In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the ...spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.
We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC025 (lower end of the IC 95% credibility interval) >0 is deemed significant.
We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 11.6–18.4, IC025 = 3.34), sarcoidosis (n = 94; ROR = 9.6 7.9–11.9; IC025 = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 5.2–9.2; IC025 = 2.24), myositis (n = 465; ROR = 4.9 4.5–5.4; IC025 = 2.12), arthritis (n = 606; ROR = 1.4 1.3–1.5; IC025 = 0.34) and scleroderma (n = 17; ROR = 2.0 1.2–3.2; IC025 = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6–2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1–4.4, p < .05). Median time to onset occurred early for myositis (31 days 19.2–57.8) and was the most delayed for scleroderma (395 days 323.8–457.2, p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to 0–6.7% for other RMS-irAE (p < .0001).
Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
•We identified over 1000 individual case safety reports related to RMS-irAE induced by ICI.•RMS-irAE encompassed arthritis, myositis, sarcoidosis, polymyalgia rheumatica, Sjogren's syndrome, and scleroderma.•Myositis occurred early within weeks after initiation of ICI therapy and carried a high fatality rate, particularly when concurrent myocarditis was reported; whereas other RMS-irAE had a low mortality burden.
Biomarkers as parameters of pathophysiological conditions can be of outmost relevance for inflammatory myopathies. They are particularly warranted to inform about diagnostic, prognostic, and ...therapeutic questions. As biomarkers become more and more relevant in daily routine, this review focusses on relevant aspects particularly addressing myopathological features. However, the level of evidence to use them in daily routine at presence is low, still since none of them has been validated in large cohorts of patients and rarely in independent biopsy series. Hence, they should be read as mere expert opinions. The evaluation of biomarkers as well as key biological parameters is an ongoing process, and we start learning about relevance of them, as we must recognize that pathophysiology of myositis is biologically incompletely understood. As such this approach should be considered an essay toward expansion of the definition "biomarker" to myositis, an emerging field of interest in biomedical research.
Neutralizing antibodies directed against adeno-associated virus (AAV) are commonly found in humans. In seropositive subjects, vector administration is not feasible as antibodies neutralize AAV ...vectors even at low titers. Consequently, a relatively large proportion of humans is excluded from enrollment in clinical trials and, similarly, vector redosing is not feasible because of development of high-titer antibodies following AAV vector administration. Plasmapheresis has been proposed as strategy to remove anti-AAV antibodies from the bloodstream. Although safe and relatively effective, the technology has some limitations mainly related to the nonspecific removal of all circulating IgG. Here we developed an AAV-specific plasmapheresis column which was shown to efficiently and selectively deplete anti-AAV antibodies without depleting the total immunoglobulin pool from plasma. We showed the nearly complete removal of anti-AAV antibodies from high titer purified human IgG pools and plasma samples, decreasing titers to levels that allow AAV vector administration in mice. These results provide proof-of-concept of a method for the AAV-specific depletion of neutralizing antibodies in the setting of in vivo gene transfer.
Although idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases nearly all patients display muscle inflammation. Originally, muscle biopsy was considered as the gold standard ...for IIM diagnosis. The development of muscle imaging led to revisiting not only the IIM diagnosis strategy but also the patients’ follow‐up. Different techniques have been tested or are in development for IIM including positron emission tomography, ultrasound imaging, ultrasound shear wave elastography, though magnetic resonance imaging (MRI) remains the most widely used technique in routine. Whereas guidelines on muscle imaging in myositis are lacking here we reviewed the relevance of muscle imaging for both diagnosis and myositis patients’ follow‐up. We propose recommendations about when and how to perform MRI on myositis patients, and we describe new techniques that are under development.
Muscle imaging and especially muscle MRI is a powerful technique for both IIM diagnosis and follow‐up. Muscle MRI is actually the best muscle imaging technique in routine, and it is widely used, but guidelines determining when and how to use it in myositis patients are lacking.
