required hyperalimentation. The other nucleolar antibody, Th/To, as well as U1-RNP were significantly increased in severe GI disease (13 and 14% compared to 5-8% in the other groups). Lung involvement, both pulmonary fibrosis and PHT, was very closely associated with specific antibody. Pulmonary interstitial fibrosis was very infrequent in patients with ACA and very common with TOPO, as previously shown (5). However, Pol-3 patients, the largest number with diffuse scleroderma, had an impressive lack of severe interstitial disease. Only 7% of Pol 3 patients had a FVC ⬍ 55% predicted, severe fibrosis (4), and the mean lowest FVC was 81% predicted. This low frequency of severe interstitial fibrosis was similar to that seen in limited scleroderma patients with ACA. In contrast, 25% of the TOPO group had severe fibrosis and their mean lowest FVC was 68% of predicted. Patients with the nucleolar antibodies, U3-RNP and Th/To, also had an increased frequency of severe fibrosis, 24 and 16%, respectively, and lower mean FVCs. Patients with ACA had the highest frequency of isolated or vasculopathy type of PHT, but patients with U3-RNP and Th/To also had an increased frequency of this type of PHT. In contrast to ACA patients with PHT who usually have minimal evidence of interstitial disease and a near normal FVC, patients with PHT and a nucleolar antibody had some degree of pulmonary fibrosis. The mean FVC in these patients was 69% of predicted, which was not associated with significant hyp-
Table 2 Clinical Findings in Patients with Scleroderma-Specific Antibodies Antibody
ACA
Th/To
PmScl
U1RNP
U3RNP
TOPO
Pol 3
Number Joints (%)* Carpal tunnel (%) Tendon rubs (%)* Digital ulcers (%)* Gangrene (%)* Digital tuft resorption (%)* (X-ray numbers actually performed) Calcinosis (%)* Muscle inflammation (%)*
291 60 22 3 61 18
72 60 26 4 29 5
36 75 25 25 47 5
71 94 29 16 49 11
55 89 27 42 58 9
318 86 28 50 63 13
120 88 43 61 42 3
27 (41/151) 46 1
7 (2/28) 22 6
32 (7/22) 39 58
17 (5/29) 14 27
9 (2/22) 22 18
28 (49/173) 17 9
5 (3/54) 14 4
*P < 0.001 by ANOVA. Major differences in bold.
V.D. Steen
38 Table 3 Organ Involvement in Patients with Scleroderma-Specific Antibodies Antibody
ACA
Th/To
PmScl
U1RNP
U3RNP
TOPO
Pol 3
Number of Patients Any GI (%) Severe GI (%)* Number with PFTs Any Lung (%) Severe fibrosis (%)* Lowest FVC* (% predicted) Isolated PHT (%) Severe heart disease (%)* Renal crisis (%)*
291 57 8 (184) 45 6 87 19* 4 1
72 33 13 (49) 62 16 70 32* 7 4
36 39 0 (22) 58 27 74 3 6 4
71 39 14 (40) 53 22 75 14 11 7
55 59 25 (37) 67 24 68 24* 18 7
318 56 8 (235) 73 23 67 2 16 10
120 37 5 (74) 49 7 81 6 7 28
*P < 0.01 by ANOVA. Major differences in bold.
