A 12-year Follow-up in Sporadic Inclusion Body Myositis

An End Stage With Major Disabilities

Fieke M. Cox; Maarten J. Titulaer; Jacob K. Sont; Axel R. Wintzen; Jan J. G. M. Verschuuren; Umesh A. Badrising

Disclosures

Brain. 2011;134(11):3167-3175. 

In This Article

Discussion

This study illustrates that sporadic IBM is an extremely disabling disorder with normal life expectancy. Over a 10-year period, our patients lost almost one-third of their muscle strength. All patients used a wheelchair and almost half of them were completely dependent on it. The decline in functional grading scale scores further reflects the progressive nature of this disease. Undoubtedly, this muscle weakness resulting in functional disabilities must have a profound impact on the quality of life, as previously shown in a study of 60 patients with sporadic IBM (Sadjadi and Rose, 2010).

The mean time until the need for cane use was ~11 years. Peng et al. (2000) showed that a higher age at onset is associated with earlier use of a cane. They found the time to use of a walker in patients with comparable age at onset (50–59 years) to be 8 years. This is somewhat shorter than described in our patient group. Perhaps, subjects investigated in their study comprised more patients with onset with quadriceps muscle weakness, hence progressing earlier to the use of a walking device. Another study (Sekul and Dalakas, 1993) describes cane use in 10 out of 15 patients after 5 years.

The rate of loss of strength in the present study is lower than that found in the two other prospective studies investigating disease progression: a decline on quantitative muscle testing of 4% per 6 months and 14.9% per year, respectively (Rose et al., 2001; Dalakas et al., 2009). We calculated the decline in strength assuming it was linear, using the two available time points. It is possible that progression occurs more quickly at the start of the disease. However, the calculated rate per year in this study was within the expected range of progression of that of patients who received placebo in the methotrexate trial after 50 weeks from baseline (Badrising et al., 2002): 3.8 ± 5.1% in 50 weeks on manual muscle testing and 2.7 ± 10.0% on quantitative muscle testing, respectively. Furthermore, most patients reported that their rate of progression did not fluctuate and our clinical experience is also of a steady course.

We found a substantial difference in weakness progression between manual and quantitative muscle testing sum scores. The mean decline in the quantitative muscle testing sum score was 1.5 times greater than the manual testing sum score. The different weight and composition scores between quantitative and manual muscle tests is the most likely explanation.

We did not find any factors to be associated with the rate of weakness progression. The previous suggestion that HLA-DR3-positive patients possibly showed a faster decline than HLA-DR3-negative patients, especially in the quadriceps (Needham et al., 2008), could not be substantiated, possibly due to a lack of statistical power. For sufficient power, we would have needed at least 26 patients, but we only had 11 HLA-DR3-positive versus three HLA-DR3-negative patients. However, we did not see a trend towards faster decline in HLA-DR3-positive patients. Of the two patients showing the lowest rate of decline on manual muscle testing compared with the other patients, one was HLA-DR3-positive, the other negative.

The pattern of muscle weakness that developed during the disease was remarkably similar among patients. The lower legs demonstrated the greatest decline in strength, followed by the forearm and upper leg. There was a striking preference for involvement of the forearm flexors, quadriceps muscles and all the lower leg muscles.

The choice of which muscle test to use for future trials is not easy. Both manual and quantitative muscle tests show comparable rates of decline between subjects. Manual muscle testing scores have smaller standard deviations compared with quantitative muscle tests and manual muscle testing is easy to apply. On the other hand, quantitative muscle testing has a better inter-observer rate (Personius et al., 1994), which is important as most trials will have a multicenter character due to the rarity of sporadic IBM. Quantitative muscle testing has a better correlation compared with manual muscle testing during follow-up. Besides, quantitative muscle testing will reveal small residual pareses more precisely than manual muscle testing. Furthermore, quantitative muscle testing is a continuous variable compared with the categorical manual muscle testing score, and therefore better to use as a sum score. We would have a slight preference for using quantitative muscle testing.

We recommend using the Brooke's functional grading scale as the best measurement for functional status. This grading scale shows the most equally distributed scores at baseline between subjects and it shows the most comparable decline between subjects over time.

Although life expectancy is not shortened in sporadic IBM, the causes of death differ from an age-matched Dutch general population. Death caused by disorders of the respiratory system, especially (aspiration) pneumonia, was significantly more frequent in our patient group. Two other studies have also identified aspiration pneumonia to be a common cause of death in sporadic IBM (Peng et al., 2000; Oh et al., 2008). The high rate of respiratory disorders may be due both to aspiration caused by pharyngeal muscle weakness (Oh et al., 2008) and weakness of respiratory muscles (Cohen et al., 1993; Voermans et al., 2004; Teixeira et al., 2005).

Furthermore, a significant proportion of patients died of cachexia, illustrating the impact of dysphagia and muscle wasting at the end stage of the disease. An interesting finding was that compared with the general population, cancer was less frequently a cause of death in patients with sporadic IBM. The difference may be explained by a failure to detect cancer due to the severity of sporadic IBM symptoms.

An unexpectedly high incidence of euthanasia and continuous deep sedation was found in our patient group. In 2002, an act came into effect in the Netherlands, regulating the ending of life at the request of a patient, by a physician, if unbearable suffering has been established. All six patients met the stringent criteria used to guarantee proper application of this legislation. In 2005, 0.8% of all deaths in patients over 80 years of age in the Netherlands were the result of euthanasia, and in 5.4% continuous deep sedation was used (van der Heide et al., 2007). A study investigating the incidence of euthanasia and continuous deep sedation in patients with amyotrophic lateral sclerosis, clearly a devastating disease, showed that in 17% of Dutch patients with amyotrophic lateral sclerosis euthanasia was applied and continuous deep sedation was used in 3% (Veldink et al., 2002). The high frequency of euthanasia and continuous deep sedation (13% in total) in sporadic IBM, about one-third of the rate found in amyotrophic lateral sclerosis, highlights the heavy disease burden in the final stage.

A limitation of this study is the fact that a large number of the patients had died prior to follow-up examination. It is possible that the disease course was more severe in these patients, leading to an underestimation of the mean rate of progression for the whole group. Not unexpectedly, the patients who died were significantly older and more severely affected based on the results of the functional grading scales and muscle testing. The deceased patients had a normal survival period, therefore the rate of weakness progression was not likely to be much higher.

At baseline, the surviving patients were younger, had a lower age at onset and also showed a trend for a shorter disease duration at the time of diagnosis. This is a logical consequence of the study methods, as younger patients who already had a definite diagnosis of sporadic IBM were of course more likely to be still alive at the second time point.

Three surviving patients had used prednisone 5 mg once daily for several years due to a concomitant autoimmune disease. The calculated decline in strength per year on manual muscle testing, for example, was diverse between these three patients, ranging from 0.5% to 4.8%, and fell within the range of the individuals who did not use prednisone. Therefore, we do not think this therapy had a substantial effect on the natural history in these patients.

This study shows that sporadic IBM is a severe disease, in which ongoing progression of muscle weakness leads to significant disabilities and a sustained disease burden. Patients have a normal life expectancy, but death as a result of sporadic IBM is often due to respiratory disorders. Whether these respiratory disorders are worsened by ventilatory muscle weakness and if non-invasive ventilation can improve quality of life, as shown in some patients with amyotrophic lateral sclerosis (Radunovic et al., 2009), is not yet known for sporadic IBM.

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