“…Regulation of abnormal complement activation would have the potential for successful treatment in patients with IMNM; however, a trial using a complement component 5 inhibitor did not show an effective result in patients with anti-HMGCR and anti-SRP antibody-positive IMNM. 9 The severe phenotype of anti-SRP antibody-positive IMNM might be associated with the development of TMA in the present case. Although the definition of refractory anti-SRP antibody-positive IMNM has not been established, patients who showed deterioration after standard therapies, such as corticosteroids and immunosuppressive drugs, were considered to have refractory IMNM.…”
Section: Discussionmentioning
confidence: 51%
“…Although the deposition of anti‐SRP antibodies on the vessel walls of tissues other than muscle tissues has been unclear so far, we suggest that serum anti‐SRP antibodies could also be implicated in the development of TMA in this patient owing to complement deposition on the renal vascular walls. Regulation of abnormal complement activation would have the potential for successful treatment in patients with IMNM; however, a trial using a complement component 5 inhibitor did not show an effective result in patients with anti‐HMGCR and anti‐SRP antibody‐positive IMNM 9 …”
We describe the case of a 61‐year‐old woman with anti‐signal recognition particle (SRP) antibody‐positive immune‐mediated necrotizing myopathy (IMNM) who exhibited biopsy‐confirmed thrombotic microangiopathy (TMA). The patient developed proximal‐dominant muscle weakness and was diagnosed with anti‐SRP antibody‐positive IMNM based on muscle biopsy results and serological examination. A high‐dose corticosteroid prescription was initiated, followed by intravenous methylprednisolone and intravenous immunoglobulin therapy (IVIg). The patient showed IVIg‐induced hemolytic anemia with preserved ADAMTS13 activity. Transient oral tacrolimus administration was initiated. Approximately 8 weeks after admission, the serum creatinine levels gradually increased. Renal histological examination revealed TMA, including ischemic changes in the renal tubules, stenosis, and occlusion of the interlobular arteries with fibrinoid necrosis of the afferent arteriolar walls. The arteriolar walls demonstrated an accumulation of C1q and C3c. Myofiber damage in patients with IMNM accounts for the activation of the classical pathway of the complement cascade in the sarcolemma due to antibody deposition. Additionally, a membrane attack complex is observed on capillaries in the muscle tissues of patients with anti‐SRP antibody‐positive IMNM. Although drug‐induced pathomechanisms, such as IVIg and tacrolimus, can trigger the development of TMA, we suggest that the presence of serum anti‐SRP antibodies would be implicated in complement‐associated kidney vascular damage.
“…Regulation of abnormal complement activation would have the potential for successful treatment in patients with IMNM; however, a trial using a complement component 5 inhibitor did not show an effective result in patients with anti-HMGCR and anti-SRP antibody-positive IMNM. 9 The severe phenotype of anti-SRP antibody-positive IMNM might be associated with the development of TMA in the present case. Although the definition of refractory anti-SRP antibody-positive IMNM has not been established, patients who showed deterioration after standard therapies, such as corticosteroids and immunosuppressive drugs, were considered to have refractory IMNM.…”
Section: Discussionmentioning
confidence: 51%
“…Although the deposition of anti‐SRP antibodies on the vessel walls of tissues other than muscle tissues has been unclear so far, we suggest that serum anti‐SRP antibodies could also be implicated in the development of TMA in this patient owing to complement deposition on the renal vascular walls. Regulation of abnormal complement activation would have the potential for successful treatment in patients with IMNM; however, a trial using a complement component 5 inhibitor did not show an effective result in patients with anti‐HMGCR and anti‐SRP antibody‐positive IMNM 9 …”
We describe the case of a 61‐year‐old woman with anti‐signal recognition particle (SRP) antibody‐positive immune‐mediated necrotizing myopathy (IMNM) who exhibited biopsy‐confirmed thrombotic microangiopathy (TMA). The patient developed proximal‐dominant muscle weakness and was diagnosed with anti‐SRP antibody‐positive IMNM based on muscle biopsy results and serological examination. A high‐dose corticosteroid prescription was initiated, followed by intravenous methylprednisolone and intravenous immunoglobulin therapy (IVIg). The patient showed IVIg‐induced hemolytic anemia with preserved ADAMTS13 activity. Transient oral tacrolimus administration was initiated. Approximately 8 weeks after admission, the serum creatinine levels gradually increased. Renal histological examination revealed TMA, including ischemic changes in the renal tubules, stenosis, and occlusion of the interlobular arteries with fibrinoid necrosis of the afferent arteriolar walls. The arteriolar walls demonstrated an accumulation of C1q and C3c. Myofiber damage in patients with IMNM accounts for the activation of the classical pathway of the complement cascade in the sarcolemma due to antibody deposition. Additionally, a membrane attack complex is observed on capillaries in the muscle tissues of patients with anti‐SRP antibody‐positive IMNM. Although drug‐induced pathomechanisms, such as IVIg and tacrolimus, can trigger the development of TMA, we suggest that the presence of serum anti‐SRP antibodies would be implicated in complement‐associated kidney vascular damage.
