Sibling disability risk at onset and during disease progression in familial multiple sclerosis

Abstract

Background: The objective of this study was to address the differences in onset and disease progression between familial and sporadic multiple sclerosis (MS) and the association within sibling pairs.

Methods: Ninety-eight siblings and their controls were included from a database of 763 sporadic MS-patients, randomly pair-matched for age, gender, clinical course, disease duration and treatment. Sixty-eight available siblings completed a prospective six-year follow-up. Outcome parameters included baseline Expanded Disability Status Scale (EDSS), age at onset, mono- or multifocal onset, disease progression and conversion to secondary progression of initially relapsing–remitting MS. For statistical analyses Wilcoxon’s signed-rank statistics for categorical differences, t-statistics for continuous variables, McNemar’s test for relative frequencies of categories, intra-class correlations for within sibling-pair associations, or Kaplan–Meier analysis for survival analyses were used; all two-sided at the 5% level.

Results: Disease onset was slightly earlier (29.01 vs. 29.44 years, p = 0.0492) and multifocal onset significantly more often (p = 0.0052) in familial than in sporadic MS. Notably, a substantial within sibling-pair correlation for disease progression (rho = 0.40; p = 0.0062) as well as a higher risk for siblings than for controls to convert into secondary progression (0.545 vs. 0.227; p = 0.018) could be observed.

Conclusions: Familial MS differs from sporadic cases with respect to age at onset, multifocal involvement as first clinical event, and conversion into secondary progression. The progression rate of one out of two affected siblings may act as a predictor for the other sib.

Keywords

genetics multiple sclerosis progressive relapsing–remitting

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) clinically characterized by relapses and/or progressive disability in the majority of cases. In middle Europe its prevalence is estimated as about 1:1000.¹ Epidemiological and genetic data suggest both a relevant genetic² and environmental³ impact on its pathogenesis. Depending on geographical background prevalence, duration of follow-up, gender or ascertainment strategies, in 5–26% of all cases another family member is also affected by MS.⁴^–⁶ In MS high risk regions monozygotic twins show concordance rates of up to 30%^6,7 with a major contribution from female pairs, resulting in far exceeding those rates for dizygotic twins.^6,7 An additional 13% of the other, clinically not affected monozygotic and 9% of the respective dizygotic twins indeed demonstrate asymptomatic central demyelination in brain MRI studies,⁸ though the fewest seem stringently to convert into multiple sclerosis (denoted in Willer et al.⁷) In general, the closer the relationship between family members, the higher is the risk of disease manifestation.⁶ However, to transfer this epidemiological issue into definite gene associations even in regions of tight linkage disequilibrium sometimes caused confusion rather than clarification, because both the affected MS patients and their unaffected relatives carry susceptible alleles, concomitantly. Recently, epistasis among MS susceptibility haplotypes, especially of the HLA locus, provided evidence to determine not only the development of the disease⁹ but eventually also the disability outcome.¹⁰

Clinically, the individual disease evolution is modestly predictable and depends mainly on MRI data, disability evolution or relapse rate in the first years of the disease.^11,12 Whether familial or genetic factors determine the clinical outcome in MS affected patients or not is an issue of ongoing discussion.¹³^–¹⁵ This study focuses prospectively on epidemiological six-year follow-up data in familial MS in Germany. We here provide evidence for a comparatively strong within-sibling pair concordance for disease progression, and significantly higher familial risks for multifocal onset and conversion to secondary progression of familial MS.

Patients and methods

Patients and their controls

One-hundred and eighty adult patients with familial MS were recruited from the Marburg University MS database, containing sociodemographic and clinical data of n = 943 MS patients (August 2010). All patients were diagnosed according to the McDonald criteria¹⁶ and had at least one first or second degree relative with MS. Patients with a history of a concomitant disabling disease, affected but adopted relatives, refusal of participation of one of the affected relatives, or withdrawal of consent were excluded from the study. From all 156 evaluable familial cases, 98 siblings were included for the prospective follow-up analysis (Figure 1). Each affected sibling was carefully pair-matched for gender, age (±1 year), clinical course, disease duration (±6 months), and immunomodulating treatment (IFN-β 1a/1b vs. glatirameracetate vs. treatment naïve) with a patient from the remaining n = 763 non-familial sporadic cases (Table 1). All siblings were further stratified into pairs of sister/sister, sister/brother or brother/brother. To estimate the disease progression, n = 68 siblings (69.4%) and their matched controls were followed up prospectively each for a six-year period. All patients and controls gave written informed consent. The study was approved by the Institutional Review Board of Marburg University.

