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.

Neutropaenia and splenomegaly without arthritis: think rheumatoid arthritis.

Felty syndrome(FS) is an uncommon, but severe, extra-articular manifestation of rheumatoid arthritis (RA). It occurs in patients with longstanding RA. It is extremely rare for RA to present as FS or develop after initially presenting as neutropaenia and splenomegaly. We describe a case of 47-year-old woman who was diagnosed simultaneously with FS and possible RA after testing positive for anticyclic citrullinated peptide antibody, but a negative rheumatoid factor. She had an excellent response to methotrexate. We review the existing literature of such cases and emphasise the importance of serological testing for RA in patients presenting with neutropaenia and splenomegaly, even in the absence of joint symptoms or prior diagnosis of RA.

Gastrointestinal and hepatic manifestations of rheumatoid arthritis.

Rheumatoid arthritis (RA), characterized by inflammation of the synovium and surrounding structures, has a prevalence of 0.5-1%. Rheumatoid vasculitis (RV) is an inflammatory condition of the small- and medium-sized vessels that affects up to 5% of patients with RA with intestinal involvement in 10-38% of these cases. Clinically apparent RV of the gastrointestinal (GI) tract, while rare, is often catastrophic, resulting in ischemic ulcers and bowel infarction. Vasculitis of the colon may present as pancolitis clinically similar to ulcerative colitis. Rectal biopsies that include submucosal vessels are positive for vasculitis in up to 40% of cases. Abnormal esophageal motility in RA may result in heartburn and dysphagia. Chronic atrophic gastritis may be associated with hypergastrinemia and hypo- or achlorhydria, promoting small bowel bacterial overgrowth. RA is the most common cause of secondary amyloidosis with GI symptoms in 22% of affected patients. Although amyloid is usually found in the liver, it is rarely evident clinically. Felty's syndrome occurs in less than 1% of patients with RA and is characterized by neutropenia and splenomegaly. The liver may be involved with portal fibrosis or nodular regenerative hyperplasia. Liver histology is abnormal in 92% of RA patients at autopsy, although the changes are usually mild without associated hepatomegaly. Drug-induced liver disease may occur with aspirin, sulfasalazine, and methotrexate. Significant liver damage is rare if the drug is discontinued or the patient is properly monitored. RA can affect both the GI tract and the liver; changes are usually mild except with RV.

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.

Anti-cyclic citrullinated peptide-2 (CCP2) autoantibodies and extra-articular manifestations in Greek patients with rheumatoid arthritis.

The objective of our study was to establish whether there is an association between rheumatoid arthritis with extra-articular manifestations (exRA) and anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies in Greeks. A retrospective study of 220 Greek patients with RA, 95 with exRA and 125 without extra-articular manifestations (cRA). Serum anti-CCP2 antibodies and IgM rheumatoid factor (RF) were measured. CCP2(+) were 65.3% of exRA and 58.4% of cRA patients. RF(+) were 69.5% of exRA and 60.0% of cRA patients. Among exRA patients, 37.9% had high serum anti-CCP2 antibody levels (>100 IU/ml) compared to 21.6% cRA patients (p = 0.008). Serositis and pulmonary fibrosis were found to be associated with high levels of anti-CCP2 antibodies (52.9 vs 26.6%, p = 0.02 and 63.6 vs 26.8%, p = 0.008, respectively). Serum RF levels were 265.0 +/- 52.0 IU/ml (mean +/- SEM) in exRA and 205.1 +/- 40.6 (mean +/- SEM) in cRA (NS). High serum RF levels (>268 IU/ml) were more likely to have sicca syndrome. In Greek patients with rheumatoid arthritis (RA), high serum anti-CCP2 antibodies are associated with serositis and pulmonary fibrosis. Therefore, anti-CCP2 antibodies have prognostic significance in patients with RA.

Association of autoantibodies to glucose-6-phosphate isomerase with extraarticular complications in rheumatoid arthritis.

OBJECTIVE: In the K/BxN mouse model, autoantibodies against glucose-6-phosphate isomerase (GPI) cause arthritis. The relevance of this model for human disease remains a subject of controversy. We set out to determine whether GPI autoantibodies occur in patients with rheumatoid arthritis (RA) and, if so, at what stage of the RA. METHODS: Using an enzyme-linked immunosorbent assay, serum from 131 RA patients and 28 healthy controls was tested for autoantibodies against recombinant human GPI. Patients were grouped according to disease duration and presence of rheumatoid nodules, rheumatoid vasculitis, and Felty's syndrome, which are extraarticular complications of RA. RESULTS: Elevated levels of autoantibodies against GPI were present in 5% of patients with uncomplicated RA and 4% of controls. In RA complicated by extraarticular manifestations, anti-GPI antibodies were observed in 18% of patients with rheumatoid nodules, 45% of patients with rheumatoid vasculitis, and 92% of patients with Felty's syndrome. CONCLUSION: In patients with RA, autoantibodies to GPI are associated with the occurrence of extraarticular complications.

