Matrix changes in articular cartilage in the knee of patients with rheumatoid arthritis after biological therapy: 1-year follow-up evaluation by T2 and T1ρ MRI quantification.

AIM: To estimate the morphological changes in the articular cartilage of the knees of patients with rheumatoid arthritis treated with biological disease-modifying anti-rheumatic drugs (bDMARDs). MATERIALS AND METHODS: Cartilage-specific magnetic resonance imaging (MRI) results, including T2 and T1ρ mapping of the femorotibial joint of 17 patients, were obtained before and 1 year after starting treatment with bDMARDs. Regions of interest were selected on the sagittal images of the cartilage of the medial and lateral femoral condyles (MFC, LFC) and the tibial plateau (MTP, LTP). Cartilage thickness, T2, and T1ρ were measured, and the correlations of their changes were evaluated. RESULTS: The mean changes in cartilage thickness tended to decrease in all four condyles, and the rate was significant in the MFC. T2 and T1ρ tended to increase, and T2 in the MFC significantly increased. Changes in cartilage thickness after 1 year showed a moderate correlation with the baseline T2 in the MFC as well as changes in T2 in the MTP. CONCLUSIONS: Decreasing cartilage thickness and matrix changes appeared in the MFC after 1 year of treatment with bDMARDs. Microstructural damage of the cartilage at baseline is a predictor for further cartilage damage in the knee joint, even if treatment with bDMARDs is effective.

Efficacy of etanercept in patients with AA amyloidosis secondary to rheumatoid arthritis.

OBJECTIVE: The efficacy of biological therapies in rheumatoid arthritis (RA) is well known, but their hypothetical benefit in amyloid A (AA) amyloidosis secondary to RA still remains to be considered. We evaluated the efficacy and safety of etanercept in serum amyloid A (SAA) 1.3 allele Japanese patients with AA amyloidosis secondary to RA. METHODS: Seven RA patients with histologically confirmed AA amyloidosis and renal involvement who were treated with etanercept were enrolled. They all had the SAA1.3 allele, which has been shown to be a risk factor not only for the association of AA amyloidosis but also for a poor prognosis in Japanese RA patients. Efficacy was assessed as a sustained decrease in RA inflammation and an amelioration of renal function. RESULTS: RA inflammation and AA amyloidosis were improved and stabilized after 43.4 +/- 16.5 weeks. At week 20 the number of tender (p = 0.017) and swollen (p = 0.017) joints, and levels of serum C-reactive protein (p = 0.018) and albumin (p = 0.045) had improved. The values for SAA, serum creatinine, calculated creatinine clearance, and proteinuria also ameliorated. No severe adverse events were observed. One patient eventually had to go on hemodialysis but her tolerance of etanercept remained stable. CONCLUSION: Etanercept can be used safely and effectively in AA amyloidosis secondary to RA with renal involvement, and is of clinical benefit in the short-term, even in patients on hemodialysis. It appears that SAA1.3 allele may be used as a clinical parameter for the introduction of etanercept in Japanese RA with AA amyloidosis.

A multicenter study of leukocytapheresis in rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA) that is refractory to disease modifying antirheumatic drugs (DMARDs), we conducted a prospective, multicenter, open-label clinical trial. METHODS: We enrolled 38 active RA patients, including 32 patients who showed an inadequate response to > or = 2 DMARDs and 6 patients with rapidly progressive RA. All patients continued drug therapy and were treated with 5 LCAP sessions conducted at 1-week intervals. The clinical response was evaluated at baseline before starting LCAP and at 4 weeks after the completion of all the LCAP sessions using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of the European League Against Rheumatism (EULAR). RESULTS: Of the 35 patients who fulfilled the study's eligibility criteria, 24 (69%), 10 (29%), and 23 (66%) patients achieved 20% (ACR20), 50% (ACR50), and DAS28-C-reactive protein (CRP) EULAR improvement, respectively. The mean DAS28-CRP score of the 35 patients decreased significantly from 5.99 +/- 0.92 at baseline to 4.54 +/- 1.39 after treatment. Comparison analysis of the ACR20 responders and non-responders to LCAP revealed that 22 of 24 responders (92%) concomitantly received methotrexate, whereas significantly fewer, that is, 6 of 11 non-responders (55%) received methotrexate. Less frequent and transient mild-to-moderate adverse events, including nausea and headache, were seen in 12 of 189 LCAP sessions (6.3%). CONCLUSION: These results demonstrate the usefulness of LCAP in combination with DMARDs, particularly methotrexate, as an effective and safe treatment for refractory RA.

