Aristea Papageorgiou

Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome.

AbstractSjögren syndrome (SS) has been associated with the development of non-Hodgkin lymphoma (NHL). From a cohort of 584 SS patients followed in our department from 1980 to 2010, we retrospectively analyzed 53 consecutive NHL cases. Considerations included histologic type, clinical manifestation and NHL staging, treatment, response rate and overall survival (OS), event-free survival (EFS), and standardized mortality ratio (SMR).Mucosa-associated lymphoid tissue (MALT) lymphomas constituted the majority (59%) of NHL subtypes, followed by nodal marginal zone lymphomas (NMZLs) (15%) and diffuse large B-cell lymphomas (DLBCLs) (15%). Six lymphoma patients died during the median follow-up of 40.8 months. The corresponding age/sex-adjusted SMR of SS with and without NHLs versus the general population was 3.25 (95% confidence interval [CI] 1.32–6.76) and 1.08 (95% CI, 0.79–1.45), respectively. A “watch and wait” policy was adopted for 9 patients with asymptomatic localized salivary MALT lymphomas. Eight patients with limited-stage MALT lymphomas and extraglandular manifestations were treated with rituximab. Ten MALT lymphoma patients with disseminated disease received chemotherapy with or without rituximab. The 3-year OS and EFS in patients with MALT lymphomas was 97% and 78%, respectively. Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was the chosen therapeutic intervention for patients with DLBCLs. A successful outcome was recorded for this group, with 100% OS and EFS at 3 years. Patients with NMZLs had a less favorable outcome, with a 3-year OS of 80% and EFS of 53%. Our results describe the course and prognosis of SS-associated NHL and highlight the need for a risk-stratified treatment approach.

Predicting the Outcome of Sjogren’s Syndrome-Associated Non-Hodgkin’s Lymphoma Patients

Background Non-Hodgkins lymphoma (NHL) development in Sjögren’s syndrome (SS) remains a potentially lethal complication and efforts should focus on the identification of predictors that could aid in appropriate therapeutic decisions. Methods In order to identify potential prognostic factors for outcome in SS-associated NHL, we retrospectively analyzed a cohort of 77 patients, diagnosed with NHL according to WHO classification criteria and meeting the American-European Consensus Classification (AECC) criteria for SS and examined the effect of SS-activity (defined as the EULAR SS disease activity index-ESSDAI) in the prognosis of SS-related NHLs, as defined in terms of overall and event-free survivals (OS and EFS). An event was defined as lymphoma relapse, treatment failure, disease progression, histological transformation or death. The effect of NHL clinical and laboratory characteristics was also investigated. Results MALT lymphomas constituted the majority (66.2%) of lymphomas. During the follow-up (median = 57.93 months), the 5-year OS was 90.91% (95% CI: 82.14–95.80%) and the EFS was 77.92% (95% CI: 67.37–85.82%). Patients with high ESSDAI score at lymphoma diagnosis had a greater risk for death (OR = 5.241, 95% CI: 1.034–26.568) or for event (OR = 4.317, 95% CI: 1.146–9.699, p = 0.008). These patients had also significantly worse EFS (HR = 4.541, 95% CI: 1.772–11.637) and OS (HR = 5.946, 95% CI: 1.259–28.077). In addition, post-chemotherapy ESSDAI improvement was significantly lower in patients who had experienced an event (p = 0.005). An unfavorable International prognostic index (IPI) score (high-intermediate/high) was associated with high risk of death and event (OR = 13.867, 95% CI: 2.656–72.387 and OR = 12.589, 95% CI: 3.911–40.526, respectively), worse EFS (log-rank p<0.001, HR = 8.718, 95% CI: 3.477–21.858), as well as with worse OS (log-rank p<0.001, HR = 11.414, 95% CI: 2.414–53.974). After adjustment for identified risk factors, IPI score retained a significant prognostic role following by a strong effect of ESSDAI in survival outcomes. Conclusions At the point of NHL diagnosis, IPI and ESSDAI might be proved useful predictive tools in SS-associated lymphoma prognosis, directing to a more patient-tailored approach.

Clinical picture, outcome and predictive factors of lymphoma in Sjӧgren syndrome

The intrinsic and complex nature of primary Sjӧgrens syndrome (pSS) makes it difficult to identify risk factors that can predict the development and outcome of non-Hodgkins lymphoma (NHL), yet patients at high risk for such complication seem to bear certain clinic-serological characteristics that render them a unique profile. In the last decade, research focusing on B-cell hyperactivity as the hallmark of pSS-related lymphoproliferation has shed light on certain biological and molecular factors that participate in disease evolution and lymphoma development, thus indicating possible predictors of lymphoma development and outcome. In this review, we explore all the available data concerning the clinical picture, risk prognostication and outcome of pSS-associated NHLs.

A BAFF Receptor His159Tyr Mutation in Sjögren's Syndrome–Related Lymphoproliferation

To study the prevalence, clinical associations, and functional implications of the His159Tyr mutation of the BAFF receptor (BAFF‐R) in patients with Sjögrens syndrome (SS).

Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report

BackgroundAdenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment.Case presentationWe present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine.ConclusionsPolymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.

Low miR200b-5p levels in minor salivary glands: a novel molecular marker predicting lymphoma development in patients with Sjögren’s syndrome

Objectives Development of non-Hodgkin’s lymphoma (NHL) is the major adverse outcome of Sjögren’s syndrome (SS) affecting both morbidity and mortality. Preliminary evidence suggested that, although not deregulated compared with sicca controls, miR200b-5p levels are decreased in the minor salivary glands (MSGs) of SS patients with NHL. The aim of the current study was to evaluate the MSG expression of miR200b-5p in SS-associated NHLs and its potential predictive value for the identification of patients with SS susceptible to develop NHL. Methods miR200b-5p expression was investigated in MSG tissues of patients with SS who were at: (A) low risk and did not develop NHL during follow-up (n=27; median follow-up time on biopsy performance, range: 8.9 years, 1.33–14 years), (B) high-risk and diagnosed with NHL during follow-up (prelymphoma; n=17; median follow-up to until lymphoma diagnosis, range: 3.67 years, 0.42–8.5 years) and (C) had NHL (n=35), as well as non-SS sialadenitis controls (sarcoidosis and hepatitis C virus (HCV) infection, four each). The differential miR200b-5p expression, correlations with disease features and its discriminative/predictive value, was evaluated by appropriate statistical approaches. Results The MSG levels of miR200b-5p were significantly downregulated in patients with SS who will develop or have NHL and strongly discriminated (p<0.0001) them from those without lymphoma or non-SS sialadenitis. Furthermore, they were reduced long before clinical onset of lymphoma, did not significantly change on transition to lymphoma and, importantly, were proved strong independent predictors of patients who will develop NHL (p<0.0001). Conclusions These findings support that miR200b-5p levels in MSGs represent a novel predictive and possibly pathogenetic mechanism-related factor for the development of SS-associated NHL, since its expression is impaired years before lymphoma clinical onset.

B-cell chronic lymphocytic leukaemia presenting as lower motor neuron disease and SS

H-ferritin plays the major role in the rapid detoxification of iron and intracellular iron transport, whereas L-ferritin is involved in iron nucleation, mineralization and long-term storage. The expression of ferritin is regulated at both the transcriptional and post-transcriptional levels by iron, hormones, cytokines, including IL-1a and TNF-a, and oxidative stress. Ferritin protects cells against damage due to oxidative stress [8 10]. In the present study, the high level of serum ferritin may be attributable to the intensity of the hypoxia and inflammation caused by systemic activated macrophages in patients with C-ADM-related RP-ILD. In general, DAD is not always associated with significant macrophage presence. However, it has been reported that DAD with a pronounced increase in macrophages was seen in the alveoli and the interstitium of the lung in severe acute respiratory syndrome (SARS) and that direct injury of virus on alveolar epithelium, prominent macrophage infiltration and distinctive fibroblast proliferation may play major roles in the pathogenesis of SARS. We speculated that increasing alveolar macrophages could be found specifically in some kind of DAD, such as SARS and C-ADM-related RP-ILD. We hypothesized that the regulation of activated macrophages may represent a potent therapy for C-ADM-related RP-ILD.

Response to: ‘Is miR200b-5p a new predictor of lymphoma or associated with lymphocytes infiltrate within salivary glands?’ by Nocturne et al

We would like to thank Nocturne et al 1 for their comments regarding our paper,2 giving us the opportunity to clarify possible obscurities and signify the predictive value of low miR200b-5p levels in minor salivary glands (MSGs) for the development of lymphoma in primary Sjogren’s syndrome (pSS). Our findings disclosed that low miR200b-5p levels in MSGs of patients with pSS (1) strongly discriminate patients with SS who will develop or have lymphoma from those who will not, (2) independently predict lymphoma development, (3) are reduced long before the clinical onset of lymphoma, enabling thus, the identification and efficient monitoring of high-risk patients and (4) may have an application in the monitoring of therapeutic response. These findings strongly support the predictive value of miR200b-5p for monitoring lymphoma development in pSS. Furthermore, the simplicity of the detection assay facilitates the easy and reproducible application worldwide. As addressed in the original manuscript, this new biomarker was found to correlate with several histological, clinical and laboratory parameters previously associated with lymphoma development, including biopsy focus score and infiltration by various types by infiltrating cells.2 Although the later associations …

THU0221 Downregulated expression of MIR200B-5P in minor salivary glands (MSG) of patients with sjÖgren's syndrome (SS) associated lymphoma