Figure 1.

Flow-chart of analyses of n = 98 siblings with MS and their randomly matched sporadic controls. n = 68 (69.4%) were followed up prospectively for a six-year period.

Table 1.

Clinical characteristics of n = 98 siblings with concomittant MS and their n = 98 controls of sporadic MS, randomly matched for age, gender, clinical course, disease duration and treatment at study entry

		Study entry					Six-year follow up^a
	All	Clinical course			Disease duration Mean (SD), years	EDSS	Change in clinical course (RR → SP)^b n/n (%)	EDSS
	n (%)	RR n (%)	SP n (%)	PP n (%)	Disease duration Mean (SD), years	Mean (SD)	Change in clinical course (RR → SP)^b n/n (%)	Mean (SD)
Familial MS, all	98 (100.0)	63 (64.3)	31 (31.6)	4 (4.1)	11.8 (7.8)	4.5 (1.7)	24/44 (54.5)*	5.2 (1.9)
Female	78 (79.6)	51 (65.4)	24 (30.8)	3 (3.8)	12.2 (7.9)	4.5 (2.0)	21/24 (87.5)	5.2 (1.9)
Male	20 (20.4)	12 (60.0)	7 (35.0)	1 (5.0)	11.1 (9.1)	4.3 (1.6)	3/24 (12.5)	5.8 (1.8)
Sibling pairs
Sister/sister	59 (60.2)	39 (66.1)	18 (30.5)	2 (3.4)	12.1 (7.2)	4.4 (1.6)	14/24 (34.1)	5.2 (2.0)
Sister/brother	33 (33.7)	20 (60.6)	11 (33.3)	2 (6.1)	11.4 (9.3)	4.1 (1.9)	8/24 (34.8)	5.4 (1.7)
Brother/brother	6 (6.1)	4 (66.7)	2 (33.3)	0 (0.0)	12.9 (8.9)	4.9 (1.7)	2/24 (33.3)	6.0 (1.9)
Sporadic MS, all	98 (100.0)	63 (64.3)	31 (31.6)	4 (4.1)	12.1 (7.9)	4.4 (2.0)	10/44 (22.7)*	5.3 (2.2)
Female	78 (79.6)	51 (65.4)	24 (30.8)	3 (3.8)	12.5 (7.8)	4.2 (1.9)	9/10 (90)	5.2 (2.1)
Male	20 (20.4)	12 (60.0)	7 (35.0)	1 (5.0)	10.7 (9.5)	5.1 (2.3)	1/10 (10)	6.1 (2.0)

Included n = 68 siblings and their matched controls.

n = 44 of all included, n = 68 siblings and their matched controls.

p < 0.018 (Kaplan–Meier analysis).

RR: relapsing–remitting, SP: secondary-progressive, PP: primary-progressive, EDSS: Expanded Disability Status Scale.

Clinical characteristic items and scores

For all siblings and their matched controls the following items were documented at study entry and continuously during the follow-up period of six years (Table 1): (1) the clinical course was defined as relapsing–remitting (RR), secondary-progressive (SP) or primary-progressive (PP);¹⁷ (2) age at onset and disease duration were recorded from the database, external medical records or from anamnestic information; (3) any initial presentation suggestive for a first clinical event of MS, and more than 24 hours of duration, was defined as first onset and further classified as mono- or multifocal; (4) disability and involvement of functional systems were assessed using the Expanded Disability Status Scale (EDSS) (modified according to Kurtzke¹⁸); (5) rate of disease progression was defined as the ratio of differences in the EDSS and the observation period in years (ΔEDSS/years); (6) conversion into secondary-progression was diagnosed after a progressive EDSS decline of ≥0.5 points over a period of at least six months without evidence of a relapse.

Data analyses

The within-group distributions of all variables of interest were analysed by means of standard descriptive techniques including graphical displays of empirical cumulative distribution functions. Most comparisons between patients suffering from familial and sporadic disease were performed using methods for matched pairs. In particular, Wilcoxon’s signed-rank statistic was used for evaluating categorical differences between familial and sporadic MS. T-tests for paired samples was performed for testing continuous variables. To test for differences with respect to the relative frequencies of two categories, we used McNemar’s test for correlated binomial proportions. The within sibling-pair association of the rates of disease progression was assessed by means of a non-parametric analogue of the intra-class correlation coefficient. Kaplan–Meier survival analysis and a hazard ratio were applied to estimate the risk for conversion into SPMS in familial versus sporadic MS. All tests were performed two-sided at the 5% level using SAS system 9.1 and SPSS 17.0.

