Giant cell myositis and myocarditis revisited.

Giant cell myositis (GCMm) and giant cell myocarditis (GCMc) are two rare autoimmune conditions. Among these, GCMc is a life-threatening disease with a 1-year mortality rate of 70%. Lethal ventricular arrhythmias, rapid evolution to heart failure and sudden death risk makes GCMc an emergency condition. It is thought to be mediated by T-cells and characterized by the presence of myofiber necrosis and giant cells in biopsies. Most commonly co-manifesting conditions with GCMm and/or GCMc are thymoma, myasthenia gravis and orbital myositis, all of which are treatable. As suspicion is the key approach in diagnosis, the physician following patients with thymoma with or without myasthenia gravis and with orbital myositis should always be alert. The fatal nature of GCMc associated with these relatively benign diseases deserves a special emergency attention with prompt institution of combined immunosuppressive treatment and very early inclusion of heart failure teams. ©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.

Giant cell myositis/giant cell myocarditis

Giant cell myositis and myocarditis, diseases of skeletal and cardiac muscles are both abbreviated as GCM. As both conditions are the subjects of this report abbreviations will be GCMmuscle (GCMm) for giant cell myositis and GCMcardiac (GCMc) for giant cell myocarditis.

Myositis with giant cells is a rare but treatable acquired inflammatory disease of the skeletal muscle. As cardiac involvement rapidly leads to lethal ventricular arrhythmias, heart failure or sudden death, combination of GCMm with GCMc can develop into a fulminant and fatal condition. Without any treatment, the 1-year mortality approaches 70% when GCMc takes the stage [1]. Diagnosing and differentiating the entity from other more frequent cardiomyopathies and inflammatory myopathies depend on demonstrating the presence of a non-granuloma forming, diffuse giant cells in biopsy specimens [2]. Therefore, if not suspected it is arduous to make a prompt and accurate diagnosis. Furthermore, the importance lies in its recognition not only by cardiologists but also by other disciplines such as neurologists, rheumatologists, and ophthalmologists for rapid involvement of necessary emergency teams to start an aggressive treatment [3].

First description of GCM cases was on fatal idiopathic GCMc and was made by Saltykow in 1905 [4]. The main pathological findings in this report were widespread inflammation and myocyte necrosis with abundant giant cells. The condition was considered in tandem with sarcoidosis until the 1950s when received recognition as a separate entity with the diffuse nature of inflammation and necrosis versus granuloma and fibrosis formation in sarcoidosis (Veia A, 2014). From 1905 to 1980s, all reported GCMc cases were diagnosed at autopsy [1]. The development of diagnostic tools such as endomyocardial biopsy (single or repeated), imaging-guided endomyocardial biopsy, apical vedge-sectioning during placement of ventricular assist devices, cardiac gadolinium-enhanced MRI, FDG-PET, has allowed diagnosis and treatment in living patients only after mid 1980s, prolonging transplant-free survival and life expectancy [5,6]. Tissue histopathology is still the gold standard of diagnosis and almost all studies on the inflammation of muscle tissue with giant cells is performed in GCMc. Due to the rarity of the condition, a multicenter Giant Cell Myocarditis Registry was established in the early 1990s in the United States [7].

The first description of GCMm was appended to GCMc and appeared in the report of Giordano and Haymond in 1944. This patient also manifested thymoma and myasthenia gravis [8-10]. From 1944 to 1974, only 10 patients with idiopathic GCMm were found to be reported in the literature with additional 3 patients with GCMc. All the reported GCMc patients were associated with thymoma [11]. As GCMc is a more serious manifestation of the GCMm/GCMc, the combination and diagnosis is established by myocardial histopathology and there is usually no time to evaluate any skeletal muscle pathology unless the patient presents relative symptoms. Thus, as it is not known how much latent GCMc patients also have GCMm it could be way more common than reported [13]. On the other hand, there are also patients with GCMm without GCMc [14,15].

GCMc is a very rare condition that affects otherwise healthy young adults. Incidence rate is 0.007% in Japan and 0,051% in India [16]. Review of 377,841 autopsies over a 20-year period found myocarditis in 0.11% but giant cell myocarditis in only 0.007% of the cases [17]. Considering that patients passed away before reaching the hospital, this incidence rate might even be higher.

