Thierry Maisonobe

OBJECTIVE: To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis). METHODS: We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2). RESULTS: Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059-16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement. CONCLUSIONS: irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.

We describe a long-term observational study of a large cohort of patients with sporadic inclusion body myositis and propose a sporadic inclusion body myositis weakness composite index that is easy to perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52%), or by extraction from previous medical records (48%). One hundred and thirty-six patients [57% males, 61 (interquartile range 55-69) years at onset] were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale <3/5 in 48%, distal British Medical Research Council scale <3/5 in 40%, swallowing problems in 46%). During their follow-up, 75% of patients had significant walking difficulties and 37% used a wheelchair (after a median duration from onset of 14 years). The sporadic inclusion body myositis weakness composite index, which correlated with grip strength (correlation coefficient: 0.47; P < 0.001) and Rivermead Mobility Index (correlation coefficient: 0.85; P < 0.001), decreased significantly with disease duration (correlation coefficient: -0.47; P < 0.001). The risk of death was only influenced by older age at onset of first symptoms. Seventy-one (52%) patients received immunosuppressive treatments [prednisone in 91.5%, associated (in 64.8%) with other immunomodulatory drugs (intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 40.8 months]. At the last assessment, patients who had been treated were more severely affected on disability scales (Walton P = 0.007, Rivermead Mobility Index P = 0.004) and on the sporadic inclusion body myositis weakness composite index (P = 0.04). The first stage of disease progression towards handicap for walking was more rapid among patients receiving immunosuppressive treatments (hazard ratio = 2.0, P = 0.002). This study confirms that sporadic inclusion body myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies. Furthermore, our findings suggest that immunosuppressant drug therapy could have modestly exacerbated progression of disability. The sporadic inclusion body myositis weakness composite index might be a valuable outcome measure for future clinical trials, but requires further assessment and validation.

Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.

OBJECTIVE: Polymyositis is a rare inflammatory muscular disease of unknown cause. Corticosteroids and immunosuppressive drugs are the first choice of therapy but are not always effective and may cause serious side effects. Many studies have shown that polyvalent intravenous immunoglobulin (IVIG) may be of interest for the treatment of dermatomyositis. We carried out an open, prospective study to evaluate the efficacy of IVIG in subjects with polymyositis that was refractory to traditional treatments, and we evaluated the benefits of this therapy over a long-term period of followup. METHODS: Thirty-five adult white patients (20 female, 15 male, mean age 43.5 years [SD 16.8]) with chronic, refractory polymyositis were treated with high doses of IVIG, after the patients had received the following traditional treatments: prednisone (n = 35), methotrexate (n = 24), azathioprine (n = 13), cyclophosphamide (n = 4), cyclosporine (n = 7), chlorambucil (n = 1), plasmapheresis (n = 8), lymphopheresis (n = 1), and total body irradiation (n = 1). There had been no changes in the patients' treatment in the 2 months before the initiation of IVIG therapy, and doses were not increased during IVIG treatment. We used preparations of polyvalent human IVIG with increased concentrations of intact IgG. The patients received 1 gm/kg/day for 2 consecutive days per month. The mean course of treatment was 4-6 months. The clinical assessment involved the evaluation of proximal muscle power, muscle disability scale score, and esophageal disorders. The biochemical evaluations carried out before each treatment period were compared by Student's t-test and nonparametric Wilcoxon test. Results were considered to be significant at P = 0.05. RESULTS: In the short-term, significant clinical improvement was noted in 25 of the 35 patients (71.4%). Mean muscle power was estimated before and after IVIG therapy and was found to be significantly improved (P < 0.01). All patients had a significant biochemical response. Mean creatine kinase levels during IVIG therapy decreased significantly before the fourth IVIG perfusion (P < 0.01). Side effects, usually minor, were noted in 6 patients. This benefit allowed the initial prednisone dose to be reduced by >50% in all patients. The mean (+/- SD) followup time for the 25 patients who responded favorably to IVIG treatment was 51.4 +/- 13.1 months. Twelve of these 25 patients remained in full remission following their initial course of IVIG, resulting in complete stoppage of medication in 5 patients or low doses of steroids in 7 patients. The condition of 6 patients remained improved and no other drugs were prescribed, but the patients remained dependent on IVIG infusions. Seven of the 25 patients who responded well to IVIG treatment relapsed at an average of 17.1 months (range 4-23 months) after the discontinuation of IVIG. CONCLUSION: IVIG is an interesting therapy for the treatment of polymyositis, with results showing that the condition of approximately 70% of the patients tested improved. After the discontinuation of the IVIG therapy, the efficacy remained stable in 50% of the patients, with a followup of over 3 years.