Results

Clinical characteristics

Basic statistical characteristics of the distributions of the matching criteria and the clinical characteristics of both groups are given in Table 1. The majority of siblings were sister/sister pairs (60.2%), with no obvious difference in disability or disease duration in comparison with sister/brother pairs (33.7%) or brother/brother pairs (6.1%). Mean disease duration in the familial as well as the sporadic cohort was about 12 years with an EDSS of 4.2 ± 1.7. During the six years of follow-up, the EDSS increased up to 5.2 ± 1.9 (vs. 5.3 ± 2.2 in the controls; NS). Because assessment of the EDSS is critical for analysing progression, it was not included for matching siblings with their controls. However, the pairwise distribution of differences in the EDSS between siblings and their respective controls was symmetric, with a peak at zero (not shown; p = 0.499). This suggests that both groups had an equivalent distribution in disability at study entry.

Age at onset

Figure 2 shows the empirical cumulative distribution functions of the age at onset in patients with familial and sporadic MS. The mean age at onset differed slightly but significantly between both groups (29.0 ± 9.2 familial MS vs. 29.4 ± 10.5 in sporadic cases; p = 0.0492), and was similar to epidemiologically based surveys.¹⁹ In both cohorts, the disease onset of 80% of all patients was between 20 and 40 years; 9% occurred at age < 20 years and 11% at age > 40 years.

Figure 2.

Cumulative percentage of age at MS onset of patients with familial (continuous line) and sporadic (dotted line) MS. Familial MS occurs significantly earlier than sporadic cases (29.0 ± 9.2 vs. 29.4 ± 10.5; p = 0.0492).

Multifocal versus monofocal onset

The distribution we obtained among all n = 82 matched pairs with sufficiently complete data regarding their symptoms and signs at onset by applying the dichotomy of multi- vs. monofocal onset is shown in Table 2. The proportion of siblings with a multifocal disease onset was (vs. 14.6% of the controls, p = 0.0052) with a disconcordance to their control pairs of 82.1%.

Table 2.

Clinical onset in patients with familial vs. sporadic MS

	Familial MS
	Multifocal onset n (%)	Monofocal onset n (%)	Σ n (%)
Sporadic MS
Monofocal onset n (%)	47 (57.3)	23 (28.1)	70 (85.4)
Multifocal onset n (%)	7 (8.5)	5 (6.1)	12 (14.6)
Σ n (%)	54 (65.9)	28 (34.2)	82 (100)

Disease progression during six-year follow-up

The distribution of the within-pair EDSS differences over the six-year follow-up period between familial and sporadic MS was symmetric, suggesting that there are no differences in disability evolution between both groups (Figure 3). Neither their means (0.158 ± 0.16 vs. 0.173 ± 0.172; p = 0.642) nor the mode of distribution differed significantly (p = 0.962). However, a significant rank correlation was obtained (r = 0.4035; p = 0.0062), after ranking the siblings within each pair according to their disease duration and after stratifying their progression into three progression risk categories: ‘low’ (EDSS ≤ 0.5/6 years), ‘medium’ (EDSS between 0.5/6 and 1.5/6) and ‘high’ (EDSS > 1.5/6). Additionally, the odds ratio for one sibling to enter the same risk category as the other was calculated to be 3.5. Both suggest that the progression rate of one appears to be predictive for the other sib.

Figure 3.

Within-pair EDSS differences (range −4.5 to +3.5 EDSS points) over the six-year follow-up period (−4.5/6 to 3.5/6) between sib pairs and their matched paired sporadic controls. The distribution is symmetric (maximum at ‘0’), suggesting no differences between the two groups (NS; p = 0.962).

Conversion into secondary-progressive MS

From the n = 44 siblings with RRMS, who were followed over six years, n = 24 entered a secondary-progressive course (Table 1). For survival analysis (Figure 4) n = 19 patients were censored, all at the time of inclusion into this study. Though age at onset, baseline EDSS and disease duration in the subgroup of RRMS patients were similar, the odds not to convert into SPMS were significantly lower in the siblings (0.455 ± 0.075) than in their controls (0.732 ± 0.069; p = 0.018).

