François-Jérôme Authier

Marked efficacy of a therapeutic strategy associating prednisone and plasma exchange followed by rituximab in two patients with refractory myopathy associated with antibodies to the signal recognition particle (SRP).

We report two patients with myopathy associated with anti-signal recognition particle Ab, refractory to conventional therapy, who were treated with prednisone and plasma exchange, followed by rituximab. A marked response was observed in both patients, with partial to complete recovery of muscle strength, which was sustained.

Myopathy associated with anti–signal recognition peptide antibodies: Clinical heterogeneity contrasts with stereotyped histopathology

We report three patients with anti–signal recognition particle antibodies who had different presenting clinical pictures, mimicking acute polymyositis, limb‐girdle muscular dystrophy, and acute rhabdomyolysis. Muscle biopsies typically showed necrotizing myopathy with little or no inflammation and deposits of membrane attack complex (C5b‐9) in endomysial capillaries. The clinical course was severe in two patients and mild in one. The combination of corticosteroid with either an immunosuppressive agent or intravenous immunoglobulins was required to improve the condition of these patients. Muscle Nerve, 2006

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.

Aluminum inclusion macrophagic myofasciitis: a recently identified condition

The authors conclude that the persistence of aluminum hydroxide at the site of intramuscular injection is a novel finding which has an exact significance that remains to be established fully. It seems mandatory to evaluate possible long-term adverse effects induced by this compound, because this issue has not been addressed (in the past, aluminum hydroxide was believed to be cleared quickly from the body). If safety concerns about the long-term effects of aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to rescue vaccine-based strategies should be proposed to ensure the enormous benefit for public health that these vaccines provide worldwide.

Systemic Sclerosis‐Associated Myopathy

Abstract:u2002 Skeletal muscle involvement is a common feature in systemic sclerosis (SSc) because muscle weakness is found in up to 90% SSc patients when systematically assessed. Muscle clinical, biological, and electromyographic features are similar to those of polymyositis or dermatomyositis, except for a higher proportion of mild symptoms. SSc‐associated myopathy is more prevalent in diffuse SSc and is also associated with cardiomyopathy. The pathophysiological process leading to SSc‐associated myopathy is likely to be complex, given the heterogeneity of pathological muscle findings, including stigma of microangiopathy, and also inflammatory infiltrate in about half of the cases and interstitial fibrosis. Conflicting results have been reported regarding the correlation between clinicobiological presentation and pathological muscle features, nevertheless there is a general agreement that histologically proven inflammatory myopathies usually regress under high‐dose corticosteroid therapy, or even low dose in case of positive anti‐PM/Scl antibody. In contrast, noninflammatory myopathies often result in milder clinical expression but do not respond to immunosuppressive treatment.

Al(OH) 3 -adjuvanted vaccine-induced macrophagic myofasciitis in rats is influenced by the genetic background

Macrophagic myofasciitis (MMF) is a specific histopathologic lesion involved in the persistence for years of aluminum hydroxide [Al(OH)(3)] at the site of previous intramuscular (i.m.) injection. In order to study mechanisms involved persistence of MMF lesions, we set up an experimental model of MMF-lesion in Sprague-Dawley and Lewis rat, by i.m. injections of 10 microL of an Al(OH)(3)-adjuvanted vaccine. An evaluation carried out over a 12-month period disclosed significant shrinkage of MMF lesions with time. A radioisotopic study did not show significant aluminium uptake by Al(OH)(3)-loaded macrophages. A morphometric approach showed that Lewis rats with Th1-biased immunity had significantly smaller lesions than Sprague-Dawley rats with balanced Th1/Th2 immunity. Concluding, our results indicate that genetic determinatives of cytotoxic T-cell responses could interfere with the clearance process and condition the persistence of vaccine-induced MMF-lesions.

Type 2 myotonic dystrophy can be predicted by the combination of type 2 muscle fiber central nucleation and scattered atrophy.

