Recalcitrant Leg Ulcers as the Only Manifestation of Essential Type 2 Cryoglobulinemia

Chronic leg ulcers are persistent conditions that might be a diagnostic and therapeutic challenge, with great impact in health care costs and patients’ quality of life. We report a case of a 60-year-old woman, with long-lasting recalcitrant leg ulcers, which led to left leg amputation 10 years ago. Several attempts to heal the right leg were made, including skin grafting in three different occasions and several surgical debridements, all with unsatisfactory outcome. Some months before the ulcers began, the patient had been diagnosed with undifferentiated connective tissue disease because of arthralgia and positive antinuclear antibodies, therefore low dose systemic corticosteroids and azathioprine were prescribed. For the last 4 years she has been followed in our department and since then no evidence of clinical or laboratorial criteria for autoimmune diseases was found, thus the immunosuppressive therapy was stopped. She maintained ever since a high rheumatoid factor but without other evidence of autoimmune disease. Medical history was otherwise irrelevant. Several cutaneous biopsies were performed, with no evidence of malignancy or vasculitis. Recently, cryoglobulins became positive, with type 2b cryoglobulin identification on immunofluorescence. Serology for Hepatitis C virus was consistently negative, hence an Essential type 2 Cryoglobulinemia diagnosis was established. No renal impairment, vascular purpura, arthralgia or arthritis was found. The authors emphasize the importance of considering less common etiologies for chronic leg wounds, even in the absence of other suggestive symptomatology, as well as the pertinence of reconsidering diagnosis in highly suspect cases.

Gain-of-Function Mutations in IFIH1 Cause a Spectrum of Human Disease Phenotypes Associated with Upregulated Type I Interferon Signaling

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.