Familial vs sporadic rheumatoid arthritis (RA). A prospective study in an early RA inception cohort

T. R. D. J. Radstake, P. Barrera, J. M. C. Albers, H. L. Swinkels, L. B. A. van de Putte and P. L. C. M. van Riel

Department of Rheumatology, University Hospital, Nijmegen, The Netherlands


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To study potential differences in demographic, process and outcome variables between familial and sporadic rheumatoid arthritis (RA) in an early RA inception cohort.

Methods. In 1998, we ascertained the familial status of all collaborative patients in a large early RA inception cohort at our department. Familial RA was defined by the presence of at least two siblings fulfilling the American College of Rheumatology criteria for RA. Baseline demographic data and prospectively recorded disease activity variables, therapies and radiological damage during the first 6 yr of disease were included in the analysis. A regression analysis was performed to assess whether familial clustering is a prognostic factor.

Results. We identified 142 patients with sporadic and 36 with familial RA. The most striking difference between these groups was the larger sibship size in multicase families (8.2 ± 2.5 vs 5.5 ± 2.8; P < 0.0001). Age at onset was similar in both groups, although males with familiar RA were younger at disease onset than those with sporadic RA (median 50 vs 57 yr; P=0.03). No differences were found in gender, presence of rheumatoid factor (RF), antinuclear factor and HLA-DR typing or in disease activity, interventions and outcome over 6 yr of follow-up. Early radiological damage and disease activity, but not familial history of RA were prognostic for X-ray damage.

Conclusion. We show that sibship size is the only relevant risk factor for familial RA. No differences in genotypic and phenotypic characteristics, disease severity or radiological damage were observed among familial and sporadic RA. Familial history of RA is not a poor prognostic factor. This prospective study confirms previous cross-sectional findings in the Dutch population.

KEY WORDS: Rheumatoid arthritis, Familial aggregation, Early RA inception cohort.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a complex multifactorial disease with genotypic and phenotypic heterogeneity where inherited and environmental factors are implicated [1–3]. The influence of genetic factors, particularly the HLA class II molecules, on disease susceptibility and/or severity is generally accepted. The ‘heritability’ of the disease has been put forward by twin, family and segregation studies [2, 4–9].

Although not strong, the familial aggregation of RA has been recognized for years. Community-based studies have shown that the risk of RA among first-degree relatives is only 1.6–1.7-fold higher than in the general population [10, 11]. Previous analyses on the differences between familial and sporadic RA have yielded conflicting results. Whereas none were found in some studies [12, 13], phenotypic differences in gender [14, 15], age at onset [14–16rsqb;, sibship size [16, 17], and some other clinical characteristics [16–18] have been claimed by some authors. A strong association of familial RA with HLA-DR4 has been proposed in other studies [16, 17, 19–21] but not always confirmed.

In a recent cross-sectional study among our RA patient population, sibship size was the factor most clearly linked with familial aggregation. In that study though, some other phenotypic characteristics also seemed to be related to higher RA concordance rates and the influence of HLA could not be analysed [22]. Moreover, the cross-sectional design of this and all aforementioned studies precludes comparison of disease course and outcome correcting for disease duration. Since potential differences between familial and sporadic RA could provide more insight into the pathogenesis and might have therapeutic consequences, further studies with a prospective setting seem warranted. The availability of a large early RA inception cohort at our department makes such a study possible.

The aims of the present study were to compare sporadic and familial RA in terms of demographic data and disease course using prospective assessments of process variables, therapies and outcome during 6 yr of follow-up. Furthermore, we ascertained whether familial clustering of RA is a prognostic factor for radiological damage.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study population and RA ascertainment
Collaborative patients from an early RA inception cohort started in 1985 at our department were enrolled in the present study. This cohort, which now encompasses approximately one-third of our total RA population [22], includes only patients who meet the American College of Rheumatology (ACR) criteria for RA [23], have a disease duration shorter than 1 yr and have not been treated with disease-modifying anti-rheumatic drugs (DMARDs) at presentation [2424–26]. Since the study was aimed at detecting differences in prospectively collected process variables we did not include patients with a follow-up shorter than 2 yr.