Treatment of Felty's syndrome with leflunomide.

Felty's syndrome (FS) is a rare manifestation of severe rheumatoid arthritis (RA). It is an immune mediated inflammatory process, usually treated with standard disease modifying antirheumatic drugs. We describe a case of severe FS that developed in a patient receiving methotrexate therapy for RA. Treatment with etanercept resulted in severe allergic cutaneous reactions. The patient subsequently responded to treatment with leflunomide. The response included dramatic improvement of leukopenia and neutropenia as well as excellent control of his arthritis. Leflunomide has recently been used effectively for the treatment of RA and may be useful for the management of patients with FS.

[Inflammatory rheumatism and celiac disease in adults. Coincidence or pathogenic relationship?]. / Rhumatisme inflammatoire et maladie coeliaque de l'adulte. Coïncidence ou lien pathogénique?

Five adults had inflammatory rheumatic disorders 6 to 20 years before the diagnosis of coeliac disease. It is known that joint inflammation occurs in certain patients with adult coeliac sprue who develop either a specific inflammatory rheumatic disease or an atypical progressive polyarthropathy, sometimes as the first manifestation of the intestinal disorder. The diagnosis of adult coeliac sprue should be entertained in these cases even in absence of major digestive disorders or malabsorption. IgA anti-reticulin antibodies and atrophy of the duodenojejunal villosities are the best indicators for diagnosis. There are two important reasons for making the diagnosis of "asymptomatic adult coeliac sprue". First a gluten-free diet can improve or even cure the inflammatory joint disease, a rare situation which emphasizes the causal relationship between these two diseases. Second, the risk of developing lymphoma (especially in the small bowel) is apparently lower in patients on gluten-free diet. Pathogenesis is unclear. Frequently the two autoimmune disorders simply appear to coincide in the same patient; more rarely, arthritis is a symptom of coeliac disease. The immunological mechanisms probably begin when antigens cross an excessively permeable intestinal mucosa.

[Felty's syndrome]. / Felty's syndrom.

Felty's syndrome (FS) consists of the triad: rheumatoid arthritis (RA), leukopenia and splenomegaly. FS occurs in approximately 1% of patients with RA. In this syndrome, the risk of infection is increased and anaemia, thrombocytopenia and cutaneous ulcers are more frequently observed. The literature is reviewed on the basis of a case history. The pathogenesis is unknown but is probably multifactorial. Cell antibodies, increased occurrence of immune complexes, inhibited neutrophil production, altered neutrophil distribution and reduced neutrophil function have been observed. The main indication for treatment is present if the patient has severe neutropenia (less than 0.1 x 10(9)/l) and repeated infections. Various methods of treatment are available. The most important are: gold, low-dose methotrexate, lithium, methylprednisolone pulse therapy, penicillamine and splenectomy. According to the literature, conventional steroid treatment cannot be recommended.

Prevalence of granular lymphocyte proliferation in patients with rheumatoid arthritis and neutropenia.

PURPOSE: Granular lymphocyte proliferation and neutropenia with or without splenomegaly occurs with unknown frequency in rheumatoid arthritis. We decided to evaluate the prevalence of Felty's syndrome and granular lymphocyte proliferation among patients with rheumatoid arthritis and to determine the fraction of patients with granular lymphocyte proliferation who also had rheumatoid arthritis. PATIENTS, METHODS, AND RESULTS: We retrospectively analyzed 1,053 cases of rheumatoid arthritis and 13,505 marrow examination reports for the decade 1978 to 1987. Among patients with Felty's syndrome rheumatoid arthritis with neutropenia/leukopenia, and rheumatoid arthritis with splenomegaly, we identified 18 patients with neutropenia as a manifestation of rheumatoid arthritis. We also identified marrow examinations in 150 patients with rheumatoid arthritis. Using blood counts, microscopy of marrow, and surface antigen analysis of mononuclear cells, we determined that 12 patients had typical Felty's syndrome and six had granular lymphocyte proliferation, representing prevalences of 1.1 percent and 0.6 percent, respectively. No patient had granular lymphocyte proliferation without neutropenia. CONCLUSION: Granular lymphocyte proliferation and neutropenia with or without splenomegaly in rheumatoid arthritis commonly resembles typical Felty's syndrome. Further, the six patients with granular lymphocyte proliferation represent 20 percent of our institution's patients with granular lymphocyte proliferation, supporting the previously described common association of this disorder with rheumatoid arthritis. The relatively large fraction of deaths (due to malignancy and infection) among the patients with typical Felty's syndrome suggests that their mean survival may be comparatively less than in those with granular lymphocyte proliferation.