oxia. Thus, it is unlikely that the fibrosis causes secondary increases in the pulmonary artery pressure. In PHT patients, the mean pulmonary artery systolic pressure by echocardiogram on right heart catheterization was 84 mm Hg in the nucleolar patients, the same as that seen in ACA PHT patients. Thus, the severity of the PHT was out of proportion to the degree of fibrosis and primarily from vasculopathy. Most of these patients developed moderate fibrosis early in their illness, which then stabilized for several years, but was followed by the development of severe PHT, rapid deterioration, and death. One other helpful way of determining whether the primary process is vasculopathy or not is the ratio of the FVC/DLCO (12,13). In patients with PHT who had ACA or U3-RNP this ratio was greater than 1.6 in 85% of patients, consistent with vasculopathy. This increased ratio and this type of vasculopathy causing PHT was not seen in the Pm/Scl, TOPO groups and was infrequent in the Pol 3 group. Heart and kidney involvement were seen most often in the diffuse scleroderma subgroups, U3-RNP, TOPO, and Pol 3. There was a particular propensity for renal crisis to occur in Pol 3 patients of whom 25% had scleroderma renal crisis in comparison to only 12% in other patients with diffuse cutaneous disease. Severe heart disease was seen infrequently in Pol 3 patients despite a high frequency of diffuse scleroderma and renal crisis. Severe heart disease and renal crisis were very infrequent in the limited scleroderma patient subsets. It is difficult to compare the survival of scleroderma patients with limited cutaneous and diffuse cutaneous disease because of the differences in disease duration at the time of diagnosis. Patients with ACA had a longer survival from the date of the diagnosis of scleroderma compared with patients in the TOPO subgroup (5). However, the disease duration in the ACA patients was significantly longer at the time of diagnosis than in the TOPO patients. To better compare the survival of patients in specific scleroderma antibody subgroups, we focused on antibody subgroups that predominantly included limited scleroderma patients and those that predominantly included diffuse scleroderma patients. Comparing similar groups makes it easier to determine whether there are differences in survival that are specifically associated with the antibody as opposed to the scleroderma subtype. Figure 1
shows the survival from diagnosis in these limited scleroderma subgroups. The best survival was in the patients with U1-RNP who were some of the youngest patients. Patients with Th/To had the worst survival perhaps because they had an increased frequency of both fibrotic and vascular types of lung disease. The ACA patients’ 5- and 10-year cumulative survival rate, 84 and 76%, was significantly better than the Th/To patients, 76% versus 58%, P ⬍ 0.03. Most patients with TOPO, U3-RNP, and Pol 3 have diffuse scleroderma. Their disease duration at the time of diagnosis was similar, ranging from 1.9 to 3.4 years. However, the 5and 10-year cumulative survival rates from the time of diagnosis were significantly better in the Pol 3 patients despite having more severe skin thickening and a higher frequency of renal crisis (P ⬍ 0.01) (Fig. 2). The lower frequency of severe interstitial lung disease in the Pol 3 group compared with the TOPO and U3-RNP groups likely accounted for their improved survival.
Discussion Autoantibodies have been associated with systemic sclerosis since the 1960s when they were first identified (14). The observation that the ACA and TOPO antibodies were closely
Figure 1 Survival from time of diagnosis for patients with specific autoantibodies that are most frequently associated with limited cutaneous scleroderma.
Autoantibodies in systemic sclerosis
39
Figure 2 Survival from the time of diagnosis for patients with specific autoantibodies that are most frequently associated with diffuse cutaneous scleroderma.
related to the classical manifestations of the 2 major subsets of scleroderma, limited (CREST syndrome) and diffuse scleroderma, led to a better understanding of these distinct clinical subsets (5,10,15). Since then, at least 7 sclerodermaspecific antibodies have been identified, each with unique clinical associations. The presence of antibodies associated with specific clinical manifestations raises questions as to what role these antibodies have in scleroderma. There is little evidence that these antibodies actually cause any pathologic abnormalities. Theories of the relationship of autoantibodies to the pathogenesis of scleroderma include the possibilities that antibodies may be biologic markers of tissue injury, or they could cause epitope spreading (16) or could be receptors that mediate contractions in muscles (17). None of these theories have adequate data to account for the entire disease process and most importantly they have little to no correlation with the clinical manifestations of the disease (18). Patients with a specific genetic makeup may respond in a certain manner to an antigen resulting in a specific set of disease manifestations and a specific antibody. Reproducible genetic associations have been identified with most of the antibodies (19). However, only 1.6% of patients have a firstdegree relative with scleroderma. Recent twin studies did not
