Cost-effectiveness of infliximab in the treatment of rheumatoid arthritis in clinical practice.

OBJECTIVE: We evaluated the cost-effectiveness of infliximab therapy in Finnish RA patients in a real-life clinical setting and identified factors influencing it, using the national register of biological treatment (ROB-FIN). METHODS: A cost-utility analysis was performed, derived from EQ-5D, and related to HAQ score and disease activity using multiple regression. QALYs were calculated based on these utilities, using patient-level data up to the last control registered. Cost-effectiveness analyses included costs per ACR50 responder, and costs per low DAS28 score (<3.2) achieved, in combination with a clinically significant improvement (>1.2). The costs considered were direct medical costs of infliximab and cost of intravenous infusion. Patient-level costs were calculated based on dose and dosage frequency, and were related to the difference in QALYs resulting from infliximab therapy. RESULTS: The 297 patients had been treated with infliximab for an average of 21 months. The HAQ score and patient's global assessment improved significantly on infliximab therapy. More than two-thirds of the patients achieved a clinically important improvement in HAQ. A QALY gain occurred in 76%. 35% of these had an incremental cost-effectiveness ratio of < or =40,000 Euro/QALY gained, the median cost being 51,884 Euro. The cost per QALY gained was significantly lower for patients achieving an ACR50 response at 3, 12 and 24 months. CONCLUSION: Treatment with infliximab and aiming at ACR50 response appears cost-effective, remembering the restrictions of an observational study set up. Current Care guidelines, which require sufficient disease control when deciding on continuing biological therapy, get support from these findings.

Mononuclear cell response to enterobacteria and Gram-positive cell walls of normal intestinal microbiota in early rheumatoid arthritis and other inflammatory arthritides.

OBJECTIVE: To study whether enterobacteria and Gram-positive bacterial cell walls (BCW) derivedfrom normal intestinal microbiota are involved in the etiopathogenesis of early rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were isolatedfrom patients with early RA (the average duration of 5 months) and the controls (other types of inflammatory arthritis). The mononuclear cell proliferation and tumor necrosis factor-alpha (TNF-alpha) responses to heat-killed Salmonella enteritidis (SE). Yersinia enterocolitica (YE), and Escherichia coli (EC), and to Gram-positive BCW derived from four common intestinal indigenous bacteria, Eubacterium aerofaciens (EA), Eubacterium limosum (EL), Lactobacillus casei (LC), and Lactobacillus fermentum (LF), and a BCW derived from a pathogen, Streptococcus pyogenes (SP) were investigated. RESULTS: 39% or 56% of patients with early RA showed significant proliferation responses by PBMC or SFMC against enterobacteria, respectively. In other types of arthritis, corresponding figures were 59% or 66%. When BCW were used as antigens, 8.1% or 23% of patients with early RA showed proliferation responses by PBMC or SFMC, respectively. In other types of arthritis the corresponding figures were 7.5% or 35%, respectively. However, TNF-alpha production by SFMC stimulated by EA BCW, SE, YE or EC, was significantly higher in early RA than in other types of arthritis. CONCLUSION: These results suggest that SFMC reacting with enterobacteria or BCW exist in some patients with early RA, but also in other types of inflammatory arthritis. Intestinal bacterial agents may play a role in the etiopathogenesis of RA, but the effect appears to be non-specific.

Somatic serogroups, capsular types, and species of fecal Klebsiella in patients with ankylosing spondylitis.

The purpose of the present study was to find out whether patients with ankylosing spondylitis (AS) carry fecal Klebsiella strains that belong to serotypes or species specific for AS. Somatic serotypes (O groups), capsular (K) serotypes, and biochemically identified species were determined for fecal klebsiellae isolated from 187 AS patients and 195 control patients. The controls were patients with fibromyalgia or rheumatoid arthritis. The 638 isolates of Klebsiella that were obtained represented 161 strains; 81 from AS patients and 80 from the controls. The average number of Klebsiella strains per patient was 1.7 for the AS group and 1.5 for the control group. The most common O group was O1, which was observed for isolates from 23 of 187 AS patients and 24 of 195 control patients. Next in frequency was group O2, which was observed for isolates from 17 AS patients and 15 control patients. Regarding the K serotypes, 59 different types were identified, revealing a heterogeneous representation of Klebsiella strains, without a predominance of any serotype. By biochemical identification, Klebsiella pneumoniae was the most frequently occurring species, being found in 45 AS patients and 45 control patients. Next in the frequency was K. oxytoca, which was observed in 26 AS patients and in 29 control patients. K. planticola and K. terrigena occurred in only a minority of patients. Altogether, when analyzed either separately or simultaneously according to O groups, K serotypes, and biochemically identified species, no evidence of the existence of AS-specific Klebsiella strains was obtained. These findings do not indicate participation of Klebsiella in the etiopathogenesis of AS.