[Mechanism of Felty's syndrome and long-term course]. / Mécanisme du syndrome de Felty et évolution à long terme.

The authors report 18 cases of Felty's syndrome followed, in an average, for 5 years (1 to 12 years). There were 3 deaths, 9 patients are in complete remission, 6 others still show signs of the disease: splenomegaly (4 cases), leucopenia (1 case) and only one complete Felty's syndrome. Steroid therapy has proved to be effective regardless of the mechanism of the neutropenia specified in 9 cases by an isotopic study. Prognosis and infectious risk are difficult to determine but the overall course was rather favorable.

HLA DQ alpha and DQ beta restriction fragment length polymorphisms associated with Felty's syndrome and DR4-positive rheumatoid arthritis.

HLA DQ alpha and DQ beta cDNA probes were used to study TaqI generated restriction fragment length polymorphisms (RFLPs) in DR4-positive patients with Felty's syndrome (FS), seropositive rheumatoid arthritis (RA), and in HLA-DR4 positive controls. The results of this analysis revealed two DQ beta RFLP patterns (DQ beta 3a and DQ beta 3b) associated with DR4, of which DQ beta 3b was found at significantly higher frequency in patients with FS (73%) or with RA (52%) than in DR4 controls (29%). Hind III generated RFLPs provide evidence that DQ beta 3b is in strong linkage disequilibrium with the gene encoding the serologically recognized epitope TA10. Results obtained using a DQ alpha chain probe revealed polymorphic differences between DQ alpha chain genes associated with different DR types, thereby providing a possible explanation for the lack of association between RA and other DR haplotypes in linkage disequilibrium with TA10. We conclude that both DQ alpha and DQ beta genes may be important in determining HLA-linked susceptibility to severe forms of RA.

Neutropenia occurring during the course of chrysotherapy: a review of 25 cases.

The records of 25 patients who developed neutropenia (granulocyte count less than or equal to 2500 mm3) while receiving intramuscular gold sodium aurothiomalate (GSTM) were reviewed. According to commonly used clinical criteria, 3 patients developed Felty's syndrome, 8 gold myelotoxicity, and 14 mild, chronic benign granulocytopenia. Myelotoxicity occurred exclusively during the initial course of therapy (less than or equal to 1 g GSTM). Twelve of the patients with chronic granulocytopenia continue to receive gold without other signs of serious toxicity. We conclude that Felty's syndrome can develop during gold administration, and that many patients may continue safely to receive gold despite neutropenia.

Felty syndrome: autoimmune neutropenia or immune-complex-mediated disease?

Immunofluorescence on polymorphonuclear cells (PMN) of patients with Felty syndrome (FS) revealed increased amounts of IgG, IgA, and IgM bound to the PMN surface compared with PMN of patients with rheumatoid arthritis alone. A positive correlation was found between the score for surface-bound immunoglobulins on FS-PMN and the results of the Clq binding assay in FS sera. After preincubation with sera from 20 patients with FS, immunofluorescence on PMN from healthy controls (HC) showed that these cells had bound IgG, IgA, and IgM. However F(ab')2 fragments of IgG from FS sera did not bind to PMN, although the antigen-binding reactivity of the F(ab')2 fragments was maintained as shown by control experiments. Immunoglobulins eluted from FS-PMN failed to bind to HC-PMN, whereas the corresponding IgG of patients with autoimmune neutropenia was bound. Gel filtration of FS sera on Sepharose 4B showed that the binding of IgG in FS sera to PMN did not coincide with the 7S peak but occurred mainly in fractions containing larger material. No binding of IgA and IgM to HC-PMN was found after incubation with FS sera pretreated with polyethylene glycol (PEG) to precipitate immune complexes. These results indicate that in sera of patients with FS the PMN-binding reactivity of IgG, IgA, and IgM is due to the binding of immune complexes containing these immunoglobulins and not to presence of autoantibodies directed to antigens on the neutrophil surface.