From 10% to 25% of patients with autoimmune and autoinflammatory diseases presenting in the emergency room require hospitalization, of which 30% requiring intensive care. The conditions more frequently admitted in intensive care unit (ICU) are rheumatoid arthritis, systemic vasculitis (particularly antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV)), systemic lupus erythematosus, catastrophic antiphospholipid syndrome (CAPS), systemic sclerosis, and myositis. The crosstalk between the immune system and the different organs affected is the key to understanding the pathophysiology of these immune-inflammatory conditions. Some rheumatic conditions should always be considered as a possible diagnosis, especially in the context of a multisystem disease, when the diagnosis is not immediately evident. For instance, the combination of respiratory and renal failure could be a new diagnosis of AAV, presenting with pulmonary-renal syndrome. Therefore, a prompt assessment should be undertaken (i.e., thoracic CT scan, urinalysis, bronchoscopy, etc.). Another example is that the combination of digital ischemia, ulceration, and superficial gangrene of the lower extremities with multiorgan failure, livedo reticularis, and splinter hemorrhages should suggest CAPS syndrome. In all these cases, it is essential to involve rheumatologists early in the management of the patients, even if the condition is only suspected. In this chapter, we focus on the more severe clinical presentation of immune-mediated/autoinflammatory conditions, to highlight the key findings and overlap between signs and symptoms, providing guidance on diagnosis and management.