GCMc can be idiopathic or occur in various conditions, such as infection (tuberculosis, syphilis, pneumocystis jirovecii parvovirus, coxsackie), inflammation, drug sensitivity, hypersensitivity and vasculitis [7]. At least one group of the condition is considered as an autoimmune disease in 19% of patients in some registries that co-manifest with other autoimmune diseases such as inflammatory bowel disease, cryofibrinogenemia, optic neuritis, Hashimoto thyroiditis, rheumatoid arthritis, Takayasu arteritis, temporal arteritis, myasthenia gravis (MG), alopecia totalis, vitiligo, orbital myositis, autoimmune hepatitis, Guillain-Barré syndrome, systemic lupus erythematosus, Sjögren’s and pernicious anemia [16]. Furthermore, the inducibility of a similar idiopathic myocarditis in Lewis rats by cardiac myosin strongly suggests that GCMm and GCMc are both autoimmune conditions [16,18]. Combined immunosuppression retards the progression of the disease and results in a partial remission both in humans and experimental rat models. This fact, together with the up-regulation of genes involved in T-cell response are other evidences of autoimmunity [7]. Tumors of the immune cells such as thymoma and lymphoma – thymoma being the most common – are the main tumours accompanying GCMm and GCMc, either separately or in combination [7]. Considering that other autoimmune diseases also accompany thymoma, this feature also suggests autoimmune or dysimmune mechanisms in GCMm/GCMc. When looked at from GCMm point of view, almost – if not all- cases reported are present in patients with myasthenia gravis with or without thymoma.

Although clinically presents similar to other myocarditis conditions GCMc is more severe and has a unique pathology [11]. Histopathological hallmark of GCMm or GCMc adheres to the presence of diffuse inflammation including giant cells without well-formed granuloma formation. Muscle fiber destruction in the muscle biopsy specimens from heart and skeletal muscles, CD8(+) lymphocytes, plasma cells and eosinophils all accompany giant cells at different proportions [2,16]. Giant cells generally embrace necrosis areas diffusely but they don’t form granulomas. Origin of these giant cells are reported to be histiocytic and/or myogenic. It was immunohistochemically demonstrated in one patient that myogenic giant cells express increased lysosome-proteasome system (cathepsins A, B and D) and late endosomal system (LAMP-2) proteins, whereas histiocytic giant cells express only lysosome-protein system proteins (cathepsins A, B, D, L and S) but not the late endosomal marker LAMP-2. They were both negative for ubiquitin-proteasome system, autophagosome and aggresome systems [19]. Thus, it is assumed that the digestion of the same endocytotic material by more than one macrophage engenders these macrophages to fuse and form a giant cell [19].

GCMm/GCMc and thymoma

Approximately 1% of patients with thymoma exhibit GCMc and/or GCMm [10,20]. Being an autoantigen expressing tumor which results in production of antibodies mainly against muscle and nerve tissues such as acetylcholine receptors (AChr), voltage gated calcium channels (VGCC), voltage gated potassium channels (VGKC/Kv1.4), and striational proteins called ryanodine (RyR) and titin, thymoma is the most common tumor associated with GCMc or GCMm [21]. These antibodies are either clinically silent or they cause MG, myositis, neuro-myotonia, encephalitis, autonomic neuropathy, subacute hearing loss and even encephalitis [22]. Most of the cases with co-manifestation of thymoma and GCMm and/or GCMc bear Kv1.4, RyR and/or titin antibodies [19]. The defective immunity found in patients with thymoma is thought to play a role in a giant cell immune reaction against heart and skeletal tissues (Fig. 1) [10].

Figure 1.

Muscle biopsy of a 58-year old patient with GCMm, who had been followed up for AChR and Titin antibodies positive generalized MG under corticosteroid therapy. He also had had metastatic colon cancer and received anti-VEGF therapy 1 year before the development of GCMm. He did not develop GCMc and the GCMm was controlled by increasing the corticosteroid dose. A) H&E (320x): diffuse myonecrosis with inflammatory cells including many giant cells; B) H&E (640x): abundance of giant cells; C) CD68 positive macrophages (320x): macrophages diffusely invade the necrosis area. Giant cells are also positive for macrophage marker CD68; D) Desmin (320x): only the normal areas and redundant, atrophic myofibers are positive for desmin.

