Multiple sclerosis (MS) is an inflammatory disease that is often dominated by relapsing-remitting symptoms.¹ However, inflammation is not only present in acute and relapsing MS, but also in the secondary and progressive disease.² Chronic-active or “smouldering” inflammatory lesions contribute to progressive disease.

In his presentation at the ECTRIMS 2021 meeting, Robert Fox, a neurologist from the Cleveland Clinic (Ohio, United States), discussed the impact of smouldering inflammation in MS from a clinical perspective, following on from previous presentations on pathological and MRI-related aspects of smouldering inflammation.

Patient case – smouldering MS

Dr Fox began by presenting the case of a 38-year-old female patient with MS, who had been treated with disease-modifying therapy (DMT) and appeared clinically stable (no new lesions or relapses, had not taken time off work, was still running regularly, and still able to drive). He noted that on paper his patient seemed to be doing well, but looking closely, the picture was less positive; she was no longer running as far, made more mistakes at work, and had had a car accident. Compared to her previous level of functioning, her condition had deteriorated. Dr Fox explained that in other patients, when told that their disease is stable (no new or active lesions, no relapses), they may struggle to understand this, saying that they feel like they have gotten worse. Conventional MRI, therefore, does not seem to provide a complete clinical picture. He noted that there can be a reluctance among clinicians, though, to use the word “progressive” to explain these changes, because patients often do not want to hear that their disease is advancing to the next stage. This does not mean, however, that smouldering disease is not present, and Dr Fox commented that it is important to remain attentive to it.

Impact of “invisible” symptoms

In addition to the typical symptoms, people with MS are affected by the development or worsening of symptoms related to social/emotional well-being, relationships, and employment. This is supported by data from a recently published large global survey, which assessed a broad range of emotional and social factors (including self-esteem, general outlook, well-being, maintaining/starting relationships, ability to progress in their career/keep their job, and ability to cope with life roles).³ To identify the difficulties that patients face, Dr Fox suggested asking the patient simple questions, e.g. about how things are going at home and at work, or if they have noticed any changes to their daily routines. In his own experience, patients often reply that they can still perform their daily tasks, but that they take longer or require more effort.

Smouldering MS may blur the transition preceding progressive MS

Although distinctive features are associated with acute versus progressive/smouldering disease (with the acute stage characterised by more transient effects), the difference between relapsing-remitting MS and progressive MS is not clear-cut. The transition between these stages is imperceptible, and they overlap considerably, with one study reporting an average period of uncertainty of 2.9 years.⁴ The most common form of progression is described by the PIRA concept – “progression independent of relapses” – typically defined by changes in the Expanded Disability Status Scale (EDSS). NEDA, on the other hand, means “no evidence of disease activity” (absence of new lesion/relapses and no new progression). Dr Fox noted that these concepts are useful, but they do not capture the more subtle aspects of progression. In reality, PIRA develops over an extended timescale that begins well before the sudden upward EDSS increases with which it is typically associated.

Conclusion

Dr Fox concluded that although patients may appear clinically stable, with no relapses or enlarging lesions, many areas of difficulty can be identified upon closer investigation. These symptoms may represent the smouldering inflammation that contributes to progressive disease.

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References

1. Schumacher A-M, et al. Neur Int Open. 2017;1:E171-83
2. Frischer JM, et al. Brain. 2009;132:1175-89
3. Bass AD, et al. Int J MS Care. 2020;22:158-64
4. Sand IK, et al. Multi Scler. 2014;20:1654-7