Cryoglobulinaemia is an immune disorder caused by the presence in the circulation of cold-precipitable immunoglobulins. 

Patients with idiopathic hypocryoglobulinaemia have a significantly lower prevalence of HCV+ and C4 consumption. They have trace amounts of polyclonal (type III) cryoglobulins. In most cases, they are also negative for HCV infection and could have normal rheumatoid activity and complement levels.

In this instance, the standard diagnostic criteria for mixed cryoglobulinemia are absent. A thorough analysis of cryoprecipitate immune complexes could be an additional diagnostic tool for the complete range of cryoglobulinemia. Several technical factors are worthy of emphasis.

1. The diagnostic evaluation should include stringent controls on blood samples and processing to confirm the absence of circulating cryoglobulins.
2. The relevance of trace levels of cryoglobulins is generally underestimated, and clinicians should pay special attention to them in HCV-negative patients.
3. To avoid misdiagnosis, a comprehensive description of the manifestations is necessary, which should include a tissue examination, especially if there is a suspicion of renal involvement.

Rituximab represents the best tool for the more severe cases of idiopathic hypocryoglobulinaemia. Rituximab is safer than conventional immunosuppressants and can achieve long-term remission, especially with intensive regimens.

Reference: Roccatello, D., Sciascia, S., Naretto, C. et al. Recognizing the new disorder "idiopathic hypocryoglobulinaemia" in patients with previously unidentified clinical conditions. Sci Rep 12, 14904 (2022).