GCMm/GCMc and MG (with or without thymoma)

Although rare, presence of polymyositis with lymphocytic inflammation in autoimmune myasthenia with or without thymoma has been a well-known entity. Myositis-MG combination has gained more importance lately due to the employment of immune checkpoint inhibitors (ICI) in cancer therapy with widespread uncontrolled T-cell response attacking different tissues [23,24]. Myocarditis is also discernible in ICI myositis and may co-manifest with skeletal myositis and myasthenia gravis [20]. However, the description of GCMm, GCMc or the combination of them in patients with MG with or without thymoma is an extremely rare but a more important situation as GCMm has a very rapid course and fatal outcome [22]. In the report of Evoli, among 50/207 patients 3 of whom died without any previous cardiac disease, had sudden death, giving the suspicion that they may have held GCMc [25]. Uchio et al reported 8/889 (9%) myositis cases with MG, only one of them had GCMm [26].

Case reports on GCMm are almost exclusively in myasthenic and/or thymomatous patients, whereas only some of GCMc cases do occur in the same patient population [22]. Therefore, idiopathic GCMc cases without an autoimmune etiology do exist and these cases are much more frequent (around 80%) than the autoimmune disease related group (19%) [15]. In general patients with MG and myositis are more likely to express striational antibodies Titin, RyR, Kv1.4. This is the same for GCMm or GCMc in myasthenic patients that express Kv1.4, titin or RyR antibodies [19,27]. Heart and skeletal muscles may be the autoimmune targets in some patients with MG [27].

GCMm/GCMc and orbital myositis

Orbital myositis is a self limited condition under immunosuppressive treatment. This self-limited disease becomes life-threatening when co-manifests with GCMc. Presence of GCMc in orbital myositis was first described in 1989 by Klein BR [29]. In this report, authors suggested that this combination could be regarded as a separate entity [29]. To date, less than 10 cases of GCMc and/or GCMm with orbital myositis are reported, most of which have died due to cardiac involvement [3,29-34]. It has also been described in a pediatric patient [33]. In all reported cases cardiac disease manifested later in the course with a time lapse of days, months or even years [34]. Therefore, the possible development of GCMc and/or GCMm should be kept in mind in the follow-up of patients with orbital myositis [34,35].

Management of GCMm and GCMc

Immunosuppressive treatment either with corticosteroids or in combination with others is sufficient for GCMm only, like in other inflammatory myopathies, and it responds well. Long term maintenance therapy is necessary to prevent relapses and also for its potential to develop GCMc. However, the potential of developing GCMc in the course of GCMm is a factor that alerts the physician than in other inflammatory myopathies. Therefore, it is of vital importance to start an immunosuppressive treatment immediately upon suspicion or diagnosis and include cardiology dicipline for supportive therapy right from the beginning in the follow-up [22,34]. As GCMm may start simultaneously or before the diagnosis of thymoma or MG and also most GCMc patients carry striational antibodies, every patient with GCMm should be checked for thymoma and thymoma-related striational antibodies. Presentation of GCMm and/or GCMc in all reported orbital myositis cases manifest later in the course of orbital myositis. Therefore, orbital myositis itself should raise the suspicion of potential emanation of GCMcm or GCMc.

As mentioned before, most of the research on GCM has been performed in GCMc patients and Lewis rat models. It has been shown that the GCMm transferred to rats were prevented by cyclosporine or anti-T-lymphocyte antibodies but not by corticosteroids alone [6,9,36-38]. Although there are no controlled large scale trials, due to the positive response in anecdotal cases or small patient groups of this fulminant disease, different combinations of immunosuppression with corticosteroids, azathioprine, cyclosporine-A and anti-T-lymphocyte antibodies are used [6, 8,11,39]. In a multicentric retrospective study of 63 biopsy- proven GCMc patients showed that the median survival was 3 months in patients who did not receive any immunosuppression, 3,8 months in the ones receiving corticosteroids only, but was 12.6 months in the patients who received cyclosporine with different combinations (corticosteroids, azathioprine, muromonab-CD3) [8]. As fast tapering and cessation of immunosuppression is associated with the recurrence of GCMc even up to 8 years after the initial diagnosis careful tapering of the drug doses without discontinuation is recommended 40.

Supportive treatment has vital importance in GCMc. If the diagnosis is prompt or GCMc is suspected in a living patient, left ventricular assist devices, medical therapy of heart failure and timely heart transplantation is life-saving when needed. However, it should be noted that and although the cause is unknown, a transplanted heart may also develop GCMc as well. To avoid this probability,, immunosuppression should be maintained in tolerable doses [6,8,39].

Conclusions

The consequences of developing GCMc during the course of some neurological diseases which are treatable and have more benign courses such as GCMm, thymoma, MG or orbital myositis are devastating. Neurologists should be alert in prompt diagnosis of the condition and should immediately include cardiology teams into the diagnostic and treatment process.