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.     

Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis

Secondary amyloid A (AA) amyloidosis is an uncommon yet important complication of rheumatoid arthritis (RA). It is one of the most relentless of the extra-articular features of RA, and suitable treatments have not yet been found. We studied the efficacy of cyclophosphamide (CYC) combined with prednisolone (PSL) in amyloidotic patients who had serum amyloid A (SAA) 1.3 genotype, which is a risk factor for secondary amyloidosis in Japanese RA patients. Fifteen RA patients who were SAA1.3 homo- and heterozygotes with biopsy-confirmed AA amyloidosis were treated with a combination of CYC and PSL. Laboratory variables of C-reactive protein (CRP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), serum albumin (Alb), serum creatinine (Cre) and Lansburys index were carried out by statistical analysis of changes between before and during the medication. According to the Mann–Whitney rank test, CRP, RF, ESR, Alb and Cre levels improved significantly with the combination treatment (p<0.05). Also, paired t-tests showed significance in Lansburys index between before and during the medication (p=0.007). CYC combined with PSL ameliorated not only laboratory markers but also clinical rheumatoid activity in patients with amyloidosis secondary to RA, whose genotypes were SAA1.3 homo- and heterozygous. CRP, ESR, RF, Alb and Cre will be surrogate markers of therapeutic efficacy. The combination of CYC and PSL appears to be beneficial for Japanese RA patients who are SAA1.3 homo- and heterozygous carriers, associated with secondary AA amyloidosis.Abbreviations AA Amyloid A - CRP C-reactive protein - Ccr Creatinine clearance - CYC Cyclophosphamide - DMARD Disease-modifying antirheumatic drugs - ESR Erythrocyte sedimentation rate - NSAID Non-steroidal anti-inflammatory drugs - PCR Polymerase chain reaction - PSL Prednisolone - RA Rheumatoid arthritis - RF Rheumatoid factor - SAA Serum amyloid A     

Effect of etanercept on serum amyloid A protein (SAA) levels in patients with AA amyloidosis complicating inflammatory arthritis

We assessed changes in serum amyloid A protein (SAA) levels during treatment with etanercept in AA amyloidosis complicating inflammatory arthritis. Five women and four men with AA amyloidosis and inflammatory arthritis received etanercept. SAA levels were recorded before and after commencement of treatment. Previous immunosuppressive drugs included cyclophosphamide (four patients), azathioprine (three patients), methotrexate (two patients) and chlorambucil (in one patient). Two patients received no disease modifying drugs between the time of diagnosis of AA amyloidosis and commencement of etanercept. In seven out of nine patients the median SAA level during etanercept treatment was lower than levels before anti-tumour necrosis factor therapy. In five out of nine patients, the median post treatment level was <11 mg/l. There were no significant changes in serum creatinine or proteinuria during periods (median, 23 months; range, 1-24 months) of etanercept therapy. The etanercept was stopped in four patients because of: acute bacterial endocarditis, psoriasiform rash, psychosis and leukopenia. In two of these patients alternative biologics were commenced (adalimumab or anakinra) and one was restarted on etanercept. One patient died of cerebral haemorrhage during the study. Etanercept therapy was associated with a fall in SAA levels in seven of nine patients, five of whom achieved levels which might be expected to be associated with stable or regressing amyloid deposits. Etanercept represents a useful alternative to immunosuppressant therapy such as cyclophosphamide or chlorambucil. Further work is needed to establish whether organ damage related to AA amyloidosis is slowed by etanercept.     

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

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. Received: September 13, 1999 / Accepted: April 5, 2000     

Ageing: a risk factor for amyloid A amyloidosis in rheumatoid arthritis

Abstract

Objective.?Acceleration of amyloid A (AA) amyloidosis induction by ageing has not been extensively studied in rheumatoid arthritis (RA). The aim of this study is to clarify contribution of ageing to the development of AA amyloidosis associated with RA in our large cohort.

Methods.?388 adult-onset RA patients whose RA was complicated by biopsy-proven AA amyloidosis were enrolled. The ages of RA onset and AA amyloidosis diagnosis were estimated in each patient. The contributions of ageing, inflammatory activity, SAA1 exon 3 polymorphism as well as gender to the pathogenesis of AA amyloidosis in 144 cases were also studied by multiple regression analysis.

Results.?Subjects with RA onset at older age had a shorter period to develop amyloidosis than those with disease onset at younger age (p < 0.001). The interval between RA onset and AA amyloidosis diagnosis was significantly shorter in the SAA1.3 positive group than in the SAA1.3 negative (p?=?0.001). Multiple regression analysis indicated that the interval from RA onset to diagnosis of AA amyloidosis is determined by age at RA onset (p < 0.001), the most recent median annual CRP concentration (p?=?0.006) and SAA1.3 allele (p?=?0.058). Gender did not significantly contribute to the onset of AA amyloidosis (p?=?0.569).

