Clinical features and treatment of Still’s disease in adulthood

In this study, we investigated the clinical characteristics of elderly patients with MSA from a multicenter cohort. The results showed that elderly patients had different characteristics compared to younger patients, including less frequent sore throat, more frequent pleurisy, higher frequency of serious complications, such as DIC and MAS, higher levels inflammatory markers, lower hemoglobin levels and rates of CMV infections. Treatment and outcomes were not significantly different in the two groups; however, in recent years the use of immunosuppressants and TCZ instead of GCs has tended to increase, and infections and relapses have tended to decrease.

To date, some national epidemiological surveys assessing the prevalence of MSA have been conducted in Japan using questionnaires. Before 2000, the proportion of elderly patients was very low; the first survey in 1988 showed that no patient aged ≥ 66 years developed MSA9. The second survey in 1994 showed that only six patients (4.9%) were aged ≥ 65 at diagnosisten. The mean age at disease onset in previous surveys in 1988 and 1994 was 32.3 and 38.1 years, respectively. A recent survey in 2010-2011 showed a high mean age of onset (46 years), although the proportion of patients with older-onset MSA is unknown11. An epidemiological study using the Japanese administrative database from 2010 to 2012 demonstrated that the mean age at onset was 53.1 years, and 32.1% of patients were over 66 years old.12. In this study, the mean age at onset was the highest (57.1 years) and the proportion of patients with elderly onset was the highest compared to previous Japanese studies. Therefore, MSA is no longer a rare condition in the elderly.

Few studies have focused on the characteristics of elderly patients with MSA. Maruyama et al.13 recently examined age of disease onset in Japanese MSA patients and reported several similarities between elderly MSA patients and our cohort, including frequency of sore throat, frequency of pleurisy and DIC, and hemoglobin levels. However, there were some differences between these two studies. In our cohort, there was a high proportion of elderly patients (42% were > 65 years old in our study versus 33% were > 60 years old in a previous study) and SAM complications. Moreover, the prognosis of elderly patients in our study was similar to that of younger patients, whereas poor prognoses of elderly patients had been shown in a previous study. Although the exact reasons for these differences are unclear, in our study patients with older-onset MSA were treated more aggressively, with a higher proportion of patients treated with methotrexate or TCZ than in the studies. previous ones. Therefore, adequate treatment, even in elderly patients, can improve the prognosis.

In our study, elderly patients had higher levels of inflammatory markers and more frequent complications of pleurisy, CID and SAM than younger patients. This is not due to diagnostic delay as the interval from onset to treatment was not different in the two groups. Macrophages play an important role in the immune response to inflammation and contribute to the onset and severity of ASD3. Regarding the relationship between aging and macrophages, the nature of macrophages in adipose tissue shifts towards a pro-inflammatory type (M1) with aging.23. Additionally, phagocytosis of apoptotic neutrophils by macrophages is low in aging mice, making it difficult to resolve inflammation.24.25. In addition to these immunosenescences associated with dysregulation of innate immunity, cellular senescence, pro-coagulation factors, cellular debris and intestinal dysbiosis are causes of “inflammaging”, which is defined as a chronic inflammation of low grade occurring without infection.26.27. When a certain stimulation is applied to it, the inflammation may persist even after the initial stimulation has been removed. Coronavirus disease 2019 is known to cause a cytokine storm in some elderly patients, although it is less common in younger patients28. Although it is unclear why SAM occurs more frequently in patients with older-onset MSA, these inflammations may lead to more prolonged inflammation after disease onset.

CMV infections are common in elderly patients. Jia et al. reported that anti-CMV antibodies are elevated and CMV DNA copy number is increased in patients with MSA, suggesting that CMV may be associated with the development and exacerbation of MSA29. In contrast, MAS can be triggered by various infections30and there are case reports of SAM patients triggered by CMV infections31.32. In our study, SAM was common in elderly patients, and all cases of SAM occurred in the active state of MSA; however, one patient had a complication of CMV infection during SAM development. Since CMV infections can be a risk factor for worsening ASD and can lead to complications of SAM, frequent monitoring and prompt treatment are important to stabilize the patient’s condition.

As shown in Figure 2, the predominant treatment for patients with older-onset ASM about 10 years ago was GCs, and more than half of them experienced some form of infection. Studies of treatment of elderly patients with rheumatoid arthritis (RA) have shown that, compared to younger patients, initial treatment is less aggressive and they are less likely to receive anti-tumor necrosis factor therapy -α due to the risks of adverse effects and the hypothesis of comorbidities33.34. However, in elderly patients, a delay in adequate treatment can easily lead to a decrease in activities of daily living. Meanwhile, current exposure to GCs, especially at higher doses, carries the highest risk of serious infection in RA patients.35. Additionally, patients with older-onset ASM in our study had a higher frequency of comorbidities and most of them deteriorate easily with GCs. These results suggest that elderly patients require adequate treatment with drugs other than GCs. With the elucidation of the pathogenesis, including the cytokine profile of patients with MSA, several established targeting therapies have been developed. Methotrexate and anti-cytokine therapy, such as IL-1 or IL-6 inhibitors, have shown not only potent anti-inflammatory effects, but also GC-sparing effects18. In our study, we also found that the treatment of elderly patients with MSA changed over time. The frequency of use of TCZ and immunosuppressants has increased even in elderly patients, and there is a dropout from GC-dependent treatment in this group. Regarding TCZ, a biological agent available in Japan, a meta-analysis of AOSD showed excellent efficacy, especially in refractory patients, and TCZ may reduce the need for GC36. Additionally, a randomized, double-blind trial of TCZ for refractory MSA found significant improvement in systemic symptoms37. IL-1 inhibitors are also effective for patients with MSA. Anakinra showed excellent effect for patients with mainly systemic symptoms and revealed GC-sparing effect38. The efficacy and safety of canakinumab are also reported in a systematic review39. As IL-1 inhibitors are not available in Japan due to off-label use for MSA, none of our patients used these agents. However, it is expected that we will be able to use several anti-cytokine therapies, including IL-1 inhibitors, in the near future. The development of methods to reduce infections should be pursued through the appropriate use of drugs other than GCs, especially for elderly patients with ASD.

This study has certain limitations. First, this study has a retrospective design with a small number of patients. Second, we did not examine information from clinical models, such as monocyclic, polycyclic, and chronic joint, in this study. A national survey including this information is needed in the future. Third, infection and relapse rates may be affected by differences in length of follow-up; however, since most infectious episodes were prolonged hospitalizations, the influence is likely to be limited. Fourth, the large proportion of patients with MSA in the elderly may be due to the fact that the study was conducted in Japan, the country with one of the highest rates of aging in the world. The world population is also aging; therefore, these situations could occur in all countries in the future.

In conclusion, the proportion of elderly patients with MSA is gradually increasing. The disease activity of patients with older-onset MSA was similar to that of patients with younger-onset MSA, and the frequency of complications, such as DIC and MAS, was high. CMV infections were common in patients with older-onset MSA, but had declined in recent years with the discontinuation of GC-dependent therapy. In elderly patients with MSA, appropriate use of immunosuppressive agents, including cytokine inhibitors, may be necessary for rapid control of disease activity and early reduction of GC dose.

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