Familial RA was defined by the presence of at least two siblings fulfilling the ACR criteria for RA [23]. Parental status was also investigated although not taken into account for the definition since it is often difficult to verify.

Ascertainment of the familial RA status was performed using a multistep approach. The familial history for RA, as reported at the first visit, was updated and controlled by means of a questionnaire spread among the patients in 1996 [22] and by personal contacts, held from April 1996 to September 1998, with patients who had failed to return the questionnaire. Any first-degree relative with a history of RA or other past or present inflammatory articular complaints was ascertained. Therefore, medical records and X-rays were obtained from the general practitioner and/or rheumatologist and checked for the 1987 American Rheumatism Association (ARA) criteria for RA modified for population studies [27]. If necessary for diagnostic purposes, physical, laboratory or radiological examination was repeated at our centre.

The study was approved by the ethics committee of the University Hospital Nijmegen, The Netherlands.

Assessments of disease activity and outcome
Table 1Go shows all demographic, clinical and laboratory assessments and the therapeutic interventions and outcome measurements included in the present analysis.


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TABLE 1. Demographic data, process and outcome variables and therapeutic interventions of the early RA inception cohort included in the present analysis

 
HLA-DR typing was performed using serological methods (data on 12 patients with sporadic RA were not available). The use of DMARDs during follow-up was analysed as to the lag-time before starting therapy, the number of DMARDs used per patient, and the proportion of follow-up time (in %) in which DMARD therapy was prescribed. Therapeutic strategies were classified as aggressive (methotrexate, sulphasalazine, azathioprine, cyclophosphamide and combinations of those), intermediate (aurothioglucose, D-penicillamine) and mild (hydroxychloroquine, auranofin).

Besides DMARDs, other therapeutic interventions subdivided into total joint arthroplasties (TJA), non-total joint arthroplasties (NTJA) and admissions due to flares were also included in the analysis.

Outcome variables consisted of the total radiographic damage and its progression from baseline to 3 and 6 yr. The X-rays were scored by one blinded observer using the modified Sharp's method [28].

Statistical analysis
Analysis was performed with the SAS statistical package (SAS 6.04 PC version). Between-groups comparisons were tested using Student's t-test and the Mann–Whitney rank sum test for continuous variables and chi-square tests for dichotomous variables. For process variables, such as the disease activity score (DAS) and its individual components, the area under the curve (AUC) from baseline to 3 and 6 yr of follow-up were compared. P values in the text are reported without adjustments for multiple comparisons. Using the Bonferroni correction, most P values would have to be less than 0.017 for significance at the 0.05 level to be retained.

Multiple linear regression was performed to assess whether familial aggregation is an independent explanatory factor to the extent and progression of radiological damage. Dependent variables were the (root normalized) radiological scores at 3 and 6 yr, and its increase (0–3, 3–6, and 0–6 yr). Besides familial clustering, and based on previous findings [29], the following independent variables were included in the analysis: gender, age at onset, presence/absence of IgM rheumatoid factor (IgM-RF), HLA-DR4/DR1, HLA-DR2 (protective), X-ray damage at baseline and mean DAS during 6–12 months (DAS6–12) as assessment of early disease activity. Potential relations between the independent variables were assessed prior to performing the regression analysis.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Baseline patient characteristics
In 1998, a total of 273 living patients enrolled in the inception cohort were available for participation in this study. Exclusion of patients who failed to return the questionnaire and could not be contacted (n = 50) and those who could not provide reliable family data (n = 19) yielded 204 (75%) collaborative patients whose familial status was ascertained. We identified 162 cases of sporadic RA and 42 multicase families and retained 142 and 36 patients, respectively, with a follow-up of >=2 yr. Seven multicase families included three affected individuals and the additional 29 encompassed one affected sibpair per family. A total of 106 patients with sporadic and 32 patients with familial RA had a follow-up of >=6 yr.