Conclusion.?Ageing is an independent risk factor for the induction of AA amyloidosis complicating RA.     

Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by extent of joint destruction

Adiponectin is a hormone released by adipose tissue with antidiabetic, antiatherogenic, and anti-inflammatory properties. The present observational study focused on the relation between serum adiponectin level and the disease severity of established rheumatoid arthritis (RA). Ninety patients with more than 5-year diagnosis of RA and 42 age- and BMI-matched control were enrolled. The severity of RA was evaluated according to the number of destructed joints of overall 68 joints on plain radiographs (37 patients had mild RA and 53 had severe RA). Serum adiponectin level was significantly higher in the severe RA group (17.7 ± 6.7 μg/ml) than in the control (9.1 ± 3.8 μg/ml) and mild RA groups (13.9 ± 6.5 μg/ml) (control vs. mild RA group, P < 0.001; mild RA vs. severe RA group, P < 0.01). These results suggest that increased number of joint destruction is associated with hyperadiponectinemia in established RA patients.     

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.     

The significance of platelet activation in rheumatoid arthritis

We evaluated the significance of platelet activation in patients with rheumatoid arthritis (RA). The expression of CD62P and CD63 by platelets was determined using flow cytometry in 18 active RA patients, 10 remission RA and 15 normal controls. Meanwhile, the erythrocyte sedimentation rate (ESR) and C-reactive protein was also determined in all groups. The expression of CD62P in active RA patients (11.88 ± 2.47%) was significantly higher than that in remission RA group (2.85 ± 1.60%; P < 0.01) and control group (2.78 ± 1.04%; P < 0.01). The expression of CD63 in active RA patients (9.90 ± 3.02%) was significantly higher than that in remission RA group (4.11 ± 2.00%; P < 0.01) and control group (4.13 ± 1.85%; P < 0.01). The level of CRP (54.33 ± 23.35 mg/l) and ESR (86.06 ± 33.67 mm/h) in active RA patients was higher than that in remission RA group (2.55 ± 1.01 mg/l, 14.70 ± 4.57 mm/h; P < 0.01 for both) and normal control group (3.21 ± 2.18 mg/l, 12.25 ± 5.05 mm/h; P < 0.01 for both). There was a positive correlation between CD62P and ESR (r = 0.5224, P < 0.01) and also a positive correlation between CD62P and CRP (r = 0.7048, P < 0.01) as well as between CD63 and ESR (r = 0.4476, P < 0.05) but no correlation between CD63 and CRP. Platelet activation may be a sign of RA exacerbation.     

A case of AA amyloidosis associated with rheumatoid arthritis effectively treated with Infliximab

We report the case of a 55-year-old Japanese woman with reactive AA amyloidosis associated with rheumatoid arthritis, in which inflammatory disease was completely suppressed with infliximab. Nephrotic syndrome was observed and renal biopsy specimens revealed amyloidosis deposits. Treatment with infliximab normalized the serum amyloid A (SAA) protein level, and subsequently nephritic syndrome disappeared and her creatinine clearance improved. Serial gastrointestinal biopsy specimens showed marked lasting regression of amyloid deposits. Thus treatment with infliximab represents an important therapeutic strategy for AA amyloidosis associated with RA.     

Lipid profile in Tunisian patients with rheumatoid arthritis

This study aims to assess the prevalence of dyslipidaemia in Tunisian patients with active RA and to investigate the clinical and biological associated factors. A cross-sectional study was conducted on 92 unselected patients with active RA (77 females and 15 males, aged 49.1 ± 12.5 years) and 82 healthy subjects (68 females and 14 males, aged 50.8 ± 13.3 years). We recorded the patients' characteristics and the results of a lipid profile test (total cholesterol, TC; high-density lipoprotein cholesterol, HDL-c; low-density lipoprotein cholesterol, LDL-c; triglyceride, TG; lipoprotein (a), Lp (a); apolipoprotein A-1, apo A-1 and apolipoprotein B, apo B). In comparison to the control group, RA patients showed a higher prevalence of associated dyslipidaemia (95.7% versus 65.9% of cases, p < 0.001). Sera of patients showed higher TC (4.86 ± 1.07 versus 3.98 ± 0.73 mmol/L, p < 0.001), LDL-c (3.49 ± 0.98 versus 1.99 ± 0.62 mmol/L, p < 0.001), Lp (a) (288.04 ± 254.59 versus 187.94 ± 181.37 mmol/L, p = 0.004) and lower HDL-c (0.66 ± 0.24 versus 1.12 ± 0.3 mmol/L, p < 0.001). TC/HDL-c, LDL-c/HDL-c and non-HDL-c/HDL-c were also higher in RA patients; they were 8.24 ± 3.20 versus 3.76 ± 1.26 (p < 0.001), 5.91 ± 2.48 versus 1.92 ± 0.99 (p < 0.001) and 7.24 ± 3.20 versus 2.76 ± 1.26 (p < 0.001), respectively. Apo A-1 was correlated to Lp (a) (r = 0.291, p = 0.005). Corticoid dose was not associated to dyslipidaemia, but in multiple regression models, corticoid dose may be negatively related to some atherogenic markers, in particular non-HDL-c. Tunisian patients with markedly active RA experience substantially reduced serum HDL-c and increased TC, LDL-c and Lp (a) concentrations as well as increased TC/HDL-c, LDL-c/HDL-c and non-HDL-c/HDL-c ratios.     