The diagnosis of Type 2 myotonic dystrophy (DM2/proximal myotonic myopathy) is often overlooked because of a nonspecific clinical presentation and muscle biopsy findings of a denervation-like pattern of unknown specificity that combines increased fiber size variation, central nucleation, small angulated fibers, Type 2 fiber atrophy, and nuclear clumps. We determined the presence of these features in 104 patients designated as having an unidentified myopathy from a series of 2,100 muscle biopsies. Because CCUG expansions form pathogenic ribonuclear accumulations that can be detected by in situ hybridization, we validated and then used automated (CCUG)8 in situ hybridization as a reference standard to evaluate the value of each histologic feature for DM2 detection, identifying 8 DM2-positive and 96 DM2-negative cases. Multivariate analyses identified the combination of Type 2 fiber atrophy and central nucleation as the most predictive of DM2 (sensitivity, 1.0; specificity, 0.92). These features were mutually exclusive in non-DM2 patients (p < 0.0001). The relevance of this combination of features was confirmed in an additional independent series (15 DM2-positive vs 17 DM2-negative). Further investigation revealed that central nucleation selectively affects Type 2 fibers in DM2 and, conversely, that it affects Type 1 fibers in DM1 (p < 0.0001). These results will facilitate the routine detection of DM2 and further support the concept that DM2 has a distinct pathophysiology involving type 2 myofibers.

Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxide-induced macrophagic myofasciitis (MMF) ☆

Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. Representative features of MMF-associated cognitive dysfunction (MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear extinction at dichotic listening test. In present study we retrospectively evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits seemed unusually severe. MACD remained stable over time, although dysexecutive syndrome tended to worsen. Long-term follow-up of a subset of patients with 3 or 4 consecutive neuropsychological evaluations confirmed the stability of MACD with time, despite marked fluctuations.

Whole microvascular unit deletions in dermatomyositis

Objectives The pathophysiology of dermatomyositis (DM) remains unclear, combining immunopathological mechanisms with ischaemic changes regarded as a consequence of membranolytic attack complex (MAC)-induced capillary destruction. The study is a reappraisal of the microvascular involvement in light of the microvascular organisation in normal human muscle. Methods Muscle microvasculature organisation was analysed using 3D reconstructions of serial sections immunostained for CD31, and histoenzymatic detection of endogenous alkaline phosphatase activity of microvessels. An unbiased point pattern analysis-based method was used to evaluate focal capillary loss. Double immunostainings identified cell types showing MAC deposits. Results The normal arterial tree includes perimysial arcade arteries, transverse arteries penetrating perpendicularly into the endomysium and terminal arterioles feeding a microvascular unit (MVU) of six to eight capillaries contacting an average of five myofibres. Amyopathic DM cases (n=3) and non-necrotic fascicles of early DM cases (n=27), showed patchy capillary loss in the form of 6-by-6 capillary drop-out, corresponding to depletion of one or multiple MVUs. MAC deposits were also clustered (5–8 immunostained structures, including endothelial cells, but also pericytes, mesenchymal cells and myosatellite cells). Conclusions Capillary loss may not be the primary cause of muscle ischaemia in DM. The primary event rather stands upstream, probably at the level of perimysial arcade arteries around which inflammatory infiltrates predominate and which lumen may show narrowing in chronic DM. Ischaemia-reperfusion injury, which is favoured by autoimmune backgrounds in experimental models and which activates the complement cascade in capillaries, could represent an hitherto unsuspected (and potentially preventable) mechanism of muscle damage in DM.

Overexpression of MHC Class I in Muscle of Lymphocyte-Deficient Mice Causes a Severe Myopathy with Induction of the Unfolded Protein Response

Muscle fibers do not normally express major histocompatibility complex class I (MHC-I) molecules, and their reexpression is a hallmark of inflammatory myopathies. It has been shown in mice that overexpression of MHC-I induces a poorly inflammatory myositis accompanied by the unfolded protein response (UPR), but it is unclear whether it is attributable to T-cell-mediated MHC-I-dependent immune responses or to MHC-I forced expression per se. Indeed, besides presenting antigenic peptides to CD8(+) T cells, MHC-I may also possibly exert nonimmunologic, yet poorly understood pathogenic effects. Thus, we investigated the pathogenicity of MHC-I expression in muscle independently of its immune functions. HT transgenic mice that conditionally overexpress H-2K(b) in muscle were bred to an immunodeficient Rag2(-/-) background. The muscle proteome was analyzed by label-free high-resolution protein quantitation and Western blot. Despite the absence of adaptive immunity, HT Rag2(-/-) mice developed a very severe myopathy associated with the cytoplasmic accumulation of H-2K(b) molecules. The UPR was manifest by up-regulation of characteristic proteins. In humans, we found that HLA class I molecules not only were expressed at the sarcolemma but also could accumulate intracellularly in some patients with inclusion body myositis. Accordingly, the UPR was triggered as a function of the degree of HLA accumulation in myofibers. Hence, reexpression of MHC-I in normally negative myofibers exerts pathogenic effects independently of its immune function.