“…In addition to the approvals in Japan, the USA and the EU, zilucoplan is also currently under regulatory review in Australia and Canada for use in the treatment of gMG. Clinical development of zilucoplan in other indications, including paroxysmal nocturnal haemoglobinuria [ 7 ], immune-mediated necrotising myopathy [ 8 ], amyotrophic lateral sclerosis [ 9 ] and patients hospitalised for COVID-19 [ 10 – 12 ], has been discontinued.…”
Zilucoplan (Zilbrysq
®
) is a subcutaneously administered macrocyclic peptide inhibitor of complement component 5 (C5 inhibitor) being developed by UCB for the treatment of generalised myasthenia gravis (gMG). Zilucoplan received its first approval, in Japan, in September 2023 for the treatment of gMG in adult patients who inadequately respond to steroids or other immunosuppressants and are positive for anti-acetylcholine receptor (AChR) antibodies. Subsequently, zilucoplan was approved in the USA in October 2023 for the treatment of gMG in adult patients who are anti-AChR antibody positive and in the EU in December 2023 as an add-on to standard therapy for the treatment of gMG in adult patients who are anti-AChR antibody positive. Zilucoplan is also currently under regulatory review in Australia and Canada for use in the treatment of gMG. This article summarises the milestones in the development of zilucoplan leading to this first approval for gMG.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40265-023-01977-3.
“…Conversely, it is conceivable that the respective autoantibodies have not yet been identified. Although complement plays a prominent role in immune mechanisms in IMNM [ 3 ], complement inhibition did not prove effective in a recent phase 2 trial [ 46 ].…”
Section: Immunological Backgroundmentioning
confidence: 99%
“…Based on our finding of considerable variation of muscle fiber necrosis, regeneration and inflammation, we suggest including the entire histopathological features of IMNM to capture the full range of disease presentation, particularly in those patients without detectable autoantibodies [ 3 , 5 , 64 ]. These criteria were recently employed for a phase 2 study of IMNM investigating the C5 inhibitor zilucoplan [ 46 ]. Fig.…”
Section: Mhc and Complement Patterns In Idiopathic Inflammatory Myopa...mentioning
Histopathological analysis stands as the gold standard for the identification and differentiation of inflammatory neuromuscular diseases. These disorders continue to constitute a diagnostic challenge due to their clinical heterogeneity, rarity and overlapping features. To establish standardized protocols for the diagnosis of inflammatory neuromuscular diseases, the development of cost-effective and widely applicable tools is crucial, especially in settings constrained by limited resources. The focus of this review is to emphasize the diagnostic value of major histocompatibility complex (MHC) and complement patterns in the immunohistochemical analysis of these diseases. We explore the immunological background of MHC and complement signatures that characterize inflammatory features, with a specific focus on idiopathic inflammatory myopathies. With this approach, we aim to provide a diagnostic algorithm that may improve and simplify the diagnostic workup based on a limited panel of stainings. Our approach acknowledges the current limitations in the field of inflammatory neuromuscular diseases, particularly the scarcity of large-scale, prospective studies that validate the diagnostic potential of these markers. Further efforts are needed to establish a consensus on the diagnostic protocol to effectively distinguish these diseases.
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