Table 2Go shows the baseline characteristics of the patients in this study. The most striking difference was the larger sibship size observed in multicase families (8.2 ± 2.5 vs 5.5 ± 2.8 in sporadic RA; P < 0.001). No differences in other demographic, clinical or laboratory parameters were observed, although the radiological scores at baseline tended to be less favourable for patients with sporadic RA (P < 0.01).


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TABLE 2. Baseline characteristics of the patients studied. Data expressed as mean ± S.D. unless otherwise stated

 
There were no differences in age at onset when the familial and sporadic RA groups were taken as a whole. Since some studies have suggested an influence of gender on the age at onset of the disease [15,16], we reanalysed the data after stratification for gender (Fig. 1Go). Males with sporadic RA (n = 53) were older at disease onset than females (n = 89) [median, (range) 57 (24–78) vs 49 (23–82), P = 0.002]. Moreover, the former were older than male probands with familial RA (n = 12) [50 (24–61), P = 0.03] and than all affected males (n = 28) in the multicase families [51 (24–71), P = 0.01].



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FIG. 1. Age at onset in females (upper panel) and males (lower panel) with familial RA (continuous line) and sporadic RA (dotted line).

 
Data on the HLA-DR typing are shown in Table 3Go. HLA-DR4 was more frequent among probands with familial RA, whereas HLA-DR1 and HLA-DR10 tended to be more frequent in probands with sporadic RA but none of these differences were significant. HLA-DR alleles coding for th shared epitope were present in 79% of the patients with familial RA vs 75% of the sporadic RA patients [OR (95% CI) 1.14 (0.45–2.76)].


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TABLE 3. HLA-DR typing in familial and sporadic RAa

 

Prospective, 6-yr follow-up. Disease activity, therapies and outcome
Disease activity, as measured by the DAS, showed a marked decrease in the first year in both groups and levelled off thereafter (Fig. 2Go). Patients with sporadic and familial RA did not differ in DAS area under the curve (DASAUC) calculated for the first 3 and 6 yr of follow-up. Analysis of individual components of the DAS showed a similar pattern (data not shown). In probands with familial RA, the DAS, Ritchie articular index and patient's global health assessment were somewhat higher at baseline, but comparison of the 3- and 6-yr AUC for these variables showed no significant differences. The course of the swollen joint count and erythrocyte sedimentation rate (ESR) were practically identical in both groups.



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FIG. 2. Course of the DAS in patients with familial RA (continuous line) and sporadic RA (dotted line).

 
Since disease activity and outcome are influenced by therapeutic interventions, the use of DMARDs and the surgical interventions that familial and sporadic RA patients underwent during follow-up were compared (Table 4Go). Except for a slightly higher mean number of DMARDs used per year in patients with familial RA (0.61 ± 0.47 vs 0.45 ± 0.29 patient/yr, P = 0.045), no other clinically relevant differences were observed either in consumption of second-line anti-rheumatic drugs or in the number of surgical interventions or admissions due to disease activity.


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TABLE 4. Therapeutic interventions in 6 yr of follow-up. Data expressed as mean ± S.D. unless otherwise stated

 
The degree of X-ray damage in the first 6 yr is represented in Fig. 3Go. As already mentioned, patients with familial RA had less radiographic damage at presentation, although this difference was not found to be significant after 3 and 6 yr of follow-up.



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FIG. 3. Radiological damage in patients with familial RA (shaded boxes) and sporadic RA (open boxes). The box plots show the range (vertical line), median (horizontal line), and the p75 and p25 values (box).