Bone mineral density of the lumbar spine in patients with advanced rheumatoid arthritis. Influence of functional capacity and corticosteroid use.

We investigated factors that are related to generalized osteoporosis in advanced rheumatoid arthritis (RA). In this cross-sectional study we measured trabecular bone mineral density (BMD), by quantitative computerized tomography (QCT), in the lumbar spine of 57 patients with RA, most of whom were premenopausal women. In our material, 27 out of 57 patients (47%) had BMD <-1 SD expressed as Z-score and five patients had suffered from fractures. Our study shows that a cumulative corticosteroid dose (r = -0.41, p<0.010) and functional impairment (r = -0.37, p<0.050) were negatively related to spinal BMD, while daily intake of calcium correlated positively on BMD (r = 0.37, p<0.010). Our results indicate that low BMD is common in patients with advanced RA and it is associated with long-term corticosteroid use. Thus, in clinical practice we have to consider the benefits and harms of corticosteroid treatment and preventive therapy to osteoporosis.

Interleukin-10 inhibits the capacity of synovial macrophages to function as antigen-presenting cells.

OBJECTIVE: We have investigated the effects of interleukin (IL)-10, IL-4 + granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha) on the phenotype and antigen-presenting capacity of synovial fluid (SF) macrophages from patients with rheumatoid arthritis. METHODS: The effects of IL-4, IL-10, GM-CSF and TNF-alpha on the expression of surface antigens on SF macrophages were studied using flow cytometry. The effects of these cytokines on the capacity of SF macrophages to activate T cells was investigated using the allogeneic mixed lymphocyte reaction (MLR). RESULTS: IL-10 reduced the expression of CD40, CD86 and HLA-DR, and increased the expression of CD14, on SF macrophages. IL-10 had no effect on the expression of CD80. Importantly, these effects of IL-10 on the phenotype of SF macrophages appear to have functional consequences, because cells incubated with IL-10 had a significantly reduced capacity to activate T cells in MLR. The effects of IL-4, GM-CSF and TNF-alpha were generally opposite to those observed in response to IL-10. IL-4 + GM-CSF, a combination of cytokines known to induce differentiation of dendritic cells, increased the expression of CD40, CD80 and CD86, and decreased the expression of CD14 on SF macrophages. Accordingly, IL-4 + GM-CSF increased the capacity of SF macrophages to activate T cells in MLR. IL-10 inhibited the effects of IL-4 + GM-CSF on SF macrophages. CONCLUSIONS: IL-10 inhibits the antigen-presenting capacity of SF macrophages, which further emphasizes the anti-inflammatory potential of IL-10 in RA. Importantly, IL-10 is able to downregulate the APC function of SF macrophages even when they are efficiently activated.

Intraosseous fat necrosis simulating septic arthritis and osteomyelitis in a patient with chronic pancreatitis.

A woman with a 20-year history of alcohol abuse and chronic pancreatitis developed an osteoarticular involvement of her right ankle in association with subcutaneous nodules. Histopathological examination of the tissue samples obtained during surgical revision of the ankle showed necrotic fat and connective tissue. Microbiological cultures remained negative. The patient was administered long-term antimicrobial treatment without any apparent benefit. Four months later, she died of pancreatic insufficiency and pneumonia. Postmortem examination showed numerous foci of intra-abdominal fat necrosis. Histopathological examination of the bone samples from the right ankle showed fat necrosis with lipophages. Based on these findings, we consider that the osteoarticular involvement in this patient was caused by intraosseous fat necrosis. This case reminds us of the importance of considering the possibility of this condition whenever a patient with chronic pancreatic disease develops sterile osteoarthritis.

Increased expression of signaling lymphocytic activation molecule in patients with rheumatoid arthritis and its role in the regulation of cytokine production in rheumatoid synovium.

