Brachio-cervical inflammatory myopathy: multilevel clinical, histopathological and multi-omic analyses of a syndrome variably associated with systemic sclerosis.

Brachio-cervical inflammatory myopathy (BCIM) is a rare and under-characterized subtype of idiopathic inflammatory myopathies (IIM), marked by prominent upper limb and neck muscle involvement. Since its initial description in 2006, few studies have addressed its clinical spectrum or pathogenesis, and its potential overlap with systemic sclerosis (SSc) remains a matter of debate. Here, we aimed to characterize the clinical, histopathological, and molecular features of BCIM in a large multicenter cohort and determine whether BCIM represents a characteristic clinico-pathological syndrome within the IIM spectrum or reflects an atypical presentation of SSc-associated myositis. We studied 26 patients with clinically and histologically confirmed BCIM from seven European centers. Clinical data, treatment responses, and autoantibody profiles were collected retrospectively from participating centers. Histopathological and immunohistochemical analyses were performed on muscle biopsies, and 12 muscle biopsy specimens underwent bulk RNA sequencing, including a comparison with 669 non-BCIM myositis datasets. Proteomic profiling was performed in an independent subset. Clinical overlap with SSc was defined using the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. The cohort was predominantly female (88%) with a mean age of 51 years [standard deviation (SD) ± 15.0]. Core features included asymmetrical proximal upper limb weakness (100%), dropped head (62%), dysphagia (46%), and facial weakness (54%). Although 35% showed clinical overlap with SSc, 65% of patients did not meet SSc criteria. All patients received corticosteroids; 65% required additional immunosuppression, yet complete clinical remission was uncommon in this retrospective cohort, although outcome assessment was limited by heterogeneous follow-up. Histopathology revealed dense endomysial inflammation with T cell predominance and prominent endo- and perimysial B-cell/plasma-cell-rich clusters with variable fibrosis. CD45⁺ and CD8⁺ cells were more abundant in patients without SSc overlap. RNA sequencing revealed a strong B-cell/plasma-cell signature, M2-like macrophage polarization, and downregulation of mitochondrial gene expression. Proteomics highlighted broad alterations in oxidative phosphorylation, aerobic respiration, and ATP synthesis pathways. BCIM shows a characteristic constellation of clinical, histological, and molecular features within the IIM spectrum. While a subset of patients meets criteria for SSc overlap, many do not, and the consistent presence of B-cell-rich inflammation together with downregulation of mitochondrial transcripts and proteins highlights shared pathogenic mechanisms within the cohort. These findings support the concept of BCIM as a myositis syndrome with heterogeneous SSc association and highlight a prominent B-cell/plasma-cell signature in BCIM, which warrants further evaluation of B-cell-directed approaches in future, prospective studies.