An up-date on health-related quality of life in myasthenia gravis -results from population based cohorts

The design was cross sectional including two large population based MG cohorts from
the entire Norway and a contigous province of South-Holland and North-Holland in The
Netherlands (Fig. 1). In order to increase the sample size of MuSK MG in the serological subgroup analysis,
we included a national population based sample (n?=?34) from a prevalence study in
the Netherlands 18].

Fig. 1. Overview over study procedure. The study was conducted among all MG patients in Norway
and the contiguous regions of South- and North Holland in the Netherlands, including
an additional MuSK Sample from entire Netherlands. The case identification and inclusion
criteria were the same in both countries. The case search in the Norwegian study area
was performed nationwide including 4 university clinics, 15 local clinics and 11 private
clinics. Recruitment started: 01.01.2008. Recruitment stopped: 01.11.2009. The case
search in the Dutch study was conducted in two regions and the affiliation to the
geographical area was defined by postal code. The area had 4 university clinics, 25
local clinics and one private clinic. Recruitment started: 01.10.2011. Recruitment
stopped: 01.01.2012. 43 patients were not eligible for questionnaire study because
of change of address, dementia and other co-morbidities and delay in registration
of ICD-code. Abbreviations: ICD?=?international classification diagnosis. F: M?=?female: male ratio

Study procedure

The details of the study are reported in a previous study 19], 20]. The patients were mailed a self-administered validated questionnaire including the
Short Form-36 (SF-36) and questions about disease severity and current treatment for
the last three months 21]. Reminders were sent to non-responders twice and missing data was completed by phone
or mail.

Clinical characteristics, disease onset and course, presence of antibodies and thymus
histology were collected from medical records.

Definitions

Disease course was grouped into remission; either complete stable or pharmocological,
ocular, bulbar or generalized symptoms at the time of testing. We subgrouped the ocular
symptoms in those who started ocular and remained ocular throughout disease course
(Ocular MG) and those who had residual ocular symptoms after generalized disease in
the MG subgroup analysis. Non-steroid immunosuppresive medicines included azathioprine,
cyclosporine, mycophenolate mofetil, tacrolimus, rituximab and cyclophosphamide.

Instruments

The Norwegian and Dutch translations of SF-36 (version 1) was used to assess HRQOL
[22, 23] in the past four weeks. This instrument is constructed for population surveys,
is short and easy and has good psychometric qualities.

The SF-36 consist of 36 questions, organized into eight domains. The eight domains
are physical functioning (PF), Role physical (problems with work or daily acitivites
as a results of physical health, RP), Bodily pain (BP), general health evaluation
(GH), Vitality (VT), Social functioning (SF), Role emotional (RE; severe problems
with work or daily acitivites as a result of emotional health) and mental health (MH).
All items are coded, scaled and transformed linearly from 0 (worst health) to 100
(best health). The first four can be summarized into a physical composite score (PCS;
PF, RP, BP, GH) and the last four into a mental summary score (MCS; VT, SF, RE, MH).

Control groups

We compared the two cohorts with published normative data, including reference data
for chronic diseases (15 different conditions) and two population-based studies of
Multiple sclerosis and Parkinsons disease 22], 24]–26].

Regulatory and ethical issues

We obtained informed constent from all participants and approval of the regional ethical
committee of South-Norway, the ethical review committee of the Leiden University Medical
Center (LUMC), The Netherlands, and the Medical Review Ethics Committee (METC) of
South-West Holland.

Statistical analysis

The statistical analysis was done using SPSS 22.0 (statistical package for social
sciences, IBM, Armonk, NY, USA) and STATA 14 (StatCorp, Texas, USA). Scoring and calculation
of the SF-36 scores were done according to the improved methods of Ware, McHorney
and Sherbourne for version 1 27], 28]. Method for impute missing data was followed for 0.7 % of the data. The MG patients
were analyzed by domains and composite scores. Since the composite scores are considered
as the most robust outcome measurement for the SF-36, we have focused on them in our
comparisons. Differences in continuous variables were tested by independent sample
t-tests and chi-square tests for contingency tables for categorical variables. When
at least 25 % of expected cell frequencies were less than 5, Fischer’s exact test
was applied. P??0.05 was considered significant. Adjustment for the confounding effect of age,
gender, disease severity and differences between both countries’ samples was done
using linear regression analysis and stratum-specific estimates. We used the population-based
cohort for all analysis (n?=?837) either stratified by gender or country or pooled
all together. For the immunological subgroup analysis, we included the responders
of a national sample of MuSK MG patients (n?=?21), leaving in total 856 MG patients
for the analysis since the information about antibodies of eight patients was missing.

To examine the relationship between PCS/MCS and the significant covariates we used
multiple regression analysis (p??0.05) Afterwards, the model was employed on the
MG subgroups with regard to antibodies to identify if the predictors played the same
role in the subgroups.

Results

858 MG patients (72 %) of the 1189 MG patients responded with a slightly higher response
rate in Norway (76.2 %) than in the Netherlands (68.7 %). There was no difference
considering age, sex, age onset, antibody profile and clinical remission rate between
responders and non-responders of the questionnaire. The Dutch national sample of MuSK
MG comprised more females (p?=?0.011), but was otherwise similar to the Dutch regional
MuSK MG cohort. No significant differences were found in the composite scores of HRQOL,
and only minor differences in the subdomains (Table 2).

Table 2. Clinical characteristics of the population-based study cohort

Comparison to healthy controls (Fig. 2)

Fig. 2. HRQOL in Myasthenia Gravis compared with healthy controls. The figure illustrates
the population based MG cohorts in Netherlands (a) and the Norway (b) compared with healthy controls from their own countries. Healthy control data is
provided by Loge et al.; Norway 24] and Aaronesen et al. 22]. In summary, MG patients scored lower than healthy controls and females scored lower
than males and those in remission similar to healthy controls. The Score range from
0-100. Higher score indicate better Health related quality of life (HRQOL).

Solid line

is score of reference population for men, and

dotted line

is score of reference population for women in their respective countries. Horizontal
axes show the 8 domains of SF-36 and composite scores

The total cohort of MG patients had lower scores than healthy controls (p-value 0.005,
adjusted for age and gender), except for the domains of bodily pain (BP) and problems
with daily activities due to mental health problems (RE). Female MG patients systematically
scored lower than male MG patients, with significant p-values 0.001 on all domains
and composite scores (Additional file 1: Table e-1).

Patients in remission (MGFA class 0) (n?=?196, 23.4 % of the cohort) and those with
ocular symptoms (MGFA class 1) (n?=?102, 12.2 %) scored similar or better than their
national normative controls on composite scores. For both groups, the HRQOL of the
domains were similar to controls, except for the domain of general health (GH), were
the score was significantly worse in male MG patients in both the Netherlands as in
Norway.

MCS in particular showed age-dependent divergent results (Additional file 1: Table e-1). In the Netherlands, the MCS was lower for those below 60 years of age;
50 % of the females and 31 % of the males compared to controls. In contrast, the elderly
MG patients from 70 years of age had reduced MCS in Norway compared to controls, representing
16.3 % of the females and 46 % of the males.

HRQOL in MG subgroups (Table 3, Fig. 3)

Table 3. HRQOL results in MG subgroups

Fig. 3. HRQOL by phenotype and antibodies. a MG patients in remission and absence of generalized symptoms scored significantly
better than the other groups on both composite scores (p??0.001). b Antibody profile did not affect HRQOL outcomes