AB0183 T-CELL LARGE GRANULAR LYMPHOCYTE LEUKEMIA IN PATIENTS WITH FELTY’S SYNDROME

Background:Felty’s syndrome (FS) is a rare subtype of seropositive rheumatoid arthritis (RA) and is characterized by neutropenia and splenomegaly. Some researchers suggest that FS and T-cell large granular leukemia (T-LGLL) may have common pathogenetic relationships [1].Objectives:to characterize the clinical and laboratory manifestations of FS, to evaluate the frequency of T-LGLL and Sjogren’s syndrome (SS) in this group of patients with RA, neutropenia and splenomegaly (pts).Methods:We observed 18 pts with ACCP-positive (100%) and RF-positive (94.5%) RA diagnosed according to ACR 2010 criteria, who also had neutropenia and hepatosplenomegaly. All 18 pts underwent T-LGLL diagnostics using blood smears and phenotyping of peripheral lymphocytes for the presence of granular lymphocytes, determination of T-cell clonality using the rearrangement of the γ-chain of the T-cell receptor of lymphocytes by PCR, histological/immunohistochemical study of bone marrow biopsy specimens for the presence of LGL invasion studies, as well as the study of 4 spleens after splenectomy. SS was diagnosed in 8 out of 18 pts (44.5%) according ACR 2016 criteria.Results:Twelve (66.6%) of 18 pts with RA, neutropenia and splenomegaly were diagnosed with T-LGLL, the patients were divided in 2 groups: FS (6 pts) and RA+T-LGL (12 pts). Pts with FS debuted with arthritis of small hand joints, extremely rarely with extra-articular manifestations, mainly at a young age (36.5±3.9 years), and developed neutropenia after 10 years of RA. Pts with T-LGLL debuted at a younger age (39,5±4,5 and 51,5 + 7,8 years, respectively), had a longer course of RA before the development of neutropenia (14.3±3.3 and 5±1.5 years, respectively, p=0.03), and more often had extra-articular manifestations at the onset of the disease. RA activity did not differ between groups and in most cases was characterized by a mild course of articular syndrome. Though the course of RA+T-LGLL group was characterized by low (50%) and moderate (33%) DAS28-CRP activity and active synovitis in only 41.5% of pts, severe joint deformities (stage III and IV) developed in 58.5% of pts. Pts with T-LGLL showed a higher incidence of hepatomegaly (75% and 16.5%, respectively, p=0.02) and more severe neutropenia (p=0.02). The development of severe leukopenia (<1x109) and massive hepatosplenomegaly was observed only in pts with T-LGLL, which required splenectomy in 4 cases. SS was more often detected in the FS group than in the RA+T-LGLL group (83.5% and 25%, respectively, p = 0.02).Conclusion:Clinical and laboratory manifestations of FS and T-LGLL are extremely close, therefore, pts who are diagnosed with FS should be examined to exclude T-LGLL.References:[1]Liu, Xin, and Thomas P Loughran Jr. “The spectrum of large granular lymphocyte leukemia and Felty’s syndrome.” Current opinion in hematology vol. 18,4 (2011): 254-9. doi:10.1097/MOH.0b013e32834760fb.Disclosure of Interests:None declared

Felty’s Syndrome

Felty’s syndrome (FS) is an uncommon subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia with or without splenomegaly. The pathogenesis of neutropenia in FS is still not fully understood, but it is believed that the principal cause is neutrophil survival defect. Autoantibodies against peptidylarginine deiminase type 4 deiminated histones, glucose-6-phosphate isomerase, and eukaryotic elongation factor 1A-1 antigen may contribute to neutropenia development in FS patients. Splenic histology in FS shows non-specific findings and spleen size do not correlate with neutropenia. Cases of T-cell large granular lymphocytic leukemia with low tumor burden in blood and concomitant RA are clinically indistinguishable from FS and present a diagnostic challenge. Examination of T-cell clonality, mutations in signal transducer and activator of transcription 3 gene, and the number of large granular lymphocytes in the blood can establish a correct diagnosis. Optimal approaches to therapy for FS have not been developed, but the use of rituximab seems promising. In this chapter, the epidemiology, pathogenesis, clinical manifestations, differential diagnosis, and treatment options for FS are discussed.

