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.

Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.

Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.

The spectrum of large granular lymphocyte leukemia and Felty's syndrome.

PURPOSE OF REVIEW: Patients with chronic large granular lymphocyte (LGL) leukemia often have rheumatoid arthritis (RA), neutropenia and splenomegaly, thereby resembling the manifestations observed in patients with Felty's syndrome, which is a rare complication of RA characterized by neutropenia and splenomegaly. Both entities have similar clinical and laboratory presentation, as well as a common genetic determinant, HLA-DR4, indicating they may be part of the same disease spectrum. This review paper seeks to discuss the underlying pathogenesis and therapeutic algorithm of RA, neutropenia and splenomegaly in the spectrum of LGL leukemia and Felty's syndrome. RECENT FINDINGS: We hypothesize that there may be a common pathogenic mechanism between LGL leukemia and typical Felty's syndrome. Phenotypic and functional data have strongly suggested that CD3 LGL leukemia is antigen-activated. Aberrations in the T-cell repertoire with the emergence of oligoclonal/clonal lymphoid populations have been found to play a pivotal role in pathogenesis of RA. The biologic properties of the pivotal T cell involved in RA pathogenesis are remarkably similar to those in leukemic LGL. SUMMARY: RA-associated T-cell LGL leukemia and articular manifestations of typical Felty's syndrome are not distinguishable. A common pathogenetic link between LGL leukemia and RA is proposed.

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.

Leg ulcer and thigh telangiectasia associated with natural killer cell CD56(-) large granular lymphocyte leukemia in a patient with pseudo-Felty syndrome.

Clonal disorders of large granular lymphocytes (LGL) represent a rare spectrum of biologically distinct lymphoproliferative diseases originating either from mature T cells or natural killer cells. Both subtypes can manifest as indolent or aggressive disorders. We report a 77-year-old woman with rheumatoid arthritis, splenomegaly, and neutropenia who developed a painful leg ulcer refractory to treatment and thigh telangiectatic lesions. Because of the association of rheumatoid arthritis, splenomegaly, and nonspecific neutropenia, the diagnosis of Felty syndrome was initially made. Further investigation allowed the diagnosis of a CD56(-) natural killer-cell LGL leukemia and documented skin infiltration by natural killer cells. Cutaneous manifestations of LGL leukemia have been rarely reported. This report of pseudo-Felty syndrome with CD56(-) LGL leukemia, presenting with a leg ulcer and telangiectasia, enhances the role of dermatology in the diagnosis of hematologic neoplasia.

Chronic neutropenia in LGL leukemia and rheumatoid arthritis.

This section reviews the diagnostic criteria and pathogenesis of large granular lymphocyte (LGL) leukemia. There is a particular focus on the overlap of LGL leukemia and rheumatoid arthritis (Felty's syndrome). Current understanding of the mechanisms of neutropenia in these disorders is discussed. Finally, treatment indications and therapeutic recommendations are outlined.

Primary cardiac B cell lymphoma: Manifestation of Felty's syndrome or TNFα antagonist.

Primary cardiac B cell lymphoma is rare. To date, fewer than 90 cases have been described in the literature. We report a 67-year-old woman with a 30-year history of rheumatoid arthritis, who had received treatment with leflunomide for 10 years and infliximab for 2 years. Secondary Felty's syndrome appeared. She was admitted to the hospital for abdominal pain. Investigations disclosed a 5cm cardiac mass in the right atrium. Histopathologic examination of tissue specimens obtained at surgical myocardial biopsy demonstrated primary cardiac B cell lymphoma. The other iatrogenic lymphoproliferative disorders are reviewed. This lesion might be a manifestation of long term TNFα antagonists treatment.

Splenectomy for Felty's syndrome. Clinicopathological study of 27 patients.

The major clinical and pathological features and the long-term follow-up of 27 patients with Felty's syndrome who were treated with splenectomy for sever granulocytpenia and for acute, chronic, or recurrent infection were studied. Granulocyte counts rose within days in most patients, although slow responses and transient granulocytopenia did occur; only 12% of the patients had persistent or recurrent granulocytopenia. Infections resolved promptly in 77% of the patients, more slowly in the remainder, and only one patient had new problems of infection after aplenectomy. Splenic enlargement, present in all but one case, was attributable to expansion of the sinusoidal pulp. The most substantial pathological features of immune stimulation included germinal center hyperplasia and prominent clusters of plasma and preplasma cells within sinuses.

