Prevalence of STAT3 mutations in patients with rheumatoid arthritis-associated T-cell large granular lymphocytic leukaemia and Felty syndrome.

OBJECTIVES: Neutropenia is a key presentation of Felty syndrome (FS) and rheumatoid arthritis (RA)-associated T-cell large granular lymphocytic (T-LGL) leukaemia. Clonal rearrangement of T-cell receptor (TCR) gene supports the diagnosis of T-LGL leukaemia but not FS. Mutations in the signal transducer and activator of transcription 3 (STAT3) gene are highly specific for T-LGL leukaemia, but their prevalence in FS remains poorly clarified. METHODS: The study included 100 patients with RA and unexplained neutropenia. TCR rearrangements were examined in blood (100 cases), bone marrow (47 cases), and spleen (12 cases) using the BIOMED-2 protocol. Patients were stratified into RA-associated T-LGL leukaemia cohort if a clonal TCR rearrangement was identified in any of the tested patient samples, and into FS cohort in other cases. Mutations in the STAT3 were examined using next-generation sequencing (NGS) technology in blood (100 cases), bone marrow (37 cases), and spleen (7 cases). RESULTS: STAT3 mutations were identified in 71% (49/69) patients with RA-associated T-LGL leukaemia and in 10% (3/31) patients with FS (p=4.7×10-8). Three samples from the RA-associated T-LGL leukaemia cohort and 5 samples from the FS cohort had STAT3 mutations in the absence of clonal TCR rearrangement. CONCLUSIONS: The results suggest that STAT3 mutations are significantly less common in FS than in RA-associated T-LGL leukaemia. Moreover, NGS can detect clones undetectable by fragment analysis. We speculate that in patients with RA and neutropenia, the detection of STAT3 mutations can point to T-LGL leukaemia even in the absence of clonal TCR rearrangement.

A case of filgrastim-induced neutrophilic dermatosis of the dorsal hands in a patient with Felty Syndrome.

Neutrophilic dermatosis of the dorsal hands (NDDH) is a variant of Sweet syndrome that presents with erythematous bullae, papules/plaques, or pustules on the dorsal hands. It is most commonly associated with hematologic and solid organ malignancies, though cases of NDDH associated with inflammatory bowel disease, rheumatologic disorders, and medication exposure have also been described in the literature. Felty syndrome is a rare complication of long-standing rheumatoid arthritis characterized by neuropathy, splenomegaly, and neutropenia. Granulocyte colony stimulating factors (e.g., filgrastim) can be utilized to rescue the neutropenia observed in Felty syndrome, but this treatment may subsequently cause Sweet syndrome. Herein, we present a 64-year-old man with Felty syndrome and a complex medical history who presented with sudden onset, painful blisters located on the dorsal and palmar aspects of his bilateral hands. Given the patient's past medical history, a broad differential diagnosis, including disseminated fungal and viral infection was initially considered. A punch biopsy of the skin lesion disclosed neutrophilic dermatosis, which together with laboratory data satisfied the von den Driesch criteria for Sweet syndrome. As the lesions were localized exclusively on the patient's hands, the qualification of NDDH was also endorsed.

Severe alveolar bone resorption in Felty syndrome: a case report.

BACKGROUND: Felty syndrome is defined by three conditions: neutropenia, rheumatoid arthritis, and splenomegaly. Neutropenia associated with pancytopenia may further affect the dental condition of a patient. Periodontal treatment and surgery in patients with Felty syndrome necessitates cooperation with a hematologist. Here we present a case of a patient with Felty syndrome who was initially referred to the oral surgery hospital attached to the School of Dentistry for extensive periodontitis. She was effectively treated in collaboration with the hematology department. CASE PRESENTATION: A 55-year-old Asian woman visited our department with concerns of worsening tooth mobility, discomfort, and spontaneous gingival bleeding. Initial periodontal examination revealed generalized severe periodontitis (Stage IV Grade C) resulting from leukopenia/neutropenia and poor oral hygiene. A thorough treatment strategy involving comprehensive dental procedures, such as multiple extractions and extensive prosthetic treatment, was implemented. Following the diagnosis of Felty syndrome, the patient was started on treatment with oral prednisolone 40 mg/day, which effectively controlled the disease. Furthermore, there was no recurrence of severe periodontitis after the periodontal treatment. CONCLUSIONS: Dentists and physicians should be aware that immunocompromised individuals with pancytopenia and poor oral hygiene are at risk of developing extensive periodontitis. If their susceptibility to infection and pancytopenia-related bleeding can be managed, such patients can still receive comprehensive dental treatment, including teeth extractions and periodontal therapy. Cooperation among the dentist, hematologist, and patient is necessary to improve treatment outcomes and the patient's quality of life.

The spectrum of somatic mutations in large granular lymphocyte leukemia, rheumatoid arthritis, and Felty's syndrome.