Figure 4.

Kaplan–Meier analysis of the six-year conversion risk from RRMS to SPMS of n = 44 patients with initial familial RR-MS course and their respective sporadic controls. Note that during the observation period familial MS patients have a 31.8% higher risk to develop SPMS (p = 0.018).

Discussion

In 7–18% of MS cases another first or second degree relative is also affected.^20,21 We here provide evidence for an increased sibling risk for (1) multifocal onset, (2) within-pair correlation of progression, and (3) for conversion into secondary progression. Remarkably, key data like disease duration, baseline EDSS or age at onset in our consecutive cohort of familial cases were largely similar to those in geographically or epidemiologically based surveys.^20,22 In contrast, a small Spanish cohort of familial MS patients showed lower EDSS at onset and more often a relapsing–remitting course.²³

In our prospective six-year follow-up, familial MS showed a higher incidence of progression in clinical surrogates than in sporadic cases. Secondary progression is the most common clinical course in MS, with an estimated proportion of 66% of all patients affected by MS.²² Therefore the conversion from RR- to SPMS is a clinical and therapeutic hallmark in the course of MS. Epidemiological data suggest the evolution of disability being more dependent on disease duration and a ‘predefined schedule of progression’ than on relapses.²⁴^–²⁶ At least data from pivotal clinical trials show a higher disability evolution among SPMS patients than among RRMS.^27,28 Though there is no difference in basic clinical data at study entry between our two cohorts of familial and sporadic MS, a higher risk of SPMS conversion was observed in familial cases. Beyond a constitutional finding, one possible explanation might be the sharing of MS susceptibility haplotypes responsible for the ‘schedule of progression’ among siblings in the context of epistasis.¹⁰ Because in MS relevant epistatic control occurs in the context of distinctive HLA loci (e.g. HLA-DRB1, -DQA1, -DQB1⁹), HLA stratified familial cohorts should be analysed for ‘immuno-disabling’ candidate genes.

However, the absence of a significant effect of familiality on the EDSS disability evolution is in line with others,^29,30 suggesting a small difference which can be detected only either with larger cohorts or a longer observation period. Due to our carefully matching of sporadic pair-controls a confounding effect of biasing immunomodulatory treatment could be excluded.

Age at onset is under genetic control,³⁰^–³² but the absence of significant differences between mono- and dizygotic twins suggests a rather mild influence of genes.⁶ Accordingly, our patients suffering from familial MS were found to have been less than one year younger at disease onset than their otherwise matched controls. Though the clinical relevance of this finding remains elusive, early attacks are believed to be relevant not only for the initiation of but also for perpetuating MS.¹² However, genetic analyses of siblings with a focus on immunological markers of disease onset may therefore add important notes to the puzzling picture of the very early MS.

Studies focusing on clinical phenotype have revealed contradictory results.^14,22,33,34 However, they conform to a heterogenous clinical presentation of MS at disease onset. Recently, the dichotomy of multifocal vs. monofocal onset became relevant for therapeutic decisions in the context of positive predictive items or disease activity assessment.^12,35 Patients with familial disease presented much more often with multifocal symptoms and signs than patients with sporadic disease. Besides its prognostic relevance of familial MS in general, larger prospective studies are required to demonstrate the therapeutic relevance of these findings in familial cases.

To our knowledge, this is so far the largest population-based cross-sectional study conducted in Germany of familial MS. The reliability of the inferences made on the population underlying the samples we analysed is comparatively high. However, due to difficulties in defining the nature and extent of already known or still cryptic genes that may be involved in the MS susceptibility, there is need for larger and well characterized cohorts of familial MS patients.

Footnotes

Acknowledgments

We thank Mrs Katrin Hülsmeier, Mrs Annette Hehenkamp and Mrs Ines Jackl for excellent technical and organizational help.

References

Fromont

Binquet

Sauleau

. Geographic variations of multiple sclerosis in France. Brain 2010; 133: 1889–1899.

Ebers

Sadovnick

Risch

. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995; 377: 150–151.

Münz

Lünemann

Getts

Miller

. Antiviral immune responses: triggers of or triggered by autoimmunity. Nat Rev Immunol 2009; 9: 246–258.

Sadovnick

Macleod

. The familial nature of multiple sclerosis: empiric recurrence risks for first, second-, and third-degree relatives of patients. Neurology 1981; 31: 1039–1041.