Significance of SAA1.3 allele genotype in Japanese patients with amyloidosis secondary to rheumatoid arthritis.

OBJECTIVE: To clarify the clinical significance of the SAA1.3 allele in the development and outcome of AA amyloidosis in Japanese patients with rheumatoid arthritis (RA). METHODS: One hundred and twenty RA patients (60 alive and 60 dead) fulfilling the 1987 ACR criteria and 62 RA patients with biopsy-confirmed amyloid A (AA) amyloidosis (36 alive and 26 dead) were enrolled. The SAA1 genotypes were determined by PCR-based restriction fragment length polymorphism. To predict the clinical outcome of AA amyloidosis, we investigated characteristics and survival, focusing on the SAA1.3 allele retrospectively. RESULTS: The SAA1.3 allele genotype was not only a risk factor for the association of AA amyloidosis but also a poor prognostic factor for the development of AA amyloidosis (P=0.015). Both the association of AA amyloidosis arising early in the RA disease course and symptomatic variety and severity were found in amyloidotic patients with the SAA1.3 allele. The presenting factors adversely influenced were age (P=0.001), lowered serum albumin (P=0.001) and creatinine concentration (P=2.14 x 10(-5)). Renal involvement was associated with poor survival in patients with AA amyloidosis (P=0.011) and the presence of cardiac involvement was likely to be a risk factor for survival (P=0.062). The rate of the causes of death in respect to the category of infection, gastrointestinal diseases, and renal failure was higher in patients with AA amyloidosis than in those without amyloidosis, gastrointestinal diseases and renal failure. Cyclophosphamide was found to be superior to methotrexate in the management of RA patients with AA amyloidosis. CONCLUSION: Our data support the fact that homozygosity for the SAA1.3 allele is a univariate predictor of survival in addition to a risk factor for the association of AA amyloidosis adversely influencing the outcome in Japanese RA patients. Renal involvement is a pivotal clinical manifestation in the development of AA amyloidosis, as is likely to be cardiac involvement in AA amyloidosis secondary to RA.

Mycobacterium kansasii arthritis of the foot in a patient with systemic lupus erythematosus.

Mycobacterium kansasii, an atypical Mycobacterium, may cause serious illness in humans. We describe a M. kansasii infection of the foot joint, which was diagnosed in a 46-year-old woman with systemic lupus erythematosus. The diagnosis was based on a positive culture from degenerative tissue and histological diagnosis of a synovium. We reviewed the literature regarding M. kansasii infection of the joint, bone, and periarticular structures focusing on the complication of rheumatic diseases.

[Clinical study on mortality of rheumatoid arthritis compared with malignant rheumatoid arthritis].

OBJECTIVE: To determine how the mortality of patients with rheumatoid arthritis (RA) behave in comparison with that of patients with malignant rheumatoid arthritis (MRA). METHODS: The mortality of RA patients selected at randam identified in 1991-2000 (n = 104) was compared with that of 18 MRA patients. Hazard ratios of death were calculated with a multivariate survival analysis. A clinical study of patients with both RA and MRA was performed in mortality. RESULTS: Excess mortality was seen in MRA patients in Kaplan-Meier survival curves (p = 0.02 by log-rank test). MRA patients were treated more often with cytostatic and immunosuppressive drugs. Infection was the main cause of death in both RA and MRA patients. Vasculitis was not reported as the cause of death in MRA patients. Secondary amyloidosis played an important role in RA death rather than MRA. CONCLUSION: There remained an excess mortality in MRA patients compared with RA, and infection was attributable to the key cause of death in both RA and MRA suggesting therapeutic side effects.

