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

Myasthenia gravis (MG) is a heterogeneous neuromuscular autoimmune disease. Clinically, the symptoms range from mild ocular symptoms to severe generalized muscle weakness and disability. In the most severe cases the respiratory muscles are affected, causing problems breathing, a so-called “myasthenic crisis”. Nowadays, with optimal treatment, mortality is rare and most patients live normal lives. Nevertheless, health related quality of life (HRQOL) remains reduced compared to healthy controls in several studies (Table 1) [1‐10].

These studies show that the disease has an extensive impact on physical, psychological and social wellbeing: the more severe muscle symptoms and disability, the lower the physical components of the outcome [1, 2, 7‐10]. There are contradictory results as to what extend the mental wellbeing is affected in MG. Reported predictors for reduced HRQOL are among others use of prednisolone and side-effects, disease severity, depression, anxiety and disease duration, however, many others are also mentioned (Table 1). There are few larger studies and the impact of clinical subgroups based on antibodies, age of onset, thymus histology and clinical presentation remains unanswered [11‐13].

Chronic immunomodulation with corticosteroid, other immunosuppressive drugs and thymectomy are often necessary to control the disease. Immunosuppressive medication produce marked improvement, however in many cases does the improvement not persist if treatment is discontinued. Consequently, treatment in MG is often a lifelong proces [14]. The choice of treatment depends on the severity of the symptoms, the specific subgroups and the pace of progression [14]. It is reported that MuSK MG and Thymoma MG are more likely to require secondary immunosuppressives than AChR MG and that elderly are more prone to side-effects [14‐17]. As more advanced immunotherapy becomes available for MG patients, it is relevant to use HRQOL as an outcome for choice of treatment strategies. Long-term follow-up studies of representative MG cohorts assessing change of HRQOL during the last decades are lacking.

Up-to-date, there is no study reflecting the HRQOL of population-based MG cohorts covering the whole spectre of disease activity and immunological markers. Based on previous studies we hypothesized that serological subgroups, thymoma, disease course and treatment strategy are factors affecting HRQOL in MG patients. Our aim was to examine these factors and HRQOL in a MG cohort as large as possible, by combining population-based MG cohorts from two countries. We also compared the HRQOL outcomes of the MG patients to healthy controls, previous studies and other chronic diseases in order to get an impression of the burden of the disease.

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].

In this population-based double cohort study, we report a reduced self-perceived HRQOL in Myasthenia Gravis patients with bulbar and generalized symptoms, while patients in remission, those with OMG and those with residual symptoms after generalized disease scored similar to healthy controls. Generalized disease course, gender, and treatment with secondary immunosuppressives were risk factors for decreased HRQOL. Having a distinct subgroup with an antibody marker, thymoma or early or late onset subtype did not influence the HRQOL outcome.

The reduced quality of life was determined by lowered physical capacities, but psychological wellbeing was affected in roughly half of the patients as well. There was no differences in HRQOL between MG patients in Norway and the Netherlands. Pooling the data could therefore be done without affecting the validity of the results and confirms the reliability of the results. Put into an historical context, the HRQOL has not changed much for MG patients over the last 10-15 years and we found the same levels as reported in 2001 [2, 5‐10] (Fig. 5). The reduced results of Padua et al. [1] may be explained by a low percentage in clinical remission and many patients with generalized symptoms compared to our cohort. The result of “the more generalized disease or active” disease, the poorer HRQOL” is in accordance with other reports [1, 3, 7, 8, 29]. Leonardi et al. [4] reported that patients in remission scored similar to Italian general population, supporting our findings from the Dutch and Norwegian MG patients. We did not find any harmful impact of antibodies or thymectomy in accordance with other studies [1, 8, 30]. Our findings of normal levels of HRQOL in ocular MG is supported by another study of 91 ocular Italian MG patients [11]. In contrast, a Japanese study reported QOL impairment of 123 ocular MG patients in those who not responded to therapy [13]. One explanation of these contradictory results may be patients selection, since ocular MG includes several symptoms (ptosis, diplopia, complete ophthalmoplegia), with potentially different grades of disability. Additionnally, the use of another questionnaire and cultural factors may account for the difference.

