Abraham C. J. Stork

Rapid worsening of IgM anti-MAG demyelinating polyneuropathy during rituximab treatment

Dear Editor, There are no proven treatments for polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (anti-MAG) antibodies (Lunn and Nobile-Orazio, 2012). Two recent randomized trials (RCTs) comparing rituximab to placebo failed to demonstrate improvement on the primary endpoints (Dalakas et al., 2009; Leger et al., 2011). In these trials, treatment with rituximab was safe and well tolerated. The total published experience with rituximab in anti-MAG polyneuropathy encompasses fewer than 100 patients (Renaud et al., 2003; RojasGarcia et al., 2003; Niermeijer et al., 2009). Because rituximab is at best effective only in a small subgroup of patients, even fairly rare side effects would be relevant to the decision to prescribe it for antiMAG neuropathy. Some side effects could have been missed because of the low numbers of patients in published series. We report three patients with IgM monoclonal gammopathy-associated polyneuropathy and anti-MAG antibodies who rapidly worsened within weeks after the start of rituximab treatment. One patient presented with mild weakness of the dorsiflexors of foot and toes (Medical Research Council [MRC] grade 4), glove and sock-patterned hypoesthesia, and sensory ataxia, which had developed slowly over the previous 2 years. His anti-MAG titer before treatment was 7,180 BTU (Buehlmann Titer Units, normal values below 2,000 BTU), total serum IgM was 13 g/l, and the M protein was 9 g/l. Nerve conduction studies showed demyelination in nerves of both arms and legs, distally more than proximally, as well as axonal loss, more pronounced in the nerves of the legs than in those of the arms (Table 1). After the second of a planned four weekly rituximab infusions (375 mg/m2), he developed proximal weakness and severe progression of the distal weakness in the legs

Complement activity is associated with disease severity in multifocal motor neuropathy

Objective: To investigate whether high innate activity of the classical and lectin pathways of complement is associated with multifocal motor neuropathy (MMN) and whether levels of innate complement activity or the potential of anti-GM1 antibodies to activate the complement system correlate with disease severity. Methods: We performed a case-control study including 79 patients with MMN and 79 matched healthy controls. Muscle weakness was documented with Medical Research Council scale sum score and axonal loss with nerve conduction studies. Activity of the classical and lectin pathways of complement was assessed by ELISA. We also determined serum mannose-binding lectin (MBL) concentrations and polymorphisms in the MBL gene (MBL2) and quantified complement-activating properties of anti-GM1 IgM antibodies by ELISA. Results: Activity of the classical and lectin pathways, MBL2 genotypes, and serum MBL concentrations did not differ between patients and controls. Complement activation by anti-GM1 IgM antibodies was exclusively mediated through the classical pathway and correlated with antibody titers (p < 0.001). Logistic regression analysis showed that both high innate activity of the classical pathway of complement and high complement-activating capacity of anti-GM1 IgM antibodies were significantly associated with more severe muscle weakness and axonal loss. Conclusion: High innate activity of the classical pathway of complement and efficient complement-activating properties of anti-GM1 IgM antibodies are determinants of disease severity in patients with MMN. These findings underline the importance of anti-GM1 antibody–mediated complement activation in the pathogenesis and clinical course of MMN.

Prevalence, specificity and functionality of anti-ganglioside antibodies in neuropathy associated with IgM monoclonal gammopathy

IgM antibodies against gangliosides and their complexes were studied in sera from 54 patients with polyneuropathy and IgM monoclonal gammopathy (IgM-PNP) without anti-MAG antibodies. Anti-ganglioside antibodies were found in 19 (35%) patients. Five (9%) patients had antibodies against ganglioside complexes. IgM antibodies against gangliosides activated complement in vitro. Light chain usage was restricted to kappa or lambda in most, but not all patients. In conclusion, anti-ganglioside antibodies in IgM-PNP are common, display pathogenic properties and do not always arise from a monoclonal B cell proliferation.

Fcγ receptor IIIA genotype is associated with rituximab response in antimyelin-associated glycoprotein neuropathy

Background Treatment with anti-B cell antibody rituximab may ameliorate the disease course in a subgroup of patients with polyneuropathy associated with IgM monoclonal gammopathy. Polymorphisms of leukocyte IgG receptors (FcγR) that influence efficiency of antibody-dependent cell-mediated cytotoxicity determine rituximab efficacy in patients with lymphoma and autoimmune disease. Objective To investigate the association of FcγRIIA and FcγRIIIA polymorphisms with the response to rituximab treatment in a cohort of patients with polyneuropathy associated with IgM monoclonal gammopathy (PNP-IgM) with and without antimyelin-associated glycoprotein antibodies. Methods We determined FcγRIIA-R/H131 and FcγRIIIA-V/F158 genotypes in 27 patients with PNP-IgM using allele-specific PCR and Sanger sequencing. Results The FcγRIIIA-V/V158 genotype was associated with functional improvement (p=0.02) after 1 year. Conclusions FcγRIIIA polymorphisms are potential biomarkers for response to rituximab treatment in polyneuropathy associated with IgM monoclonal gammopathy.

Diagnostic markers for CNS lymphoma in blood and cerebrospinal fluid: a systematic review

Diagnosing central nervous system (CNS) lymphoma remains a challenge. Most patients have to undergo brain biopsy to obtain tissue for diagnosis, with associated risks of serious complications. Diagnostic markers in blood or cerebrospinal fluid (CSF) could facilitate early diagnosis with low complication rates. We performed a systematic literature search for studies on markers in blood or cerebrospinal fluid for the diagnosis CNS lymphoma and assessed the methodological quality of studies with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS‐2). We evaluated diagnostic value of the markers at a given threshold, as well as differences between mean or median levels in patients versus control groups. Twenty‐five studies were included, reporting diagnostic value for 18 markers in CSF (microRNAs ‐21, ‐19b, and ‐92a, RNU2‐1f, CXCL13, interleukins ‐6, ‐8, and ‐10, soluble interleukin‐2‐receptor, soluble CD19, soluble CD27, tumour necrosis factor‐alfa, beta‐2‐microglobulin, antithrombin III, soluble transmembrane activator and calcium modulator and cyclophilin ligand interactor, soluble B cell maturation antigen, neopterin and osteopontin) and three markers in blood (microRNA‐21 soluble CD27, and beta‐2‐microglobulin). All studies were at considerable risk of bias and there were concerns regarding the applicability of 15 studies. CXCL‐13, beta‐2‐microglobulin and neopterin have the highest potential in diagnosing CNS lymphoma, but further study is still needed before they can be used in clinical practice.

Classical and lectin complement pathway activity in polyneuropathy associated with IgM monoclonal gammopathy

Polyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is a slowly progressive, sensorimotor neuropathy. It is assumed that complement activation contributes to IgM-PNP pathogenesis. We investigated whether innate differences in complement activity of the classical and mannose binding lectin (MBL) pathways are associated with IgM-PNP or its severity. We measured complement activity using ELISA and determined MBL serumc oncentrations and MBL gene polymorphisms in 83 patients and 83 healthy controls. We did not observe differences between IgM-PNP patients and healthy controls nor associations with different disease severities. Differences in innate complement activity are not likely to explain susceptibility to or severity of IgM-PNP.