In the present study the expression and function of signaling lymphocytic activation molecule (SLAM) in lymphocytes from patients with rheumatoid arthritis (RA) were investigated. The expression levels of SLAM were significantly up-regulated on synovial fluid and synovial tissue T cells from patients with RA compared with peripheral blood T cells from the same patients or from healthy volunteers. In addition, the expression of SLAM on peripheral blood B cells from patients with RA was elevated compared with that in healthy volunteers. SLAM+ T cells in synovial fluid coexpressed CD45RO and demonstrated decreased expression of CD27, indicative of a primed phenotype. In addition, the activation state of SLAM+ T cells was enhanced, as judged by increased expression of CD25, CD28, CD69, and CD95 on these cells. Interestingly, SLAM expression on activated CD4+ and CD8+ T cells from both patients and healthy individuals could be down-regulated by IL-10, which has been previously shown to function as an anti-inflammatory molecule in rheumatoid synovium. Furthermore, anti-SLAM mAbs increased the production of IL-10, IFN-gamma, and TNF-alpha by in vitro activated synovial fluid mononuclear cells, supporting the idea that signaling through SLAM may play a role in the regulation of synovial inflammation in patients with RA. Given the fact that SLAM was recently shown to be a high affinity self ligand, our data suggest that synovial T cells may stimulate their own cytokine production through homophilic SLAM-SLAM interactions.

Aseptic spondylitis as the initial manifestation of the SAPHO syndrome.

We describe the case of a 61-year-old female patient who presented with spondylitis of the lumbar spine. Although the microbiological cultures of the bone biopsy specimens obtained during laminotomy remained negative, the patient was treated with broad-spectrum antimicrobials for 2 months. Eight months later she started to suffer from pain and tenderness in her sternum and the medial portion of her left clavicle. The findings of computed tomography and gallium-labelled isotope scan were indicative of sternoclavicular arthritis. Again, all surgically obtained biopsy specimens yielded negative results in microbiological studies. The diagnosis of the SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteomyelitis) syndrome was then made based on the clinical presentation with recurrent sterile osteitis in two characteristic locations, and the patient was started on immunosuppressive therapy. This case is a reminder that SAPHO may sometimes occur without any skin manifestations. Since this type of patient may be admitted to an orthopedic ward, it is important that orthopedic surgeons are familiar with the syndrome.

Detection of parvovirus B19 in skin biopsy, serum, and bone marrow of a patient with fever, rash, and polyarthritis followed by pneumonia, pericardial effusion, and hepatitis.

A previously healthy 33-year-old male patient presented with fever, rash and polyarthritis. Subsequently, he developed pleuropneumonitis, pericardial effusion and hepatitis. The diagnosis of parvovirus B19 infection was based on the detection of parvovirus DNA by PCR in a skin biopsy, bone marrow cells and serum. The patient had high parvovirus IgG antibody titres but remained negative for IgM at a three month follow-up, suggesting persistence of the virus or reinfection. It is concluded that detection of viral DNA is needed to verify a parvovirus B19 infection even in an immunologically healthy host.

Systemic amyloidosis in a patient with hypogammaglobulinaemia.

A 49-year-old patient with an 18-year history of hypogammaglobulinaemia presented with nephrotic syndrome due to systemic amyloidosis. Recurrent infections as a consequence of an inadequate gammaglobulin substitution therapy were regarded as the main reason for the development of amyloidosis. When a high-dose intravenous immunoglobulin therapy was started, the clinical symptoms declined and the patient felt moderately well. Later the patient developed symmetrical polyarthritis clinically suggestive of rheumatoid arthritis. Although the incidence of arthritis is increased in hypogammaglobulinaemia, arthritis has not been reported in any of the few previously described patients with hypogammaglobulinaemia-associated amyloidosis. Moreover, this case provides further evidence that, in these patients, the amyloid fibrils may be of the AA type.

Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium.