Idiopathic inflammatory myopathies can be classified as polymyositis, dermatomyositis, immune-mediated necrotizing myopathy, sporadic inclusion body myositis or non-specific myositis. Anti-Jo-1 ...antibody-positive patients are assigned to either polymyositis or dermatomyositis suggesting overlapping pathological features. We aimed to determine if anti-Jo-1 antibody-positive myopathy has a specific morphological phenotype. In a series of 53 muscle biopsies of anti-Jo-1 antibody-positive patients, relevant descriptive criteria defining a characteristic morphological pattern were identified. They were tested in a second series of anti-Jo-1 antibody-positive patients and compared to 63 biopsies from patients suffering from other idiopathic inflammatory myopathies. In anti-Jo-1 antibody-positive patients, necrotic fibres, which strongly clustered in perifascicular regions, were frequently observed. Sarcolemmal complement deposition was detected specifically in perifascicular areas. Inflammation was mainly located in the perimysium and around vessels in 90.6%. Perimysial fragmentation was observed in 90% of cases. Major histocompatibility complex class I staining was diffusely positive, with a perifascicular reinforcement. Multivariate analysis showed that criteria defining perifascicular pathology: perifascicular necrosis, atrophy, and perimysial fragmentation allow the distinction of anti-Jo-1 antibody-positive patients, among patients suffering from other idiopathic inflammatory myopathies. Anti-Jo-1 antibody-positive patients displayed perifascicular necrosis, whereas dermatomyositis patients exhibited perifascicular atrophy.
Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy ...of rituximab on muscle and lung outcomes.
Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants.
Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1.
This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients.
Clinicaltrials.gov NCT00774462.
Sporadic inclusion body myositis (sIBM) is the most frequently acquired myopathy in patients over 50 years of age. It is imperative that neurologists and rheumatologists recognize this disorder which ...may, through clinical and pathological similarities, mimic other myopathies, especially polymyositis. Whereas polymyositis responds to immunosuppressant drug therapy, sIBM responds poorly, if at all. Controversy reigns as to whether sIBM is primarily an inflammatory or a degenerative myopathy, the distinction being vitally important in terms of directing research for effective specific therapies. We review here the pros and the cons for the respective hypotheses. A possible scenario, which our experience leads us to favour, is that sIBM may start with inflammation within muscle. The rush of leukocytes attracted by chemokines and cytokines may induce fibre injury and HLA-I overexpression. If the protein degradation systems are overloaded (possibly due to genetic predisposition, particular HLA-I subtypes or ageing), amyloid and other protein deposits may appear within muscle fibres, reinforcing the myopathic process in a vicious circle.
Mass cytometry is a powerful tool that allows simultaneous analysis of more than 37 markers at the single cell level. Mass cytometry is of particular interest in the identification of a wide variety ...of cell phenotypes in autoimmune diseases. Moreover, cells can be labelled with palladium isotopes and pooled before staining (barcoding). Nevertheless, immunologists often face an important problem concerning the choice of markers to be included in a panel. This problem arises due to the incompatibility of different buffers used for the fixation and permeabilization of cells with various cell surface epitopes. In this study, we used a panel of 27 markers (19 surface markers and 8 intranuclear markers) to demonstrate disparities in the detection of cell surface antigens when comparing different buffers to stain unstimulated peripheral blood mononuclear cells. These disparities range from mild differences to very important differences in population frequencies depending on the buffers. Finally, we demonstrate the harmful effects of permeabilization prior to barcoding on the detection of some cell surface antigens. Here, we optimize a protocol that is suitable to use when targeting a large panel including both cell surface and intranuclear markers on unstimulated human peripheral blood mononuclear cells.
Highlights • In case of immunosuppressant-resistant myasthenia gravis, rituximab appears to be efficient in 50%. • The treatment with rituximab may be considered as an early 3rd line therapy in the ...management of severe myasthenia gravis. • Rituximab increases the risk of progressive multifocal leukoencephalopathy in patients with myasthenia gravis under chronic immunosuppressant therapy. • Rituximab seems to reduce the use of prednisone in case of resistant myasthenia gravis.
Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune‐mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients ...may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone‐assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB‐crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2‐associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM‐specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process.
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