T cell large granular lymphocyte leukemia (T-LGLL) is an interesting case at the intersection of autoimmunity and cancer. In T-LGLL, T cells with somatic pathogenic mutations (mainly in STAT3) are linked to rheumatoid arthritis (RA) and neutropenia. A rare subtype of RA, Felty's syndrome, exhibits overlapping clinical features and comparable frequencies of activating STAT3 mutations in T cells as T-LGLL, which hints at a potential T-LGLL-Felty's syndrome-RA axis. Somatic mutations could shed light on the unexplained pathologies of these disorders. However, the causality of somatic mutations-do somatic mutations in immune cells cause inflammation, or does prolonged inflammation predispose to mutagenesis-remains unanswered. This review will focus on the recent advances in understanding somatic mutations in T-LGLL and related autoimmune conditions as a master regulatory network that sustains lymphoproliferation and inflammation.

Diagnosis and Management of a Chronic Lower-Limb Wound in a Patient with Felty Syndrome.

ABSTRACT: The authors report the case of a 55-year-old patient with a chronic lower-limb wound thought to be secondary to vasculitis. This case illustrates the importance of maintaining a high index of suspicion for vasculitic ulcers in patients with autoimmune disease. Management considerations in this context are also discussed.

[Visceral leishmaniasis mimicking Felty's syndrome in rheumatoid arthritis treated with methotrexate and etanercept]. / Imitation eines Felty-Syndroms durch eine viszerale Leishmaniasis bei rheumatoider Arthritis unter Therapie mit Methotrexat und Etanercept.

Visceral leishmaniasis (VL) is a chronic parasitic disease caused by pathogens of the genus Leishmania, which can mimic numerous diseases. The leading symptoms of VL (splenomegaly, pancytopenia, fever) can be misinterpreted, especially if autoantibodies are detected, and lead to the misdiagnosis of an underlying rheumatic disease (e.g. systemic lupus erythematosus, Felty's syndrome). Proinflammatory cytokines such as tumour necrosis factor alpha (TNF-α) play an important role in infection control. In this context, there are increasing reports of VL as an opportunistic infection during treatment with anti-TNF­α agents. A case of VL mimicking Felty's syndrome in a patient with rheumatoid arthritis treated with methotrexate and etanercept is presented.

The utility of therapeutic plasma exchange in Hyperviscosity syndrome associated with juvenile rheumatoid arthritis: A case report.

Hyperviscosity syndrome (HVS) is a life-threatening syndrome caused by high concentrations of large plasma proteins like IgM, rheumatoid factor, and other immune complexes, leading to increased blood viscosity and symptoms such as visual abnormalities, neurological impairment, bleeding diathesis, and thrombosis. While Waldenström's macroglobulinemia accounts for 80% to 90% of cases, HVS may develop in other clinical settings characterized by elevations in plasma proteins. Limited evidence currently exists describing the safety and efficacy of therapeutic plasma exchange (TPE) for the management of HVS secondary to non-neoplastic conditions. We report a case of recurrent HVS associated with juvenile rheumatoid arthritis and Felty syndrome that demonstrated improvement in clinical symptoms following initiation of TPE. These findings suggest that TPE may be utilized as an adjunct treatment option in patients with HVS secondary to autoimmune disorders.

Felty syndrome: a case report.

BACKGROUND: Felty syndrome is a rare manifestation of chronic rheumatoid arthritis in which patients develop extraarticular features of hepatosplenomegaly and neutropenia. The typical presentation of Felty syndrome is in Caucasians, females, and patients with long-standing rheumatoid arthritis of 10 or more years. This case report presents a patient with an early-onset and atypical demographic for Felty syndrome. CASE PRESENTATION: Our patient is a 28-year-old African American woman with past medical history of rheumatoid arthritis diagnosed in 2017, asthma, pneumonia, anemia, and mild intellectual disability who was admitted to inpatient care with fever, chills, and right ear pain for 7 days. The patient's mother, also her caregiver, brought the patient to the hospital after symptoms of fever and ear pain failed to improve. Our patient was diagnosed with sepsis secondary to pneumonia and urinary tract infection. She had been admitted twice in the past year, both times with a diagnosis of pneumonia. During this visit in September 2019, it was discovered that the patient had leukopenia and neutropenia. Bone marrow biopsy revealed increased immature mononuclear cells with left shift and rare mature neutrophils. During the hospital course, the patient was provisionally diagnosed with Felty syndrome and treated with adalimumab and hydroxychloroquine for her rheumatoid arthritis. Her sepsis secondary to pneumonia and urinary tract infection was treated with ceftriaxone and doxycycline, which was later switched to cefepime because of positive blood and urine cultures for Pseudomonas aeruginosa. She was discharged with stable vital signs and is continuing to control her rheumatoid arthritis with adalimumab. CONCLUSION: This case report details the clinical course of sepsis secondary to pneumonia and urinary tract infection in the setting of Felty syndrome. Our patient does not fit the conventional profile for presentation given her race, age, and the length of time following diagnosis of rheumatoid arthritis.

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.

Hematological Manifestations among Patients with Rheumatic Diseases.