Combined treatment with cyclophosphamide and prednisolone is effective for secondary amyloidosis with SAA1γ/γ genotype in a patient with rheumatoid arthritis.

Abstract A 41-year-old woman, who had been diagnosed with rheumatoid arthritis (RA), was admitted because of proteinuria, and rheumatoid and gastrointestinal symptoms just 1 year after onset. Renal biopsy revealed marked amyloid deposits of AA (amyloid A)-type. Genotyping of serum amyloid A (SAA) showed that she was homozygous for SAA1γ. Combined treatment with cyclophosphamide and prednisolone led to remission of both RA disease activity and proteinuria. Since the renal dysfunction arose from amyloidosis, arrested renal deterioration and a remission of proteinuria would result from a reduction of amyloid deposits. Therefore, early usage of immunosuppresive therapy such as a combined treatment with these two medicines would be useful against systemic amyloidosis secondary to RA, even if the patient has the risky SAA1γ/γ genotype.

Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis.

OBJECTIVE: To investigate the expression of folate receptors (FR) and reduced folate carrier (RFC) and determine their relevance to methotrexate (MTX) transport in synovial mononuclear cells (SMC) from patients with rheumatoid arthritis (RA). METHODS: Levels of FR and RFC messenger RNA (mRNA) were examined by reverse transcriptase-polymerase chain reaction (RT-PCR) in SMC from RA patients and peripheral blood mononuclear cells from healthy donors. Expression of FR-beta mRNA and protein was determined by Northern blot and Western blot analyses in RA SMC and monocyte/macrophage-lineage cells. FR-beta expression and folic acid binding capacity on the cell surface were examined by flow cytometric analysis and 3H-folic acid binding analysis. Studies of the inhibition of 3H-MTX uptake in the presence of unlabeled folic acid were performed to investigate the uptake of MTX through FR in RA SMC. RESULTS: RT-PCR, Northern blot, and Western blot analyses showed that FR-beta mRNA and protein were expressed selectively in activated monocytes and CD14+ RA SMC. These cells exhibited folic acid binding capacity. Furthermore, the FR-beta protein was shown to have folic acid binding capacity. Uptake of 3H-MTX through RA SMC was significantly inhibited in the presence of unlabeled folic acid. CONCLUSION: These results demonstrate that FR-beta expression is selectively elevated in RA synovial macrophages and suggest that MTX is transported through FR-beta in RA synovial macrophages. The findings suggest that folate antagonists with higher affinity for FR-beta would be useful in the treatment of RA.

Pathological significance of elevated soluble CD14 production in rheumatoid arthritis: in the presence of soluble CD14, lipopolysaccharides at low concentrations activate RA synovial fibroblasts.

In order to establish what contributes to elevated levels of soluble CD14 (sCD14) in rheumatoid arthritis (RA) plasma, levels of sCD14 were compared in RA-paired plasma and synovial fluids and, further, in the culture supernatants of monocyte-rich fractions from patients with RA and healthy donors, and macrophage-rich fractions from RA synovial tissues. The results showed elevated sCD14 in RA synovial fluid in 9 of 16 paired samples and in RA macrophage-rich fractions, suggesting that elevated sCD14 in RA plasma might be due to the sCD14 production by RA synovial macrophages. From the molecular analysis of elevated sCD14, the proteolytic cleavage of membranous CD14 (mCD14) was important in accelerated sCD14 production. Lipopolysaccharides (LPS) at low concentrations and sCD14 increased the ICAM-1 expression on RA synovial fibroblasts. This result implies that in vivo RA synovial fibroblasts may be sensitive to LPS in the presence of sCD14 and LPS-binding protein (LBP).

[Crescentic glomerulonephritis in a patient with rheumatoid arthritis].