Background The miRNAs of the miR-200 family are critical regulators of oncogene and tumor suppressor genes. Preliminary data from a limited number of patients with SS-associated lymphoma suggested that the expression of miR200b-5p in MSGs may be downregulated in lymphoma. Objectives To validate whether low miR200b-5p MSG-levels are associated with SS-related lymphomas and if they are deregulated before lymphoma development, suggesting a possible prognostic value. Methods miR200b-5p expression was analyzed by quantitative real-time PCR in total RNA from MSG tissues obtained from 77 SS patients and 9 patients with non-SS sialadenitis associated with sarcoidosis, HCV infection (4 each) or HBV (1 that was also diagnosed with MALT lymphoma). with chronic sialadenitis associated with sarcoidosis, HCV (4-each) or HBV infection (1 who was also diagnosed with MALT-lymphoma). SS-patients included 28 that did not develop lymphoma during follow-up (without lymphoma; median follow-up time since biopsy performance, range: 6yrs, 1–12.75yrs), 18 that developed lymphoma in the future (prelymphoma; median follow-up time till lymphoma diagnosis, range: 3.59yrs, 0.42–8.5yrs, 15-MALT, 2-NMZL, 1-DLCBL) and 32 with SS-associated lymphoma at the time of biopsy (lymphoma; 25-MALT, 2-NMZL, 2-DLCBL, 1-BALT, 1-LP and 1-SLL). In 15 cases, we had sequential MSG-samples from prelymphoma patients who transitioned to lymphoma (12-MALT, 2-NMZL, 1-DLCBL). Results Tukeys multiple comparison revealed that miR200b-5p levels were significantly down-regulated in MSG tissues of prelymphoma and lymphoma SS-patients (mean relative expression±SE: 0.37±0.10 and 0.26±0.06, respectively) compared to SS-patients without lymphoma (0.67±0.07; p≤0.05 and p≤0.0001 for pre- and lymphoma, respectively) or non-SS sialadenitis (0.85±0.28, p≤0.05 and p≤0.01, respectively). Interestingly, low miR200b-5p levels were detected in HBV patient that had MALT lymphoma (0.17). The expression of miR200b-5p was not found to differ between patients with SS without lymphoma and non-SS sialadenitis, or SS-associated pre-lymphoma and lymphoma. The analysis of the 15 cases of SS patients that had sequential samples before and on lymphoma diagnosis revealed that miR200b-5p levels do not significantly change over transition to lymphoma. The miR200b-5p expression levels were negatively correlated with the biopsy focus score (r:-0.6550, p<0.0001), whereas they were not associated with the site or the number of involved sites, the type or the stage of lymphoma. Conclusions The significantly low levels of miR200b-5p in MSG tissues of patients with SS-associated prelymphomas and lymphomas suggest that miR200b-5p deregulation is implicated in SS-lymphomagenesis. The downregulation of miR200b-5p in prelymphoma samples and the lack of change over transition to lymphoma suggest that it can serve as a prognostic marker for future lymphoma development. The prognostic value of miR200b-5p in SS-associated lymphomas, the expressing cell types and affected molecular pathways are under investigation. Acknowledgements Funded by the Hellenic College of Rheumatology Disclosure of Interest None declared

THU0012 BAFF Genetic Variants in Lymphomagenesis Associated with Sjogren’s Syndrome

Background Primary Sjogren’s syndrome (pSS) is complicated by B-cell lymphoma in 5-10% of patients. Several clinical and serological features are proposed as adverse predictors for such complication and define a high risk pSS phenotype. Objectives We aimed to explore whether previously described polymorphisms of the B-cell activating factor (BAFF) as well as mutation of its receptor (BAFF-R) could be related to pSS related lymphomagenesis. Methods Five single nucleotide polymorphisms (SNPs) of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and the rs9514827) and the BAFF-R mutation His159Tyr were evaluated in 111 low risk pSS patients (type II), 82 high risk/ lymphoma patients (type I) and 137 healthy controls (HC) by PCR-based assays. The classification of pSS patients into type I and II was based on the presence or absence of risk factors or lymphoma development, respectively. Genotype and haplotype analysis was performed for all variants in the pSS groups. Since the rs1041569 SNP was not in Hardy-Weinberg equilibrium in the HC group (p<0.001), haplotypic analysis was performed in the remaining four out of the five SNPs tested when comparisons with HC individuals were performed. Results The high risk pSS group was characterized by higher frequency of the minor T allele of the rs9514828 BAFF polymorphism compared to HC. Compared to the low risk pSS patients but not the HC, the high risk pSS group exhibited lower frequencies of the AA genotype of the rs12583006 polymorphismas well as the TACAC and TACC haplotypes and higher frequency of the TTTC haplotype. The low risk pSS group exhibited higher frequency of the minor A allele and AA genotype of the rs12583006 variant compared to HC. Both pSS groups were characterized by increased frequency of the haplotype TATT and GTTC and decreased frequency of the TTCT when compared to HC. A significantly increased prevalence of the mutation of BAFF-R His159Tyr was observed in type I pSS patients compared to low risk type II pSS patients (p=0.035) and HC (p=0.003). Such difference was not detected between low risk type II pSS and HC (p=0.47). Conclusions Taken together, these findings suggest the implication of the host’s genetic background in pSS related lymphomagenesis. The interaction of pSS related BAFF gene haplotypes together with distinct BAFF genetic variants appears to contribute to this complication. Disclosure of Interest None Declared