Acquired inhibitors to factor VIII and fibrinogen in the setting of T-cell large granular lymphocyte leukemia: a case report and review of the literature.

Large granular lymphocyte (LGL) leukemia is an indolent lymphoproliferative malignancy which dysregulates humoral immunity and underlies the myriad autoimmune phenomena. We describe a 62-year-old woman with Felty's syndrome who developed a severe bleeding diathesis. Laboratory evaluation demonstrated acquired inhibitors to both factor VIII (FVIII) and fibrinogen, likely secondary to T-cell LGL leukemia. After a complicated course, the patient's inhibitors were extinguished with rituximab and high-dose corticosteroids. Bleeding was controlled with alternating FEIBA (factor eight inhibitor bypassing activity) and recombinant activated FVII. This report reviews the literature comparing the efficacy of various treatment modalities for both disorders. To our knowledge, this is the first reported case of a patient with LGL leukemia acquiring an inhibitor to FVIII or fibrinogen.

The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations.

Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis. Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression.

Nodular, non-cirrhotic liver associated with portal hypertension in a patient with rheumatoid arthritis.

A patient with rheumatoid arthritis developed portal hypertension and died from bleeding oesophageal varices. The liver was small and showed a nodular, non-cirrhotic pattern similar to that described by Blendis et al (1970 and 1974) in association with Felty's syndrome. This appears to be the first report of a patient with this liver lesion associated with rheumatoid arthritis in the absence of Felty's syndrome. The liver lesions described here are compared with partial nodular transformation and nodular regenerative hyperplasia; in spite of some differences it is not proven that these are distinct entities and further study is required to settle this question.

Felty's syndrome.

Felty's syndrome (FS) comprises a triad of rheumatoid arthritis (RA), neutropenia and splenomegaly, occurring in less than 1% of RA patients. Clinically it is characterized by severe joint destruction contrasting with moderate or absent joint inflammation and severe extra-articular disease, including a high frequency of rheumatoid nodules, lymphadenopathy, hepatopathy, vasculitis, leg ulcers, skin pigmentation etc. Recurrent bacterial infections are mostly due to the severe, otherwise unexplained neutropenia. The cause of neutropenia lies in both decreased granulopoiesis and increased peripheral destruction of granulocytes. Recurrent infections may lead to increased mortality. Spontaneous remission of the syndrome also occurs. Over 95% of FS patients are positive for rheumatoid factor (RF), 47-100% are positive for antinuclear antibody (ANA), and 78% of patients have the HLA-DR4*0401 antigen. Some 30% of FS patients have large granular lymphocyte (LGL) expansion. LGL expansion associated with uncomplicated RA is immunogenetically and phenotypically very similar to but clinically different from FS. Neutropenia of FS can be effectively treated with disease-modifying anti-rheumatic drugs (DMARDs), the widest experience being with methotrexate (MTX). Results of treatment with granulocyte colony-stimulating factor (G-CSF) are encouraging, but there is no experience with other biological agents. Splenectomy results in immediate improvement of neutropenia in 80% of the patients, but the rate of infection decreases to a lesser degree.

Felty's syndrome presenting without arthritis.

A patient with splenomegaly, severe granulocytopenia and a strongly positive rheumatoid factor test initially had no clinical evidence of rheumatoid arthritis. Leukopenia responded to splenectomy and did not recur during one year of follow up. Symmetrical metacarpophalangeal joint swelling developed after nine months. This case emphasizes that arthritis may occasionally be a late and minor manifestation of Felty's syndrome.

Pure red cell aplasia in Felty's syndrome: a case report of successful reversal after cyclosporin A treatment.

We describe the first report of a patient with Felty's syndrome who developed pure red cell aplasia, likely not attributable to medication, that was successfully treated with cyclosporin A.

[Large granular lymphocyte leukemia: clinical and pathogenic aspects]. / Les leucémies à grands lymphocytes granuleux : de la clinique à la physiopathologie.

