Page 48 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
chronic recurrent urticarial rash. The Strasbourg criteria outline additional minor criteria of recurrent fever, abnor- mal bone remodeling with or without bone pain, neutro- philic dermal infiltrate, leukocytosis and elevated C-reactive protein.61 Around 300 cases have been reported to date. It is underdiagnosed and, despite its rarity, is im- portant to identify as specific treatment can significantly improve quality of life.62
Clinical characteristics
Of 281 cases in the largest case series, fever was present in 72%, anemia in 63%, arthralgia in 68%, bone pain in 55%, lymphadenopathy in 26%, and liver or spleen enlargement and neuropathy in less than 10%.63 In smaller series fatigue and weight loss were documented in up to around 50% of cases.62,64 The urticarial rash can cover any part of the body, but face, palm and sole involvement is infrequent, as is in- tense pruritis. Skin lesions typically resolve within hours.65 The time from onset of symptoms to diagnosis is long, at a median of 5 years and may be as long as 20 years.62
The monoclonal gammopathy is almost always IgMk. Bone
marrow involvement is minimal, being around 4% in one
series, and a median M-protein concentration of 6 g/L has
been documented.62 In the largest case series, 63% of the
281 bone marrow samples were reported as normal.63 The
MYD88L265P mutation was detected in the peripheral blood
of 30% of 30 patients.66 The authors suggested that the
presence of this mutation may correlate with the risk of
WM, although the mutation detection rate may have been
underestimated as the sensitivity of detecting peripheral
blood B-cell clones may be hampered when the level of
disease burden is low. The frequency of the MYD88L265P
mutation in bone marrow has not been studied. Chronic
inflammation may lead to AA amyloidosis in 2% of cases
of Schnitzler syndrome. At a median of 8 years, the rate
of evolution to lymphoma is 20%, which is in line with pro-
gression in unselected cohorts of patients with IgM MGUS.61,63
Schnitzler syndrome is associated with cytokine dysregu- lation. It bears close phenotypic resemblance to an in- herited disorder, cryopyrin-associated periodic syndrome, caused by gain-of-function mutations in the NLRP3 gene. This results in upregulation of interleukin (IL)-1b produc- tion and has informed therapeutic options in Schnitzler syndrome, by targeting IL-1b.
Diagnostic workup
There is no single diagnostic test and the diagnosis is made based on clinical characteristics. Differential diag- noses for the rash and fever include adult-onset Still dis- ease, systemic lupus erythematosus, acquired C1 esterase deficiency, cryopyrinopathies and cryoglobulinemia (cold- induced urticaria). Skin biopsy reveals a neutrophilic urti- carial dermatosis without features of vasculitis.
Treatment
Treatment is aimed at reducing the considerable associ- ated morbidity related to rash, fever and joint and bone pain. Symptoms respond poorly to historic first-line agents including antihistamines, nonsteroidal anti-inflam- matory drugs, dapsone and colchicine.65 The use of high- dose steroids, although moderately effective, is limited by long-term toxicities.
Without anti-IL treatment, morbidity is high. In a series of 21 patients, all had almost daily symptoms with a pro- found effect on their quality of life.64 Anti-IL-1 agents, such as anakinra, canakinumab, and rilonacept, have all been used but not directly compared. Anakinra is the agent with which experience is greatest and is the treatment of choice. It is a recombinant IL-1-receptor antagonist and has the greatest efficacy (94% efficacy in 86 cases),63 with durable responses (83% complete responses after a median of 36 months).67 Anakinra has a half-life (t1/2) of 4- 6 hours and provides impressive control of all signs within hours, normalization of C-reactive protein levels and ab- rogation of the risk of AA amyloidosis.64 Nonetheless, pa- tients require continuous daily injections and relapse occurs after treatment discontinuation. Canakinumab, an IL-1b monoclonal antibody, is long-acting (t1/2 21-28 days) and is, therefore, administered less frequently. Data from phase II, placebo-controlled, randomize trials have dem- onstrated its efficacy. For 17 patients in a long-term study, clinical efficacy was greatest when patients injected ca- nakinumab as needed. A systematic review of 34 patients showed that 59% achieved complete responses.68 Rilon- acept, an IL-1 binding and neutralizing fusion protein, achieved near complete responses in 50% of cases.69 To- cilizumab, an IL-6 receptor antagonist, has been beneficial in three patients who were refractory to anakinra.70 Cyclophosphamide, rituximab and ibrutinib have achieved responses when treatment was given for overt lymphoma but have been largely ineffective or untested in the absence of lymphoma.65 There is little to support the notion that anti-IL therapy affects the underlying B- cell clone.
Conclusion
We have discussed a range of distinctive entities of IgM MGCS, including their specific clinical characteristics, underlying clonal profile, and diagnostic workup as well as treatment considerations. Careful evaluation of the presenting features and thorough interrogation of the underlying clone are critical. Determining the nature of either a mature B-cell derived clone or plasma cell clone will have management implications. There is an IgMk pre- dominance in all cases except IgM-associated AL amyloi- dosis. The indication for treatment is dictated by the
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