In addition to generalized weakness, dyspnoe and dysphagia, female gender, usage of secondary immunosuppressives were minor risk factors to reduced HRQOL, similarly to results form previous studies [9, 30, 31]. Some of the gender variability could be explained by a general gender effect as the pattern is similar as seen in the normal population [22, 24]. However, we know that hormonal factors affect the symptoms [32, 33] and could thus also contribute. The second finding may suggest that long term immunosuppressive therapy may not be as harmless as assumed. This is supported by a HRQOL study from Japan, which documented an impact of steroids and calcineurin inhibitors in two studies [30, 31]. The negative effects may be related to side-effects or to the burden of constant need of medication. As reviewed by Sanders [14], the initial goal of therapy should be reducing weakness as much and as quickly as possible. Balancing side effects of immunotherapeutic agents and treatment effect remains a challenge for the clinician. The correlation between secondary immunosupressive agents and reduction of HRQOL in MG patients indicates that it is important to keep in mind the benefits of usage contra the side effects, and aim at reducing dosage to lowest possible maintenance dose. This may in particular be important for ocular MG in which no RCT has yet documented effect of any secondary immunosuppressive treatment, neither on symptoms remission nor on prevention of generalized disease [34, 35].

Early MG scored similar to early MS, however when looking at longer follow- up reports HRQOL turns worse in MS [36]. The explanation is probably because MS and Parkinsons’ disease have often a more progressive course with no or less treatment that stops progression. Rheumatoid arthritis, on the other hand, is associated with more pain and disability than MG which can explain the marked lower scores. Improvement of HRQOL scores are reported in RA within the same patients, but also improvement over the last decades [37, 38]. According to Grob et al.’s lifetime study of MG, the distribution, severity and course of disease is determined within the first two years [39] and many MG patients experience the worst phase of the disease in these years. One should therefore expect improvement in HRQOL with longer disease duration. Our study design was cross-sectional and limits therefore interpretation of HRQOL over time in the same patient. Hence, follow-up studies both of individuals over time are needed to learn more about HRQOL in MG. With better treatment strategies and therapautic options we do also expect improvement over the last decade, however the comparison with earlier studies did not confirm this. Limitations in these inter-study comparisons are that the patients are not matched in the study and many variables are not controlled, therefore the results are purely indicative.

The main strength of the study is the design, which is a true population-based, cross sectional survey of two well defined groups. Finding the same levels of HRQOL in both countries makes the results more reliable. All clinical subtypes of MG were present in sufficient numbers to give useful results. Disease specific questionnaires have been advocated for MG, and indeed may enable a more specific follow-up for the patients [40]. Our intention was, however, to use a broadly validated questionnaire to provide insights in how HRQOL in MG stands across borders and time, compare the scores to general population controls and other chronic disorders. Correlations between the SF-36 and MG disease status has been proven in several studies, and may thus be trusted to give a fair picture of the burden of MG disease. A more disease specific instrument would be able to detect smaller changes in vision, speaking, chewing and swallowing better [1, 4‐6], which was not the purpose in this study. Since the SF-36 has norm-based scoring, group level results of this study can be used to compare MG patients across countries and further improve the quality of health care systems in places where it is not optimal.

Taken together, this population based study of 857 MG patients found the same HRQOL levels as in 2001 [2], indicating no improvement in quality of life for MG patients despite more available immunotherapy choices and better diagnostics of MG subgroups. Although we included a large sample and patients with different clinical characteristics, we could not find any new clinical predictors for reduced HRQOL compared to the other studies. Therefore we suggest that the impact of non-clinical factors like job, socio-economic factors, physical activity and hormonal factors on HRQOL in MG patients should be explored in order to improve the quality of life in MG patients.