Page 42 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
ponent possessing avidity for the polyclonal component of a different isotype (most frequently IgM with rheuma- toid factor activity, the ability to bind to the Fc portion of IgG). The rheumatoid factor detected in type II cryoglobu- linemia is a monoclonal IgMk in over 85% of cases.26 While most cases of type II cryoglobulinemia are related to hepatitis C, here we focus on those related to monoclonal IgM.
Clinical characteristics
Data characterizing patients with monoclonal IgM and cryoglobulinemia are scant. The clinical characteristics have been gleaned from retrospective cohorts grouping together IgG and IgM cases. The largest series reported over 1,600 unselected patients with cryoglobulinemia. Nine percent had type I cryoglobulinemia and 47% had type II.26 The only series characterizing the symptoms of IgM type I cryoglobulinemia included 26 patients; 35% had underlying MGUS, 35% had WM and 31% had non-Hodgkin lymphoma.27 The incidence is likely underestimated as most literature reports are derived from centers that do not routinely screen for cryoglobulinemia upon recognition of an IgM clone.3
A wide spectrum of symptoms may be present (Figure 2). The symptoms of type I cryoglobulinemia are caused by vascular occlusion whereas those of type II are due to small and medium vessel vasculitis. Cutaneous involve- ment is most frequent in type I cryoglobulinemia. Cut- aneous manifestations range from purpura, livedo reticularis, acrocyanosis to cold urticaria, digital ischemia, ulcers and necrosis. Among 26 patients, 46% had skin in- volvement and less than 10% had peripheral neuropathy (8%), arthralgia (8%) or renal involvement (4%).27 Other studies found peripheral neuropathy in a higher proportion of IgM cases, mainly sensory neuropathy (70%), but sen- sorimotor polyneuropathy and mononeuritis multiplex were also seen.28 Central nervous system involvement is rare unless due to hyperviscosity.29 No studies have re- ported specific presenting features of type II cryoglobu- linemia in patients with circulating monoclonal IgM. In a mixed cohort of 203 type II patients with an underlying hematologic disorder in 23%, skin manifestations pre- dominated (85%). Compared to type I cryoglobulinemia there was a greater proportion of peripheral neuropathy (56%), joint (41%), renal (38%), gastrointestinal (6%) and pulmonary (2%) involvement. Hyperviscosity is almost never seen.
Diagnostic workup
Laboratory testing is critical as a minimal amount of measurable cryoglobulin may cause symptoms. In one study in which two-thirds of patients were symptomatic, 58% of the IgM type I cryoglobulinemia cases had a cryo- crit of <1%, which was a significantly greater proportion
than in IgG cryoglobulinemia.27 Symptoms do not correlate with the cryocrit and depend instead on the temperature at which precipitation occurs.29 Accurate detection of cryoglobulins requires samples to be taken into pre- warmed tubes which must not be allowed to cool below 37˚C until the serum is separated, as the cryoglobulin may precipitate and not be detected. Similarly, a false-negative M-protein result may result from the same process. In a French study, 9% of cases with negative results were posi- tive on a follow-up test.26 Care must be taken with pre- analytical variables; repeat testing of M-protein and cryoglobulins is indicated if the clinical suspicion is high. Increased plasma viscosity in the absence of a high IgM should trigger clinicians to consider cryoglobulinemia.
A tissue biopsy may be indicated to identify renal or nerve involvement and distinguish it from other causes. Intra- vascular precipitation of IgM triggered by exposure to cold results in thrombotic obstruction and ischemia in small vessels as evidenced on biopsy in type I cryoglobulinemia. Leukocytoclastic vasculitis may be evident in type II cryo- globulinemia.
Treatment
A treatment approach is outlined in Figure 2. There is a paucity of data to guide optimal management. Mild symp- toms may abate with cold prevention. Rapidly progressive nephropathy and neuropathy have been reported at vari- ous stages of the disease course, so careful monitoring is recommended.28 When cryoglobulinemia is tested for ex- clusively in symptomatic patients, treatment is com- menced for cryoglobulinemia-related symptoms in the majority (80%).30 Response assessment is not standard- ized and mostly focuses on symptomatic improvement.27 The cryocrit at treatment initiation, change in cryocrit and time to nadir were predictive of symptom improvement in a mixed cohort of patients with IgG and IgM type I cryo- globulinemia. The underlying diagnosis of MGUS or lym- phoma did not affect symptom improvement.30 Treatment regimens are heterogeneous and have been used in small series of patients. Plasma exchange may temporize critical symptoms and is used in up to a third of all cases of cryoglobulinemia in mixed cohorts; a warm- ing procedures should be in place.30-32 In the absence of robust evidence, definitive treatment should be directed at the underlying clone. Steroids (1 mg/kg) are used in up to 90% of all cases of cryoglobulinemia, often together with immunosuppression.31,32 Rituximab combinations or bortezomib-based treatment are typically employed27 with symptomatic responses in approximately 80% of cases.27,29,31 Disappearance of cryoglobulin may be seen in half of patients.30 Transient disease exacerbation (an ‘IgM flare’) has been described following the use of rituximab in type I cryoglobulinemia with a low disease burden (<10% infiltrate)33 and in type II cryoglobulinemia.34 Some
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