Felty’s syndrome - a rare diagnosis, but one that should not be overlooked

Diogo Souza Domiciano , Rosa Maria Rodrigues Pereira

Analysis of a single-institution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis

T-cell large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder characterized by a persistent increase in the number of large granular lymphocytes (LGLs), neutropenia, and splenomegaly. Clinical manifestations of T-LGLL in the setting of rheumatoid arthritis (RA) are often identical to those in which one would suspect Felty's syndrome (FS). These disorders are distinguished by the presence of T-cell clonality, which is present in T-LGLL but not in FS. Mutations in the signal transducer and activator of transcription 3 (STAT3) and 5b (STAT5b) genes can be used as molecular markers of T-LGLL, but their prevalence in FS is unknown.Eighty-one patients with RA and unexplained neutropenia or/and an increase in the number of LGLs above 2 × 109/L were stratified into RA-associated T-LGLL (N = 56) or FS (N = 25) groups based on the presence or absence of T-cell clonality. STAT3 and STAT5b gene mutations were assessed in each group by means of allele-specific polymerase chain reaction assays. Clinical, immunological, laboratory data and the results of immunophenotyping of blood and bone marrow lymphocytes were also evaluated.Mutations of the STAT3 gene and an increase in the number of LGLs above 2 × 109/L were detected in RA-associated T-LGLL, but not in FS (39% vs 0% and 21% vs 0%, respectively). Mutations in the STAT5b gene were not observed in either group. Expression of CD57, CD16, and CD5−/dim on CD3+CD8+ T-lymphocytes was observed in both RA-associated T-LGLL and FS.STAT3 gene mutations or LGL counts over 2 × 109/L in RA patients are indicative of T-LGLL.

Comparison of somatic STAT3 and STAT5b gene mutations between Felty's syndrome and T-cell large granular lymphocytic leukemia with rheumatoid arthritis

Objectives Approximately 15% of patients with T-cell large granular lymphocytic leukemia (T-LGLL) have rheumatoid arthritis (RA). RA-associated T-LGLL with low large granular lymphocyte counts (aleukemic presentation) and Felty's syndrome (FS) have indistinguishable clinical presentations. These disorders are distinguished by T-cell clonality which is observed in T-LGLL but not in FS. Activating somatic mutations in the signal transducer and activator of transcription 3 (STAT3) and 5 (STAT5b) genes are involved in T-LGLL pathogenesis; however, the prevalence of these mutations in FS is unknown.Methods Based on the rearrangements of T-cell receptor (TCR) gamma and beta genes according to the BIOMED-2 protocol, we examined T-cell clonality in 81 patients with RA and unexplained neutropenia. We stratified these patients by the presence or absence of T-cell clonality, respectively, into 2 groups: RA-associated T-LGLL (56 patients) and FS (25 patients). Allele-specific TaqMan Real-Time polymerase chain reaction assay was employed to detect point somatic mutations in STAT3 and STAT5b genes in each group.Results Mutations of the STAT3 gene were detected in none of the 24 cases of FS and in 22 of 56 cases of RA-associated T-LGLL (39%) (p < 0.001). No mutation of the STAT5b gene was detected in any of the patients in each group.Conclusions Although further data are needed, our results suggest that activating somatic mutations in STAT3 and STAT5b genes are not involved in the pathogenesis of FS.

Porto-Sinusoidal Vascular Disease as the Cause of Portal Hypertension in Felty’s Syndrome: A Case Report and Literature Review

Felty’s syndrome (FS) is a disorder wherein patients with rheumatoid arthritis develop splenomegaly, neutropenia, and in some cases, portal hypertension without underlying cirrhosis. Esophageal variceal bleeding is a complication of FS in patients with portal hypertension. In contrast to splenectomy, few reports exist on the management of variceal bleeding with endoscopic therapy. Moreover, the long-term outcome has not been reported. We present a patient with esophageal variceal bleeding due to portal hypertension secondary to Felty’s syndrome. The patient was followed up for two years postendoscopy intervention. Literature review was performed and the histological features of portal hypertension in FS are discussed. The patient presented with a typical triad of rheumatoid arthritis (RA), splenomegaly, and neutropenia and was diagnosed as Felty’s syndrome in 2012. She was admitted to our hospital in September 2017 for esophageal variceal bleeding. At the time of admission, her liver function test was normal. Abdominal CT showed no signs of cirrhosis and portal vein obstruction. Liver biopsy further excluded diagnosis of cirrhosis and supported the diagnosis of porto-sinusoidal vascular disease (PSVD), which was previously named as noncirrhotic idiopathic portal hypertension (NCIPH). An upper abdominal endoscopy revealed gastric and esophageal varices. A series of endoscopies was performed to ligate the esophageal varices. The patient was followed up for two years and did not show rebleeding. In conclusion, comorbid PSVD might be a cause of portal hypertension in FS patients. The present case had excellent outcome in two years, which supported the use of endoscopic therapy for the management of variceal bleeding in FS patients. Further large prospective study is needed to confirm the findings.