show an increase in frequency of scleroderma in identical twins compared with fraternal twins, although a positive antinuclear antibody was seen more frequently in the nonaffected identical twin (20). Clinical and genetic features differ from country to country supporting the importance of genetic background in the pathogenesis of systemic sclerosis. In England the ratio of limited to diffuse scleroderma is 4.7:1; in the US it is closer to 1.5:1 (21,22). Italian patients have a high percentage of antiTOPO (23,24), but only 8% of Italian patients have anti-RNA Pol 3 compared with 25 to 33% of patients in other studies (6,25). In Thailand, 100% of patients had diffuse scleroderma; anti-TOPO was present in 76% and many others had a nucleolar pattern. This is in contrast to Australians where the majority of patients have limited scleroderma (6:1) and 50% have anticentromere antibody. The prevalence of scleroderma is markedly increased in the Choctaw Indians. These patients have the anti-TOPO antibody; this has led to intensive studies looking for the gene related to scleroderma in this population (26). Tan and coworkers using microsatellite arrays have demonstrated that the fibrillin 1 gene or 1 nearby on chromosome 15q gives an increased susceptibility in the Choctaw Indians with antiTOPO (27). Autoantibodies have been noted before any manifestations of the disease, are present at the time of diagnosis of scleroderma, and remain throughout the course of the disease (28). Antibodies, as in this study, are usually mutually exclusive and do not change from 1 antibody to a different antibody during the illness (29-31). In this study we have shown that these scleroderma-specific antibodies are strongly associated with clinical subsets of scleroderma. They are very good prognostic indicators which can guide the diagnosis, monitoring, treatment, and outcome of individual patients. Several of the antibodies are not commercially available, but based on the pattern of ANA and other typical findings, 1 can determine what the patient’s antibody is with a reasonable degree of certainty (Table 4). Anticentromere is associated with the classic description of limited scleroderma or the old “CREST” syndrome (1,5). These patients have limited cutaneous disease, without cardiac and renal involvement and rarely severe interstitial fibrosis. However, more than half of these patients who die
Table 4 Predominant Features Associated with Scleroderma-Specific Autoantibodies* ACA Demographics SSc subset Joint, skin Muscle Calcinosis Vascular changes Lung Kidney
Female Limited 2Joint 22Muscles 1Calcinosis 1Tuft resorption Dig ulcers 11PHT
Th/To
U1-RNP
Limited 2Joints
MCTD Limited 1Joints Overlap
PF ⴙ PHT
*Modified from previous chart in Rheumatology (51).
PHT
PmScl Limited Overlap 1Calcinosis
U3-RNP AfroAmer Diffuse
Topo Diffuse
Muscles
PF ⴙ PHT Kidney
1Tuft resorption Dig ulcers 11PF Kidney
Pol 3 Diffuse 11Skin 2Muscles
22PF 1Kidney
40 from scleroderma-related causes die from PHT late in their illness (32-34). Patients with an anticentromere can be reassured that they will not develop diffuse cutaneous disease. They do not need to be closely monitored for renal crisis or interstitial fibrosis. However, since PHT is the major cause of death in these patients, careful monitoring of the DLCO and Echo sPAP are necessary. An isolated decrease in the diffusing capacity, a FVC/DLCO ratio ⬎1.8, or a low-level increase in the pulmonary artery systolic pressures on echocardiogram often occur before the diagnosis of PHT (12,33,35). Symptomatic PHT can be treated aggressively with newer agents (36,37) and hopefully in the future we will be able to determine whether early treatment can prevent the deadly form of PHT. A nucleolar pattern for antinuclear antibodies in connective tissue diseases includes anti-Th/To, anti-U3-RNP, and anti-Pm-Scl and is fairly specific for scleroderma (38-40), although it does occur in liver disease, hepatocellular cancer, and other malignancies (41,42). One of the 3 nucleolar antibodies seen in scleroderma, anti-Th/To, occurs in limited scleroderma patients (8,43) who have a shorter duration between the onset of Raynaud’s and swollen hands compared with the ACA patients (8,44). Although the close proximity of the onset of swollen hands to Raynaud’s suggests diffuse scleroderma, Th/To patients (Caucasians with a nucleolar antibody) do not get diffuse cutaneous disease or renal crisis (8). Like the other nucleolar antibodies, inflammatory muscle disease occurs (45). The major difference between the 2 limited scleroderma patient groups, ACA and the nucleolar antibody, Th/To, is that Th/To patients can get both interstitial and vascular pulmonary disease (13,44). Usually the fibrosis occurs early in the disease (similar to the TOPO patients) and PHT develops later. However, the degree of PHT is out of proportion to the degree of fibrosis and restrictive lung disease. The increased frequency and severity of lung disease results in decreased survival compared with other limited scleroderma patients. Patients with overlap syndromes, including those with anti-U1RNP and Pm/Scl antibodies, also usually have limited cutaneous disease (9,46). Pm/Scl patients have increased calcinosis in the distribution seen in dermatomyositis. Anti-U1RNP is associated with a high-titer speckled ANA and classic mixed connective tissue disease. Another group of patients who have limited scleroderma are those with anti-TOPO antibody, 24% of patients with TOPO have limited scleroderma. Although they have a shorter duration between onset of Raynaud’s and swollen hands (rather than just fingers), they rarely develop diffuse cutaneous disease. They have a high frequency of interstitial fibrosis, similar to the anti-TOPO diffuse cutaneous scleroderma patients and an increased frequency of PHT similar to limited scleroderma patients. Like other limited scleroderma patients, they rarely have renal crisis (47). The survival of patients with limited scleroderma with anti-TOPO was similar to those with anti-Th/To. There is a high frequency of pulmonary hypertension in ACA patients. However, their overall survival is better compared with the limited Th/To
