Tumour necrosis factor α augments the inhibitory effects of CTLA-4-Ig on osteoclast generation from human monocytes via induction of CD80 expression.

Cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) exerts anti-rheumatic action via negative regulation of the co-stimulation process between antigen-presenting cells and T cells. CTLA-4-Ig also binds to CD80/CD86 on monocytes of osteoclast precursors. However, little is known about the effect of CTLA-4-Ig on osteoclastogenesis in rheumatoid arthritis (RA). In this study we evaluated the effects of CTLA-4-Ig on osteoclast generation from human blood monocytes (PBM) and rheumatoid synovial fluid monocytes (RSFM). Highly purified monocytes were cultured with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of CTLA-4-Ig. CTLA-4-Ig inhibited RANKL-induced osteoclast generation in PBM and RSFM, as determined by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay using osteo assay surface plates. In addition, CTLA-4-Ig reduced the gene and protein expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and cathepsin K during osteoclastogenesis. Furthermore, CTLA-4-Ig significantly inhibited cell proliferation during osteoclastogenesis. Interestingly, the gene expression of indoleamine 2,3-dioxygenase-1, an inducer of apoptosis, was enhanced by CTLA-4-Ig. We next examined the effect of tumour necrosis factor (TNF)-α, a major inflammatory cytokine in rheumatoid synovium, on the expression of CD80 and CD86 by flow cytometric analysis. TNF-α potently induced the surface expression of CD80, which is known to have much higher affinity to CTLA-4-Ig than CD86, and this induction was observed at mRNA levels. Interestingly, freshly prepared rheumatoid synovial monocytes also expressed CD80 as much as TNF-α-treated PBM. Furthermore, TNF-α enhanced CTLA-4-Ig-induced inhibition of osteoclastogenesis and cell proliferation. Taken together, the TNF-α-induced CD80 may augment CTLA-4-Ig-induced inhibition of osteoclastogenesis, suggesting that CTLA-4-Ig potently inhibits osteoclast differentiation and protects bone destruction in rheumatoid inflamed joints.

Post-menopausal women with rheumatoid arthritis who are treated with raloxifene or alendronate or glucocorticoids have lower serum undercarboxylated osteocalcin levels.

BACKGROUND: Serum undercarboxylated osteocalcin (ucOC) is a biochemical bone marker of vitamin K insufficiency. It had been reported that bone resorption inhibitors tend to decrease the serum ucOC level in patients with primary osteoporosis. In rheumatoid arthritis (RA) patients, these results have never been reported. AIM: We investigated risk factors which could change serum ucOC level in post-menopausal women with RA (no.=100). SUBJECTS AND METHODS: Twenty patients received no bone resorption inhibitor (control), 30 received raloxifene (RLX), while 50 received alendronate (ALN). This cross-sectional study was limited to patients with low RA disease activity (Disease Activity Score-28 ≤3.2). We measured serum ucOC, and the data were analyzed by multivariable analysis, including ucOC and the other variables. RESULTS: Scheffe's F test demonstrated a significant difference in serum ucOC levels between controls and the RLX group (p<0.01), and between controls and the ALN group (p<0.01). Serum ucOC levels were low in both treated groups. An adjusted multivariate analysis was performed for the variables: bone resorption inhibitor use, serum alkaline phosphatase, glucocorticoid dose, age, estimated glomerular filtration rate and matrix metalloproteinase 3. As a result, serum ucOC inversely correlated with bone resorption inhibitor use (p<0.01) and oral glucocorticoid dose (p<0.01), which were independent risk factors of lowering ucOC. CONCLUSIONS: Bone resorption inhibitors and glucocorticoids were independent risk factors for lowering serum ucOC levels in post-menopausal RA patients.

Serum undercarboxylated osteocalcin level increases with 48 weeks of teriparatide treatment in pre-treated elderly rheumatoid arthritis patients who use anti-resorptive drugs.

AIM: The serum undercarboxylated osteocalcin (ucOC) level, a biochemical bone marker of vitamin K insufficiency, is often affected by anti-osteoporosis drugs. There have been no reports regarding the relationship between ucOC and teriparatide. SUBJECTS AND METHODS: We conducted a prospective observational study of 26 female rheumatoid arthritis (RA) patients. The patients were divided into 3 groups: those who underwent a direct switch from anti-resorptive drugs to teriparatide (12 cases), those who started teriparatide without pre-treatment (5 cases), and the control patients (9 cases). The median age (interquartile range) of the patients in each group was 75 (67-77), 82 (78-84), and 69 (62-80) yr, respectively. All patients, except controls, received 48-week treatments of teriparatide. We analyzed the median 48-week changes from baseline of the serum ucOC levels with the Steel-Dwass method. RESULTS: The median change from baseline in the direct switch group was higher than that in other groups (p<0.05). CONCLUSIONS: The serum ucOC levels increased with treatment of teriparatide in elderly RA patients, especially when the patients received pre-treatment.

Large-vessel vasculitis associated with PEGylated granulocyte-colony stimulating factor.

A 71-year-old female with advanced endometrial cancer was treated with pegfilgrastim. She developed a fever within seven days, and contrast-enhanced computed tomography scans repeated within three days revealed rapidly progressive thickening of the aortic wall. When clinicians administer PEGylated granulocyte-colony stimulating factor (G-CSF) to cancer patients, drug-associated vasculitis should be suspected. This report discusses the manifestation of G-CSF-associated large-vessel vasculitis (LVV).

D-penicillamine-induced glomerulonephritis with crescent formation: Remission following drug discontinuation.

We report a 71-year-old female who presented with rheumatoid arthritis complicated by proteinuria. She had been receiving D-penicillamine (D-Pc) for two years prior to presentation. A urinalysis showed proteinuria and hematuria which disappeared within 3 months after D-Pc was stopped. The renal histological findings showed focal proliferative glomerulonephritis with crescent formation. A total of 10 cases of D-Pc-induced glomerulonephritis with crescent formation without alveolar hemorrhage have previously been reported in the literature. To the best of our knowledge, this is the first case report in which the patient did not require any treatment.