Ebers

Bulman

Sadovnick

. A population-based study of multiple sclerosis in twins. N Engl J Med 1986; 315: 1638–1642.

Ebers

. Environmental factors and multiple sclerosis. Lancet Neurol 2008; 7: 268–277.

Willer

Dyment

Risch

Sadovnick

Ebers

. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003; 100: 12877–12882.

Thorpe

Mumford

Compston

. British Isles survey of multiple sclerosis in twins: MRI. J Neurol Neurosurg Psychiatry 1994; 57: 491–496.

Lincoln

Ramagopalan

Chao

. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility. Proc Natl Acad Sci U S A 2009; 106: 7542–7547.

10.

Ramagopalan

Ebers

. Epistasis. Multiple sclerosis and the major histocompatibility complex. Neurology 2009; 72: 566–567.

11.

Fisniku

Brex

Altmann

. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131: 808–817.

12.

Miller

Barkhof

Montalban

Thompson

Filippi

. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005; 4: 281–288.

13.

Brassat

Azais-Vuillemin

Yaouanq

. Familial factors influence disability in MS multiplex families. French Multiple Sclerosis Genetics Group. Neurology 1999; 52: 1632–1636.

14.

Chataway

Mander

Robertson

. Multiple sclerosis in sibling pairs: an analysis of 250 families. J Neurol Neurosurg Psychiatry 2001; 71: 757–761.

15.

Hensiek

Seaman

Barcellos

. Familial effects on the clinical course of multiple sclerosis. Neurology 2007; 68: 376–383.

16.

McDonald

Compston

Edan

. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50: 121–127.

17.

Lublin

Reingold

. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46: 907–911.

18.

Kurtzke

. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–1452.

19.

Sadovnick

Yee

Guimond

Reis

Dyment

Ebers

. Age of onset in concordant twins and other relative pairs with multiple sclerosis. Am J Epidemiol 2009; 170: 289–296.

20.

Ebers

Koopman

Hader

. The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis. Brain 2000; 123: 641–649.

21.

Nielsen

Westergaard

Rostgaard

. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol 2005; 162: 774–778.

22.

Weinshenker

Bulman

Carriere

Baskerville

Ebers

. A comparison of sporadic and familial multiple sclerosis. Neurology 1990; 40: 1354–1358.

23.

Fernandez-Perez

Barakat

Garcia-Moreno

. Clinical features of familial multiple sclerosis in Spain. Rev Neurol 1999; 29: 693–696.

24.

Confavreux

Vukusic

. Age at disability milestones in multiple sclerosis. Brain 2006; 129: 595–605.

25.

Kremenchutzky

Rice

Baskerville

Wingerchuk

Ebers

. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 2006; 129: 584–594.

26.

Scalfari

Neuhaus

Degenhardt

Rice

Muraro

Daumer

. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 2010; 133: 1914–1929.

27.

Rovaris

Confavreux

Furlan

Kappos

Comi

Filippi

. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol 2006; 5: 343–354.

28.

Koch

Kingwell

Rieckmann

Tremlett

. UBC MS Clinic Neurologists. The natural history of secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2010; 81: 1039–1043.

29.

Koch

Uyttenboogaart

Heerings

Heersema

Mostert

De Keyser

. Progression in familial and nonfamilial MS. Mult Scler 2008; 14: 300–306.

30.

Koch

Zhao

Yee

. UBC MS Clinic Neurologists. Disease onset in familial and sporadic primary progressive multiple sclerosis. Mult Scler 2010; 16: 694–700.

31.

Sadovnick

Yee

Ebers

Risch

. Effect of age at onset and parental disease status on sibling risks for MS. Neurology 1998; 50: 719–723.

32.

Oturai

Ryder

Fredrikson

. Concordance for disease course and age of onset in Scandinavian multiple sclerosis coaffected sib pairs. Mult Scler 2004; 10: 5–8.

33.

Bulman

Sadovnick

Ebers

. Age of onset in siblings concordant for multiple sclerosis. Brain 1991; 114: 937–950.

34.

Hupperts

Broadley

Mander

Clayton

Compston

Robertson

. Patterns of disease in concordant parent–child pairs with multiple sclerosis. Neurology 2001; 57: 290–295.

35.

Polman

Kappos

Freedman

. BENEFIT investigators. Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b. J Neurol 2008; 255: 480–487.