A 56-year-old female with rheumatoid arthritis was admitted because of bilateral hip pain. In a few months of her hospitalization, a relatively abrupt renal dysfunction was emerged besides complement breakdown, and renal biopsy revealed crescentic glomerulonephritis. Immunofluorescence study showed peripheral granular deposits of IgG, IgM, and C3 in the glomeruli. Cresents were predominantly composed of macrophages and glomerular epithelial cells. Amyloid nephropathy, renal vasuculitis, and association of other collagen vascular diseases were negligible for the causative factor. It was suggested that immune complexes were formed in the glomeruli, in which both humoral and cellular immune responses were to be induced, that brought cescents formation in the lesions. Crescentic glomerulonephritis in patients with rheumatoid arthritis is rare and a possible pathogenetic mechanisms involved in the development of renal dysfunction are discussed with the special reference to immune complex-induced inflammation.

IL-8/NAP-1 is the major T-cell chemoattractant in synovial tissues of rheumatoid arthritis.

T-cell infiltration into synovium is a crucial process for rheumatoid arthritis (RA). To investigate the mechanism of T-cell infiltration, we studied T-cell attracting activity in synovial tissue extracts of RA or osteoarthritis (OA) whose synovium lacks T-cell accumulation. RA extracts attracted twofold more T cells than OA extracts. By gel filtration column chromatography the activity of RA extracts was separated into two peaks; one was eluted at the 67-kDa region and the other was at the 12-kDa region, while the latter was absent in OA extracts. The activity eluted at the 12-kDa region was absorbed mostly by an antibody against IL-8/NAP-1, a potent T-cell chemotactic factor. IL-8/NAP-1 concentrations in RA extracts were much higher than those in OA extracts and correlated to T-cell attracting activity eluted at the 12-kDa region. The checkerboard analysis revealed that the 67-kDa activity was chemokinetic but not chemotactic. These results suggest that IL-8/NAP-1 is the major T-cell chemoattractant in RA-synovium.

Successful induction of severe destructive arthritis by the transfer of in vitro-activated synovial fluid T cells from patients with rheumatoid arthritis (RA) in severe combined immunodeficient (SCID) mice.

In order to investigate the role of pathogenic T cells in RA, the establishment of an RA model using patients' T cells is thought to be essential. In this study, multiple and severe destructive arthritis was established by transferring in vitro-stimulated synovial fluid T (SFT) cells from patients with RA through simultaneous injection into knee joint and peritoneal cavity of SCID mice without causing xenogeneic graft-versus-host disease (GVHD). Neither the transfer of unstimulated SFT cells nor sole i.p. injection was sufficient to induce severe arthritis. Interestingly, in contrast with SFT cells, in vitro-activated peripheral blood lymphocytes from RA patients failed to trigger such arthritis, suggesting that pathogenic T cells might be concentrated in synovial fluid of RA patients. This, the first severe arthritis model mimicking RA induced by RA patients' T cells, is expected to provide important information about RA pathogenesis and a possible therapeutic approach.

Effect of testosterone on the kinetics of the development of suppressor cells in adjuvant arthritis.

The induction of unresponsiveness to mycobacterial adjuvant took a longer time in male DA rats than in female rats. A shift in the induction time of unresponsiveness in males toward the female type was brought about by castration, but could be reverted to the male type by the application of testosterone. The transfer study revealed that cells capable of preventing arthritis required a longer incubation time for their development in males than in females. This suggests that testosterone inhibits the development of suppressor cells in adjuvant arthritis.

Characterization of low dose induced suppressor cells in adjuvant arthritis in rats.

Characterization of suppressor cells in adjuvant arthritis was performed by using highly susceptible DA strain rats. The results showed that suppressor cells were induced after a single inoculation of subarthritogenic dose of mycobacterial adjuvant. Relatively long incubation period was required for the induction of suppressor cells. Such cells were predominated in the draining lymph node and, after fractionation, only sIg- population was effective in conferring unresponsiveness. In vivo irradiation or hydrocortisone treatment suggested that low dose induced suppressor cells were resistant against such immunosuppressive treatments. In addition, by using alkyldiamine as a non-mycobacterial arthritogenic adjuvant, it was suggested that unresponsiveness induced by low dose priming with mycobacterial adjuvant was antigen specific.