V.D. Steen patients. This may be because Th/To patients also have a significant frequency of interstitial disease. The autoantibodies in patients with diffuse cutaneous scleroderma are associated with distinctive and discriminating features. Patients with anti-TOPO have classic “diffuse” scleroderma. They can have renal crisis, severe GI, and heart involvement, but the most characteristic organ involvement is severe interstitial fibrosis (48,49). Alveolitis occurs early in the disease so careful monitoring is particularly important in the first 3 to 4 years of disease (50). PFTs and HRCTs should be performed every 3 to 6 months until they are stable. During this time, patients may not have any or only mild respiratory symptoms. With time, many develop progressive disease and die of lung-related problems an average of 10 years after the onset of scleroderma symptoms. Fortunately, not all TOPO patients have this severe course and many have stable moderate fibrosis and function quite normally. Diffuse scleroderma patients with anti-RNA POL3 have the most severe cutaneous thickening and the highest frequency of renal crisis but they do not have severe interstitial fibrosis. Patients with this antibody can often be identified even without the availability of commercialized antibody testing using the following combination of features: a speckled antibody (although some are nucleolar), a negative antiTOPO, extensive skin and tendon involvement early in their disease, and a FVC that is close to normal despite the severe skin disease. This group of patients has an increased likelihood of having Pol 3 and thus should be monitored very closely for renal crisis. Patients at high risk for renal crisis should take their blood pressure at home regularly and be told what level of blood pressure should be reported to their physicians. Then, they can take their blood pressure any time they have symptoms and know when to contact their physician. Early in the illness, as soon as diagnosis of scleroderma is made, these patients need aggressive physical and occupational therapy. They rarely have severe pulmonary fibrosis and often have normal PFTs. Aggressive treatment of lung disease is generally not necessary. Survival in patients with RNA-Pol 3 is better than those with anti-TOPO since renal crisis is now more easily treated than pulmonary fibrosis. These well-established outcomes should be considered in future therapeutic trials. Clinical management focusing on these differences, particularly when an assay for Pol 3 is commercially available, could be lifesaving. Patients with the nucleolar antibody, U3-RNP, also have classic diffuse scleroderma with multiorgan involvement. More than half the patients with this antibody are black. Twenty-five percent of my Georgetown scleroderma patients are African-Americans and more than half have a nucleolar antibody. This is most likely U3-RNP. I have been impressed with the severity of disease in these patients. They have severe lung disease, both fibrosis and PTH similar to the other nucleolar antibody Th/To, severe small bowel involvement, and severe peripheral neuropathies which are uncommon in other scleroderma populations. With a similar type of lung disease as patients with the nucleolar antibody Th/To, 1 can use that pattern to anticipate the problems these patients will have. They need to be monitored early for alveolitis and
Autoantibodies in systemic sclerosis development of fibrosis, and later, 1 must anticipate the development of severe vascular PHT. This often has an acute onset and is out of proportion to the severity of fibrosis. Diagnosis is very important since treatment approaches are very different. Since African-Americans also commonly have anti-TOPO, all African-Americans should be aggressively monitored and treated for pulmonary fibrosis early in the disease. Patient survival is closely related to both the subset, limited and diffuse, and the antibody present. This, rather than socioeconomic reasons, is probably why African-Americans have such severe disease. Anti-Th/To has the worst survival in limited scleroderma patients and Pol 3 patients have the best prognosis among the diffuse scleroderma patients. In summary, scleroderma autoantibodies are very specific and associated with meaningful clinical manifestations. They should be considered in developing clinical trials, patient monitoring, treatment, and prognosis. Hopefully, the specificity of the antibodies to scleroderma and their associated specific and quite different clinical patterns will lead to a better understanding of the pathogenesis of scleroderma.
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