Neurophysiological and clinical responses to rituximab in patients with anti-MAG polyneuropathy

Objectives

Rituximab treatment has shown clinical improvement in anti-myelin associated glycoprotein (MAG) polyneuropathy. We analyzed scores of clinical scales and the most sensitive electrophysiological parameters before and after immunomodulating treatment with rituximab in a group of patients affected by anti-MAG demyelinating polyneuropathy.

Methods

Clinical scores, the percentage of CD20 B-lymphocytes, anti-MAG antibody titers and electrophysiological data in 7 patients with anti-MAG polyneuropathy were analyzed. The patients were examined before a cycle with rituximab, 6, 12 and 24 months after the end of the treatment. Two patients were treated with rituximab additional cycles and re-evaluated 48 months after the first treatment.

Results

There were no evident correlation between anti-MAG serum antibody titers or clinical scales and electrodiagnostic data. Significant decrease in the proportion of CD20 B-lymphocytes was observed. Significant anti-MAG antibodies titers reduction was detected after re-treatment. At follow-up, pinprik sensation and two point discrimination presented a significant improvement compared with the score before treatment.

Conclusions

In our patients, rituximab did not improve any electrophysiological data. No correlation with anti-MAG serum antibodies course was found. With rituximab only pin sensibility improved.

Significance

Rituximab re-treatment significantly reduces anti-MAG serum antibodies titers but improves only small fibers sensibility.     

Evidence of cells bearing interleukin-2 receptor at sites of disease activity in sarcoid patients.

The frequency of cells reactive with anti-Tac monoclonal antibody (MoAb), which recognizes the interleukin-2 (IL-2) receptor, has been evaluated in cell suspensions from peripheral blood and bronchoalveolar lavage (BAL), and in frozen sections from involved tissues in 18 patients with active sarcoidosis. Peripheral blood lymphocytes of sarcoid patients do not bear Tac determinant and reduced numbers of Tac+ cells are inducible following PHA stimulation. On the other hand, significant numbers of lymphocytes reactive with anti-TacMoAb are present in the cells obtained from the BAL and a number of Tac+ cells infiltrate the lung, lymph node and conjunctiva. The finding of Tac+ cells in the BAL fluid and in other organs in patients with sarcoidosis provides evidence that some T cells in these involved tissues have the characteristics of IL-2 responder cells and thus the potential to absorb IL-2, supporting the hypothesis that T lymphocytes replicate in situ at sites of disease activity.     

Detection of Chlamydophila pneumoniae DNA in peripheral blood mononuclear cells of blood donors in the north-east of Italy

Recent studies have implicated Chlamydia pneumoniae (now Chlamydophila pneumoniae) in the pathogenesis of atherosclerosis and demonstrated its presence within human peripheral blood mononuclear cells (PBMCs). In this study the presence of C. pneumoniae DNA was assessed, using nested PCR, in PBMCs from 169 active blood donors as a function of age, of specific antibodies and C-reactive protein. The results obtained demonstrated a high degree of global positivity (46.15%), which was higher in females (52%) than in males (43.7%). Seroepidemiological studies showed a high percentage of positivity both in subjects positive by PCR (65.91%) and negative by PCR (71.74%). The clinical implication of such finding are under study.     

NKG2A inhibits NKG2C effector functions of γδ T cells: implications in health and disease

The CD94/NKG2 complex is expressed on T and NK lymphocytes. CD94 molecules covalently associate to activating or inhibitory NKG2 molecules, and their expression finely tunes cell responses. Human γδ T cells express several NKRs. Expression of these receptors is confined to the cytolytic Vδ2 subset, which coexpresses the FcγRIII CD16 and CD45RA and has been defined as Vγ9Vδ2 T(EMRA) cells. We show that the CD94/NKG2C complex, associated with KARAP/DAP12, is fully functional in γδ T cells, as determined by measuring IFN-γ production, T cell proliferation, and cytolytic activity by γδ lymphocytes. In contrast, NKG2A expression was found on all γδ T cell memory subsets, suggesting a crucial role of the inhibitory signal provided by this receptor on γδ T cell responses. Moreover, we found Vγ9Vδ2 T(EMRA), NK, and CD8+ αβ T cells coexpressing NKG2A and NKG2C receptors. Functional experiments showed that the inhibitory signal mediated by the NKG2A receptor prevails when double-positive cells are activated. Finally, NKG2A expression on γδ LDGL correlates with asymptomatic pathology, even in the presence of NKG2C coexpression, whereas in symptomatic patients affected by severe disease, the inhibitory NKG2A receptor is absent, and a variety of activatory NKRs was found. We propose that the silent behavior of γδ cells in LDGL patients is a result of effective inhibitory HLA class I receptors.     

T-cell type lymphoproliferative disease of granular lymphocytes (LDGL) is equipped with a phenotypic pattern typical of effector cytotoxic cells

By analyzing the expression of several cytotoxic markers, killer-immunoglobulin-like receptors (KIRs), CD94/CD159, CD314 and natural cytotoxicity receptors (NCRs), in 22 CD3+ lymphoproliferative disease of granular lymphocyte (LDGL) patients we investigated whether granular lymphocytes (GLs) displayed the phenotype of fully differentiated cytotoxic cells. Our results demonstrate that GLs express a pattern consistent with fully differentiated CTLs. KIRs are expressed only in a fraction of patients (7/22), as is CD94/CD159 (5/22). In conclusion, GLs in CD3+ LDGL patients typically show the phenotype of fully differentiated CTL, whereas the expression of NK receptors does not represent a common feature of the proliferating clone.     