BACKGROUND: Rheumatic diseases have many hematological manifestations. Blood dyscrasias and other hematological abnormalities are sometimes the first sign of rheumatic disease. In addition, novel antirheumatic biological agents may cause cytopenias. SUMMARY: The aim of this review was to discuss cytopenias caused by systemic lupus erythematosus and antirheumatic drugs, Felty's syndrome in rheumatoid arthritis, and autoimmune hemolytic anemia, thrombosis, and thrombotic microangiopathies related to rheumatological conditions such as catastrophic antiphospholipid syndrome and scleroderma renal crisis. Key Message: The differential diagnosis of various hematological disorders should include rheumatic autoimmune diseases among other causes of blood cell and hemostasis abnormalities. It is crucial that hematologists be aware of these presentations so that they are diagnosed and treated in a timely manner.

Rheumatoid arthritis patients with peripheral blood cell reduction should be evaluated for latent Felty syndrome: A case report.

RATIONALE: Felty syndrome is a rare and life-threatening type of rheumatoid arthritis (RA). PATIENT CONCERNS: A patient with RA had skin rash and subcutaneous hemorrhage, with a significant decrease in blood hemoglobin (Hb), white blood cell count (WBC), and blood platelet count (BPC). DIAGNOSES: The patient had a history of RA, splenomegaly, decreased Hb, WBC, BPC, and normal immunological indexes, combined with a series of bone marrow related tests and genetic tests. INTERVENTIONS: She was given high-doses of glucocorticoids intravenously, followed by oral prednisone and cyclosporine maintenance therapy. OUTCOMES: Her symptoms were resolved within 2 weeks after the start of immunosuppression. After 2 weeks of discharge, the Hb, WBC, BPC basically returned to normal, and prednisone gradually decreased. LESSONS: Felty syndrome is a rare complication of RA. Reductions in Hb, WBC, BPC, and subcutaneous hemorrhage should be considered strongly as the possibility of Felty syndrome. Multi-disciplinary diagnosis and related tests of bone marrow and genes are helpful for diagnosis and correct treatment.

Successful abatacept treatment for Felty's syndrome in a patient with rheumatoid arthritis.

We report the case of a 69-year-old man with a 38-year history of rheumatoid arthritis (RA), who developed Felty's syndrome, successful treatment with abatacept (ABT). He was treated with etanercept 50 mg/w and methotrexate 8 mg/w for the past 5 years. He was suffered from febrile neutropenia 6 months ago. Etanercept and methotrexate was discontinued 3 months ago, however, neutrophil count was not changed. Abdominal ultrasound showed splenomegaly, the diagnosis of Felty's syndrome was made. Granulocyte colony-stimulating factor therapy showed no effect on neutropenia, he was treated with ABT. After ABT therapy, absolute neutrophil count was elevated 234/µL to 1840/µL.

T-Cell Large Granular Lymphocyte Leukemia in a Patient With Rheumatoid Arthritis.

Large granular lymphocyte leukemia (LGL) is a clonal, lymphoproliferative disorder with an indolent disease course. T-cell LGL (T-LGL) is the most common type of LGL driven from T-cell lineage (85%). The coexistence of T-LGL with several types of autoimmune disorders, mostly rheumatoid arthritis (RA), has been reported. Felty's syndrome (FS) is defined by splenomegaly, low neutrophil count, and destructive arthritis and is usually seen in <1% of patients with RA. About 30% to 40% of patients with FS have been reported to have an expansion of large granulated lymphocytes in the circulation. FS and T-LGL are similar in terms of clinical manifestations, response to immunosuppressive therapy, their smoldering course, and immunogenetic findings, proposing FS and T-LGL with RA might be different aspects of a single disease spectrum. In this article, we present a case with long-standing RA who had never been on DMARD (Disease Modifying Anti-Rheumatic Drugs) treatment found to have constitutional symptoms, neutropenia, and splenomegaly, and the patient was diagnosed with T-LGL.

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.

Tocilizumab treatment in Felty's syndrome.

Felty's syndrome (FS) is a deforming disease, characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly. Currently, FS patients are treated mainly with immunosuppressants, such as methotrexate and glucocorticoids, which however are not suitable to some patients and may cause severe side effects. Here we report a clinical FS case that was treated with Tocilizumab (TCZ) successfully. The patient had symmetrical swelling and pain of multiple joints, deformity of elbow joints with obvious morning stiffness. Joint color Doppler ultrasound showed synovial hyperplasia and bone erosion of wrist and proximal interphalangeal joints and CT scan suggested splenomegaly. Further examination showed neutropenia and anemia, a high titer of anti-cyclic citrullinated peptide antibody, rheumatoid factor and anti-nuclear antibodies, positive p-ANCA, and elevated IgA and IgG. After treating with TCZ, the patient has been relieved of clinical symptoms. His spleen has recovered to normal size. The absolute neutrophil count (ANC) tended to be stable, and joint erosion did not deteriorate. We have reviewed the literatures on FS treatment with biological agents and found only a few reports using TNF-α antagonist and rituximab treating FS, but none with TCZ. So, it is the first time to report a successful FS case treated with TCZ. This case suggests that the TCZ may be a new choice for FS treatment, under the condition of closely monitoring the ANC.