 

Regression analysis
A moderate positive correlation was observed between radiological damage at baseline and age at onset (r = 0.3, P = 0.0001). As expected, the presence of HLA-DR1 and/or -DR4 was also associated with IgM-RF positivity ({chi}2 = 6.3, P = 0.012).

The results of regression analysis are shown in Table 5Go. The radiological damage at baseline, the DAS6–12 and to a lesser extent the presence of RF and HLA-DR2 (protective effect) explained 46% and 48% of the radiological damage after 3 and 6 yr, respectively. The model-explained variance for the radiological progression between 0–3 and 0–6 yr was in contrast very low (26% and 36%). Neither the presence of RA-related HLA-DR alleles nor familial aggregation contributed significantly to any of these models.


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TABLE 5. Multiple regressison analysis of the extent of radiographical damage and the progression between 3 and 6 yr of follow-up

 
In the model with radiological damage at 3 yr as the independent variable, only X-ray damage at baseline and the DAS6–12 were explanatory variables (R2 = 0.46). Exclusion of X-ray damage at baseline from the model reduced the explained variance to 18%.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is, to our knowledge, the first study comparing familial and sporadic RA in a prospective setting, which minimizes the chance of selection and information bias. Our results demonstrate that sibship size is the only factor clearly associated with the risk of familial clustering and confirm our findings in a previous cross-sectional study [22]. Moreover, we have shown that familial clustering is neither associated with HLA types coding for the shared epitope nor with a more severe prognosis.

An association between familial clustering of RA and the sibship size has been long recognized [17, 18]. Our results do not confirm previously reported relations between familial clustering and other proband characteristics. We did not observe associations of familiarity with gender, either female [30] or male [31,32]. Nevertheless, affected males in multicase families were younger at disease onset and both early onset and protracted disease duration have been linked to increased risk for familial RA by several [11, 15, 16, 31], but not all authors [13, 17, 21].

In our study, HLA-DR4 was somewhat more frequent in patients with familial RA. Conversely, the proportions of HLA-DR1 and -DR10 were higher in the group with sporadic RA. These differences were not statistically significant and the frequency of RA-associated HLA-DR alleles was almost identical in both groups (Table 3Go). Several previous reports corroborate these findings [17, 20, 33], although others have suggested that the presence of HLA-DR4 represents a major risk for familial RA [16] and even reported a dose effect [17, 21].

The most important finding in our study was that the prospective 6-yr follow-up did not reveal any clinically significant differences in process variables and radiological progression among patients with familial and sporadic RA, despite the use of similar therapeutic strategies. Moreover, regression analysis showed that familial history of RA was not predictive for the extent or progression of radiological damage. Among the dependent variables, baseline X-ray damage, early disease activity and to a lesser extent the presence of DR2 and RF contributed to the absolute radiological damage after 3 and 6 yr. However, neither these nor other variables explained much of the radiological progression. In our study, the presence of RF, but not HLA-DR4 and/or -DR1, was related to the radiological outcome.

This confirms earlier findings in our inception cohort as well as in others showing that RF positivity is more tightly associated with disease severity than the presence of HLA-DR4 [25, 30, 34]. Despite the previously reported association of poor outcome with HLA-DR4 and other alleles encoding the shared epitope [ 35–37], several studies besides ours have failed to demonstrate a role for HLA-DR4 as a predictor of poor outcome [ 37–40].

In conclusion, this prospective study in an early RA inception cohort points only to sibship size as a risk factor for familial clustering of RA. Except for the earlier onset of RA in males, patients with a positive familial history have a similar genotype, disease severity and outcome during the first 6 yr of follow-up as those with sporadic RA. Familial aggregation of RA is not a poor prognostic factor.


    Acknowledgments
 
We are indebted to E. Brummelkamp for the data processing and to M. A. van ‘t Hof for his support in the statistical analysis.


    Notes
 
Correspondence to: P. Barrera, Department of Rheumatology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 21 May 1999; revised version accepted 20 September 1999.