OBJECTIVE: Interleukin-10 (IL-10) is an antiinflammatory cytokine that has been shown to play a role in rheumatoid arthritis (RA). We therefore investigated the effects of IL-10 on the function and phenotype of synovial fluid mononuclear cells (SFMC) derived from patients with RA. In addition, we studied the production of IL-10 in rheumatoid joints, and the role of endogenous IL-10 in the regulation of SFMC function. METHODS: The presence of IL-10 in rheumatoid joints was studied using IL-10-specific enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase- polymerase chain reaction (RT-PCR) techniques. The effects of recombinant human IL-10 or neutralizing anti-IL-10 monoclonal antibodies (MAbs) on both cytokine production and phenotype of SFMC were evaluated using cytokine-specific ELISAs and flow cytometry. The effect of IL-10 on proliferation of SFMC was determined by incorporation of tritiated thymidine. RESULTS: IL-10 was detected by ELISA in 22 of 23 SF samples, and was spontaneously produced by cultured SFMC. IL-10 messenger RNA was detectable in all 8 SFMC samples, as determined by RT-PCR. Neutralization of endogenously produced IL-10 by anti- IL-10 MAbs resulted in increased production of IL-1 beta, tumor necrosis factor alpha (TNF alpha), and granulocyte- macrophage colony-stimulating factor (GM-CSF) by SFMC, and in enhanced proliferation of SFMC. In particular, the production of TNFalpha was dramatically increased by anti-IL-10 MAbs. Moreover, the expression of HLA-DR molecules by SF macrophages was increased, and the expression of CD16 was decreased by anti-IL-10 MAbs. In contrast, addition of recombinant IL-10 significantly decreased the production of IL-1 beta, TNF alpha, and GM-CSF by SFMC, and decreased spontaneous and IL-2-induced proliferation of SFMC. Finally, IL-10 decreased HLA-DR expression and increased the expression of the Fc gamma receptors, CD16 and CD64, by SF macrophages. CONCLUSION: These data indicate that endogenously produced IL-10 functions as an immunoregulatory molecule in rheumatoid synovium. Importantly, exogenous IL-10 has potent antiinflammatory effects on SFMC, suggesting that IL-10 may be useful in the treatment of patients with RA.

An aseptic inflammation of the clavicle in a patient with Crohn's disease. A potential manifestation of the SAPHO syndrome.

A female patient with Crohn's disease developed an septic osteoarticular involvement of the left clavicle and sterno- and acromioclavicular regions. Repeated surgical revisions combined with a broad-spectrum antimicrobial treatment could not prevent the progress of the disease. However, the patient started to improve after the diagnosis of the SAPHO (synovitis, acne, pustulosis, hyperostosis and osteomyelitis) syndrome was made and the dose of her immunosuppressive therapy increased. This patient reminds of the existence of extraintestinal aseptic infections in association with inflammatory bowel disease (IBD). Moreover, it may provide further evidence on the significant association between SAPHO and IBD.

Oncogene expression in synovial fluid cells in reactive and early rheumatoid arthritis: a brief report.

Since it has been implied that cellular oncogenes might have a role in the pathogenesis of rheumatoid arthritis (RA), we have examined the expression of c-myc, c-myb, c-fos, c-jun and c-Ha-ras oncogenes in the cells from synovial fluid (SF) and peripheral blood (PB) of patients with reactive arthritis (ReA) and early RA. Oncogene expression was studied using RNA hybridizations with 32P-labelled probes. From the SF, mononuclear and granulocyte cell fractions were used separately. Significant differences between ReA and RA were observed only for c-myb in PB mononuclear cells and c-jun in SF granulocytes. Regarding the expression of c-myc, c-fos and c-Ha-ras oncogenes, no difference between ReA and RA was observed. Comparison to normal controls was made using PB mononuclear cells; only the expression of c-fos tended to be slightly increased in RA, without statistical significance, however. We conclude that oncogene activation in the synovial inflammation is not a phenomenon specific for RA.

Yersinia-specific antibodies in serum and synovial fluid in patients with Yersinia triggered reactive arthritis.

OBJECTIVES: To further evaluate the role of bacterial antigens in triggering inflammation in the joint in patients with reactive arthritis by studying local antibody synthesis in the joint. METHODS: Yersinia-specific antibodies in paired serum and synovial fluid samples from 29 patients with yersinia triggered reactive arthritis were studied using an enzyme linked immunosorbent assay (ELISA), an inhibition ELISA with six monoclonal antibodies against lipopolysaccharide or released proteins of yersinia and immunoblotting. Antibodies of IgM, IgG and IgA classes, as well as antibodies of IgA subclasses and those containing secretory component were measured against the lipopolysaccharide and the sodium dodecyl sulphate extract of whole Yersinia enterocolitica O:3 bacteria. RESULTS: It was shown that yersinia-specific antibodies, as well as antibodies against other microbial antigens (rubella, measles, Bordetella pertussis, tetanus toxoid and Candida albicans) in synovial fluid mirror those in serum by concentration, by specificity and by distribution in classes and subclasses. CONCLUSION: These results do not suggest any strong local antibody production, but indicate that the majority of yersinia antibodies in the synovial fluid are derived from the circulation.