Large granular lymphocyte leukemia (LGL) is a hematologic disorder characterized by a monoclonal expansion of large lymphocytes containing azurophilic granules with a T CD3(+)CD57(+) or Natural Killer (NK) CD3(-)CD56(+) phenotype. The World Health Organization (WHO) classification identifies three entities: the T LGL, the chronic lymphoproliferative disorder of NK-cells, and the aggressive NK-cell leukemia. T LGL and chronic lymphoproliferative disorder of NK-cells are indolent diseases frequently associated with cytopenias and a wide spectrum of auto-immune manifestations. Neutropenia can lead to recurrent bacterial infections, which represent an indication of initiating a treatment in most of the cases. Immunosuppressive therapies are usually used in this context. In contrast, aggressive NK-cell leukemia follows a fulminant course with a poor prognosis because patients are refractory to most of the treatments. There is now a considerable interest in the pathophysiology of the disease with the perspective of new therapeutic options.

Autoimmune manifestations in large granular lymphocyte leukemia.

Large granular lymphocyte (LGL) leukemia features a group of indolent lymphoproliferative diseases that display a strong association with various autoimmune conditions. Notwithstanding, these autoimmune conditions have not been comprehensively characterized or systematized to date. As a result, their clinical implications remain largely unknown. The authors offer a comprehensive review of the existing literature on various autoimmune conditions documented in the course of T-cell LGL (T-LGL) leukemia. Though some of them are thought be secondary to the LGL leukemia, others could be primary and might even play a role in its pathogenesis. A considerable clinico-laboratory overlap between T-LGL leukemia associated with rheumatoid arthritis and Felty's syndrome suggests that they are just different eponyms for the same clinical entity.

Temporal bone histopathology and immunoglobulin deposition in Sjogren's syndrome.

HYPOTHESIS: The histopathology of Sjogren's syndrome (SS) in the human inner ear correlates with mouse models of autoimmune inner ear disease. BACKGROUND: SS is an autoimmune disease in which 25% of patients have sensorineural hearing loss (SNHL). The inner ear histology in a SS mouse model has shown degeneration of the stria vascularis (SV) and immunoglobulin G deposition on the basement membrane of SV blood vessels. Correlation with human temporal bone histopathology has not been addressed. METHODS: The histopathology and immunohistochemistry of the inner ear in 4 patients with SS is described and compared with SS mouse models. RESULTS: The histopathology of the inner ear in 3 patients with SS and SNHL showed severe loss of the intermediate cells of the SV and immunoglobulin G deposition on the basement membrane of SV blood vessels. These results parallel those of known SS mouse models. Additionally, there was shrinkage of the spiral ganglia neurons in 2 patients, whereas vestibular ganglia neurons were preserved. The fourth patient with SS and normal hearing showed only mild SV atrophy. CONCLUSION: This is the first study describing the pathologic changes in the inner ear of 4 patients with SS. The 3 SS specimens with SNHL showed pathologic changes in the SV similar to the mouse model of autoimmune inner ear disease. Additionally, we propose that spiral ganglia neurons may be directly affected by SS pathology. These results highlight the importance of correlating the histopathology of human temporal bones with animal models to better understand inner ear disease in future research.

High avidity cytokine autoantibodies in health and disease: pathogenesis and mechanisms.

Numerous reports have documented the presence of autoantibodies working against naturally occurring cytokines in humans in health and disease. In most instances, their physiological and pathophysiological significance remains unknown. However, recent advances in the methodologies for detecting cytokine autoantibodies and their application in research focused on specific disorders have shown that some cytokine autoantibodies play an important role in the pathogenesis of disease. Additionally, levels of cytokine autoantibodies may also correlate with disease severity and progression in certain infectious and autoimmune diseases but not in others. This suggests that cytokine-specific pathogenic differences exist. While multiple lines of evidence support the notion that high avidity cytokine autoantibodies are present and likely to be ubiquitous in healthy individuals, their potential physiological role, if any, is less clear. It is believed that they may function by scavenging pro-inflammatory cytokines and thereby inhibiting deleterious 'endocrine' effects, or by serving as carrier proteins, providing a 'reservoir' of inactive cytokines and thus modulating cytokine bioactivity. A central hypothesis is that sustained or repeated high-level exposure to cytokines triggers defects in T-cell tolerance, resulting in the expansion of existing cytokine autoantibody-producing B cells.