Primary mediastinal large B-cell lymphoma: results of intensive chemotherapy regimens (MACOP-B/VACOP-B) plus involved field radiotherapy on 53 patients. A single institution experience

PURPOSE: The optimal therapy for primary mediastinal large B-cell lymphoma (PMLBCL) remains undefined. The superiority of intensive chemotherapy regimens (Methotrexate, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin [MACOP-B]/Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin [VACOP-B]) over Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP)-like chemotherapy is upheld by some authors. The role of radiotherapy is still debated. In the absence of randomized trials, we report clinical findings and treatment response in 53 consecutive patients treated with intensive chemotherapy and mediastinal involved-field radiation therapy (IFRT). METHODS AND MATERIAL: Fifty-three consecutive patients with PMLBCL were retrospectively analyzed. Planned treatment consisted of induction chemotherapy (I-CT; Prednisone, Methotrexate, Doxorubicin, Cyclophosphamide, Etoposide-Mechloroethamine, Vincristine, Procarbazine, Prednisone [ProMACE-MOPP] in the first 2 patients, MACOP-B in the next 11, and VACOP-B in the last 40) followed by IFRT. Planned treatment was concluded in 43 of 53 patients; in 10 patients, I-CT was not immediately followed by IFRT. Among these 10 patients, 6 received high-dose chemotherapy (HD-CT) followed by IFRT, 2 received HD-CT, and 2 received no further treatment. RESULTS: After a median follow-up of 93.9 months (range, 6-195 months), 45 of 53 patients (84.9%) were alive without disease. Eight patients died: 7 of PMLBCL and 1 of toxicity during HD-CT. The 5-year disease-free survival (DFS) and overall survival rates were 93.42% and 86.6%, respectively. The response rates after I-CT were complete response (CR) in 20 (37.73%) and partial response (PR) in 30 (56.60%); 3 patients (5.66%) were considered nonresponders. Among patients in PR after chemotherapy, 92% obtained a CR after IFRT. CONCLUSIONS: Our report confirms the efficacy of intensive chemotherapy plus mediastinal IFRT. IFRT plays a pivotal role in inducing CR in patients in PR after chemotherapy.     

Pachymeningeal involvement in POEMS syndrome: MRI and histopathological study

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare plasma cell disease. Vascular endothelial growth factor (VEGF) seems to play a pathogenic role. Peripheral neuropathy is the main neurological feature. Cranial pachymeningitis has occasionally been reported, but no histopathological studies have been performed. The authors extensively evaluated the central nervous system MRI in 11 patients (seven men, four women; mean age at diagnosis 54.45 years) with POEMS syndrome. In two patients, meningeal histopathology with staining for VEGF and VEGF receptor was performed, and pachymeningeal involvement characterised at histopathological, immunohistochemical and confocal microscopy levels. Nine patients presented with cranial pachymeningitis. One patient suffered from migraine, and none complained of cranial nerve palsies or visual loss. None showed any MRI signs of spinal pachymeningitis. No correlation was found with disease duration and VEGF serum level. Histopathology showed hyperplasia of meningothelial cells, neovascularisation and obstructive vessel remodelling, without inflammation. VEGF and VEGF receptor were strongly coexpressed on endothelium, smooth-muscle cells of arterioles and meningothelial cells. In conclusion, POEMS patients present a high prevalence of meningeal involvement. The histological changes, different from those present in chronic pachymeningitis of other aetiology, suggest a possible VEGF role in the pathogenesis of the meningeal remodelling.     

Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia

Clonal disease of large granular lymphocytes (LGLs) may arise from either CD3+ LGLs (LGL leukemia) or CD3- LGLs (natural killer [NK] cell leukemia). Other patients have chronic LGL proliferations that cannot be proven to be clonal (lymphoproliferative disease of granular lymphocytes [LDGL]). It was recently shown that clonally expanded CD3- LGLs from Japanese patients contain Epstein-Barr virus (EBV) DNA sequences, arguing for a direct causative role for EBV in NK cell leukemia. The aggressive clinical course and other clinical features of these Japanese patients differ markedly from the clinical features of LGL leukemia and CD3- LDGL patients in the United States and Europe, suggesting different pathogenic mechanisms. Therefore, we performed serologic and DNA hybridization studies for EBV in 31 patients from the United States and Europe (18 with LGL leukemia and 13 with chronic CD3- LDGL). All patients had serologic evidence for past infection with EBV. We did not detect EBV DNA sequences in peripheral blood mononuclear cell DNA from any of these patients in Southern blot hybridization analyses. EBV DNA sequences were detected after polymerase chain reaction amplification of peripheral blood mononuclear cell DNA in only 2 of 18 LGL leukemia patients and 4 of 13 chronic CD3- LDGL patients. These results argue against a direct causative role for EBV infection in LGL leukemia or chronic CD3- LDGL occurring in the United States and Europe.     

Pachymeningeal involvement in POEMS syndrome: dramatic cerebral MRI improvement after lenalidomide therapy

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare multisystemic disease associated with plasma cell dyscrasia and increased serum or plasma vascular endothelial growth factor (VEGF) levels, the latter likely responsible for several POEMS syndrome manifestations. Whereas peripheral neuropathy is the main neurological feature and a mandatory diagnostic criterium, central nervous system involvement is less common except for papilledema and stroke. We recently reported the frequent occurrence at brain MRI of cranial pachymeningeal involvement ina series of POEMS syndrome patients. Meningeal histopathology revealed hyperplasia of meningothelial cells, neovascularization, and obstructive vessel remodeling without inflammatory signs pointing to a role of VEGF in the meningeal manifestations. Here, we report the dramatic pachymeningeal improvement in patients undergoing lenalidomide therapy. These findings support the therapeutic role of lenalidomide and might shed further light on the pathophysiology of the disease