D1.323 - Concurrence of essential mixed cryoglobulinemia and cold agglutinin disease: a matter of shared light chains. Case series and literature review

Essential mixed cryoglobulinaemia (EMC) and cold agglutinin disease (CAD) are rare disorders. Recently it was reported that 15% of patients with type 1 cryoglobulinemia had concurrently CAD (Khwaja, DOI: 10.1111/bjh.19112). Here we assessed the frequency of CAD in patients with EMC.

Medical records of 43 patients with EMC and 232 with HCV-associated MC referred to the Lazio Region Referral Center for Mixed Cryoglobulinaemia, and of 541 with primary Sjögren’s syndrome (SjS), were retrospectively reviewed to identify those with concurrent CAD documented by hemolytic anemia and positive cold agglutinin test. All patients were negative for anti-HCV and anti-HIV Abs and were HbsAg negative. We also performed a systematic literature review on the heavy chain and light chain sequences of monoclonal cold agglutinins and cryoglobulinemia-associated rheumatoid factors.

Three out of 41 patients (7%) with type 2 EMC had concurrent CAD with indirect Coombs test positive for anti-red blood cell I antigen autoantibody, whereas no CAD cases were found among HCV-MC and SjS patients. Cryoglobulinemic vasculitis manifestations were mild/moderate in all 3 EMC/CAD patients, and hemolysis was mainly subclinical in one. One patient had associated splenic lymphoma. A recent study (Malecka, DOI 10.3324/haematol.2016.146126) reports that in about half of CAD patients the cold agglutinin light chain were encoded by the immunoglobulin k variable gene 3-20 (IGKV3-20). Strikingly, a literature review reveals that the complementarity determining region 3 (CDR 3) sequences of IGKV3-20-encoded cold agglutinins of about 30% of CAD patients are identical to those associated with the IGKV3-20-encoded light chains associated with the Wa cross-reactive idiotype, which accounts for over 60% of monoclonal rheumatoid factors found in type 2 MC.

On clinical grounds, it is possible that a relatively frequent association of CAD with EMC has passed so far unnoticed because some CAD manifestations (e.g.livedo reticularis and acrocyanosis) may confound those of cryoglobulinemic vasculitis, and because B cell depletion therapy with rituximab is a first line treatment for both disorders. The association of these rare diseases can be explained by the, so far overlooked, fact that in one third of CAD cases the IGKV3-20 light chain is poised to recognize both the red blood cell I antigen and IgG, consistently with the polyspecificity typical of cross-reative idiotypes associated with”natural” IgM antibodies. Further support to this view comes from the fact that the heavy chains associated with cold agglutinins and the Wa rheumatoid factor, IGHV4-34 and IGHV1-69 respectively, share the unique capacity to form hydrophobic bonds that are necessary for the efficient engagement of I antigen through the conventional binding site.