RESUMO
Dermatomyositis is an idiopathic inflammatory myopathy with cutaneous manifestations, which is associated with several types of malignancies, yet it has been rarely linked to neuroendocrine tumors (NETs). Here we report two cases of dermatomyositis associated with NETs of differing primary sites. Case 1: A 46-year-old female presented with a facial rash and proximal muscle weakness of both extremities. Investigations revealed elevated creatine kinase (CK) and positive anti-transcriptional intermediary factor 1-γ antibody (TIF1γ). The patient had been diagnosed with dermatomyositis and underwent a total body CT scan, which revealed prominent mediastinal lymphadenopathy, which a subsequent biopsy determined to be neuroendocrine carcinoma of small cell type. Treatment with high-dose corticosteroids was initiated, in addition to chemotherapy-based oncological management. Case 2: A 54-year-old female presented with a facial rash, progressive dyspnea, and general malaise. Laboratory investigations revealed positive anti-melanoma differentiation-associated gene-5 (MDA5) and positive anti-Ro antibody, with a normal level of creatine kinase (CK). A chest CT scan revealed multiple ground-glass opacities. Despite treatment with high-dose intravenous methylprednisolone, IVIG and an infusion of the anti-IL-6 sarilumab [Kevzara], the patient rapidly deteriorated and was intubated. Within days, the patient developed bowel ischemia and underwent a laparotomy which was then complicated by an invasive infection. This resulted in patient's death. Pathology results from colonic tissue demonstrated an appendiceal neuroendocrine tumor. These cases demonstrate the heterogeneity and complexity of dermatomyositis in association with neuroendocrine tumors.
RESUMO
OBJECTIVE: Anticitrullinated protein antibodies (ACPA) have major diagnostic significance in rheumatoid arthritis (RA). ACPA are directed against different citrullinated antigens, including filaggrin, fibrinogen, vimentin, and collagen. The presence of ACPA is associated with joint damage and extraarticular manifestations, suggesting that ACPA may have a significant role in the pathogenesis of RA. METHODS: To verify the effect of ACPA on RA-immune cells, peripheral blood mononuclear cells (PBMC) from cyclic citrullinated peptide (CCP)-positive patients with RA and healthy controls were cocultured in vitro with ACPA. ACPA-positive stained cells were analyzed by flow cytometry and the effect of ACPA on mRNA expression levels was evaluated by real-time PCR. We tested whether the stimulatory effects induced by ACPA could be inhibited by the addition of a new multiepitope citrullinated peptide (Cit-ME). RESULTS: We found that ACPA bind specifically to PBMC from CCP-positive patients with RA through the Fab portion. ACPA induce upregulation of pathogenic cytokine expression (4- to 13-fold increase) in PBMC derived from CCP-positive patients with RA. Moreover, ACPA upregulated IL-1ß and IL-6 mRNA expression levels by 10- and 6-fold, respectively, compared to control IgG. Cit-ME, a genuine ligand of ACPA, inhibited the ACPA-induced upregulation of IL-1ß and IL-6 by 30%. CONCLUSION: ACPA bind to a limited percentage of PBMC and upregulate inflammatory cytokine expression, suggesting that ACPA is involved in RA pathogenesis. Targeting ACPA to decrease their pathogenic effects might provide a novel direction in developing therapeutic strategies for RA.