Cryoglobulinemia types II and III with RF activity affect small and medium vessels and are immune complexes-mediated (DIF+) systemic leukocytoclastic vasculitis, with various organs involvement including the skin, liver, and kidney; peripheral neuropathy; and, less frequently, lung and endocrine gland disorders. Purpura and ulcers are the most frequent symptoms and can be present in up to 90 % of the MC patients. Purpura and skin ulcerations, especially of the lower extremities, can be intermittent, and their severity can vary from mild purpura to severe vasculitic ulceration. Ulcers appear torpid and deep and are associated with high levels of pain, inflammation, and tissue necrosis [1–4].

In particular, purpura is currently one of the major proposed classification criteria for this disease. Moreover, a possible MC complication is the appearance of a B-cell lymphoma [1–4]. Serological, pathological, and clinical criteria for the diagnosis of MC patients are reported in Table 40.2 [3, 4]. A careful patient evaluation is necessary for a correct classification of MC syndromes, with regard to a wide range of infectious, neoplastic, and other RF-positive, systemic rheumatic disorders (Table 40.1) [3, 4]. In particular, pSS and MC can share various overlap symptoms [5]. Histopathological alterations of salivary glands and specific pSS autoantibody patterns (anti-SSA/SSB) are rarely found in MC patients. On the contrary, HCV infection, orthostatic purpura, ulcers, and peripheral neuropathy are rare in pSS. Patients with MC/pSS overlap syndrome are often characterized by a more severe evolution. With regard to skin manifestations, the association of MC with FAN positivity, generalized morphea, Raynaud’s phenomenon, and sclerodattilia can be found. Finally, the coexistence of HCV-related skin diseases (i.e., lichen planus, porphyria cutanea tarda, pruritus, erythema nodosum, urticaria and urticarial vasculitis, erythema multiform, necrolytic acral erythema) and MC can be taken into account. Generally, the association of MC with other HCV-related cutaneous skin manifestations is low [3–5].