Background and Aims

The increasing use of immune checkpoint inhibitors (ICIs) for curing cancer results in a wide range of novel immune related adverse events (irAEs). Among them, myositis is a rare but potentially life-threatening event.

This study aimed at investigating the risk of ICI-related myositis in real-life settingby performing a disproportionality analysis in a global pharmacovigilance database.

Methods

We conducted a case/non-case analysis using VigiBase, the WHO’s adverse drug reactions (ADRs) database, to assess myositis reporting associated with anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, durvalumab), anti-CTLA-4 (ipilimumab, tremelimumab). Cases were defined using selected MedDRA Low Level Terms corresponding to myositis and non-cases were all other ADR. Disproportionality analysis were performed using logistic regression models to calculate Reporting Odds Ratios (ROR).

Results

A total of 14,786,263ADR were reported from January 2008 to February 2019. We identified 54,085 ICI-related ADR among which 345 myositis. ICI-related myositis was considered serious in 95% of cases, with fatal outcome in more than 20%. Association with myocarditis and myasthenia gravis was reported in 11,3% and 11,9% of cases respectively. Myositis was more than seventeen times more reported with ICI agents than with all other drugs (ROR=17.3; 95%CI:15.5–19.2). ICI-related myositis reporting was increased with anti-PD-(L)1 compared to anti-CTLA-4 agents (ROR=2.4; 95%CI:1.6–3.5), and in the group receiving combination-therapy compared to monotherapy (ROR 1.8; 95%CI: 1.3–2.4).

Conclusions

Such a strong pharmacovigilance signal suggests an increased risk of myositis under ICIs, even more increased under anti-PD(L)1 agents. Subsequent studies are required to better characterize clinical features of ICI-related myositis.

Background and Aims

Systemic sclerosis (SSc) is a life-threatening autoimmune disease with unmet medical need, where mesenchymal stromal/stem cells (MSCs) may represent a promising therapeutic approach. MSCs act primarily through the secretion of soluble factors released within extracellular vesicles (EVs). Here, we investigated the effect of adipose-derived mesenchymal stromal cells (ASCs)-EV in the murine model of hypochlorite (HOCl)-induced SSc and the role of miR-29a, a known anti-fibrotic factor.

Methods

HOCl-SSc was induced by 6-weeks daily intradermal HOCl injections. EV were isolated from ASCs. Groups of 8 mice were treated at day 21 with one intravenous injection of PBS, 2.5x10⁵ASCs, 4x10⁷EV isolated from naive ASCs or ASCs transfected by miR-29a inhibitor or control inhibitor. Skin thickness was measured weekly and skin and lung samples were recovered at euthanasia.

Results

EV significantly reduced skin thickness and the expression levels of fibrotic and inflammatory markers in skin and lung tissues, while increasing the expression of extracellular matrix remodeling markers. Injection of ASCs transfected with miR-29a inhibitor in the murine model of SSc resulted in the loss of their therapeutic effect. Interestingly, the injection of EVs isolated from ASCs transfected with miR-29a inhibitor was not able to reduce the clinical symptoms of SSc.

Conclusions

Systemic injection of ASC-derived EVs exerted a similar therapeutic effect as whole ASCs in the murine model of SSc. This effect was, at least in part, mediated by miR-29a.

Background and Aims

Data concerning malnutrition in systemic sclerosis (SSc) are scarce and contradictory, with a poor description of nutritional risks. Herein, we investigated the nutritional status of a cohort of SSc patients.

Methods

Malnutrition was defined as a weight loss of ≥10% in 6 months, or BMI <21kg/m2. We used the« Malnutrition Universal Screening Tool » (MUST) score to stratify nutritional risk.

Results

We included 120 patients suffering from limited (57%), diffuse (21%) and sine sclerodermaSSc (4%). Autoantibodies were anti-centromere (37%), anti-Scl-70 (14%), or double negative (42%). 84% of patients had GI involvement with chronic-intestinal-pseudo-obstruction in about 10% of cases. 57% of patients were considered at risk for malnutrition (MUST ≥1) while malnutrition occurred in 58% of cases during follow-up. Limitation of mouth opening, muscle and myocardial involvements were associated with high nutritional risk (MUST ≥2). Therapeutic nutrition was required in 7,5% of patients.

Conclusions

Herein, malnutrition concerned more than half of the cohort, in contrast to previous studies (10-18%), with no difference in terms of GI involvement. Of interest, we noted an association between muscle, myocardial involvement and malnutrition, that may be related to vitamin or trace elements deficiencies. Although these observations have to be confirmed through prospective studies, early detection of nutritional risk in SSc patients seems of great importance. In that context, the MUST score may be a useful tool.