Serum chemokines in patients with rheumatoid arthritis treated with etanercept

Chemokines promote leucocyte traffic into the synovium, leading to the initiation and progression of the rheumatoid arthritis (RA). The aim of the study was to determine the effects of etanercept, a soluble tumour necrosis factor receptor (sTNFr), on the serum chemokines levels in patients with active RA. Patients were treated with 50 mg of subcutaneous injection of etanercept per week and methotrexate (10–25 mg/week). Serum levels of interleukin-8 (IL-8), RANTES (regulated upon activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 (MCP-1) were assessed by ELISA at months 0, 3, 6, 9 and 12, prior to injection. 3-month treatment with etanercept diminished serum concentrations of IL-8, RANTES and MCP-1 (P < 0.05, P < 0.01 and P < 0.001, respectively). Subsequent etanercept administrations prolonged decrease in serum chemokines levels and in the case of IL-8 even intensified the reduction of its concentration in serum. These changes were accompanied by significant decrease of disease activity score (DAS28) (in all cases P < 0.001). Prior to the first etanercept administration, serum concentrations of studied chemokines correlated with markers of RA activity such as the erythrocyte sedimentation rate (ESR) and DAS28. Following next drug injection such associations were less or not significant. Therapy with etanercept and MTX not only caused a clinical improvement but also diminished serum chemokines levels in RA patients. Further treatment with etanercept sustained chemokines suppression.     

The efficacy and safety of etanercept in patients with rheumatoid arthritis and spondyloarthropathy on hemodialysis

We aimed to evaluate the efficacy and safety of long-term use of etanercept therapy in patients with spondyloarthropathy (SpA) and rheumatoid arthritis (RA) on hemodialysis (HD). Selected RA or SpA patients treated with etanercept under HD were retrospectively evaluated. Etanercept-related adverse events were closely recorded for all patients. At the follow-up, erythrocyte sedimentation rate and C-reactive protein levels were monitored. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for SpA patients and Disease Activity Score (DAS28) for RA patients were measured at every 3 or 6 months. In total five end-stage renal disease (ESRD) patients were enrolled to the study. The causes of ESRD in the study subjects were amyloidosis (n = 2), analgesic nephropathy (n = 2), and nephrolithiasis (n = 1). Three were diagnosed as SpA and two were RA. All patients used etanercept. The median age was 39 years (range 22–72 years). The median disease duration was 12 years (range 2–20 years). The median follow-up after etanercept therapy was 18 months (range 5–33 months). DAS28 score decreased after the treatment and did not increase during follow-up in RA patients. BASDAI score decreased after the treatment during follow-up in three patients with SpA. At the follow-up, only one patient was diagnosed with septic arthritis. As a result of our study, etanercept treatment in RA and SpA patients on HD seems to be safe, well tolerated, and effective in most of the patients. Above all, due to impaired host defense in patients with ESRD, enhanced risk of infections should be kept in mind during follow-up period and larger trials are needed to prove the safety of etanercept in HD patients.     

Anti-agalactosyl IgG antibodies in Thai patients with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis

This study was performed to determine the prevalence of anti-agalactosyl IgG antibodies in Thai patients with RA, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and determine the sensitivity and specificity of anti-agalactosyl IgG antibodies in the diagnosis of RA in comparison with IgM-rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Serum samples were obtained from 100 patients with RA, 50 cases of SLE, 50 cases of SSc, and 100 healthy controls and analyzed for the presence of anti-agalactosyl IgG antibodies, IgM-RF and anti-CCP antibodies. A serum value greater than mean + 2 standard deviation of normal value of anti-agalactosyl IgG antibodies and anti-CCP antibodies was considered positive. The prevalence of anti-agalactosyl IgG antibodies in RA, SLE, and SSc patients was 88.0%, 14.0%, and 12.0%, respectively. The serum level of anti-agalactosyl IgG antibodies in patients with RA (227.10 ± 353.64 AU/mL) was significantly higher than those in SLE (11.84 ± 52.04 AU/mL), SSc (18.85 ± 99.60 AU/mL), and healthy controls (2.14 ± 1.97 AU/mL), (p < 0.001). There was a good correlation between the log serum level of anti-agalactosyl IgG antibodies and IgM-RF (r = 0.92, p < 0.001), anti-CCP antibodies and IgM-RF (r = 0.49, p < 0.001), and anti-agalactosyl IgG antibodies and anti-CCP antibodies (r = 0.55, p < 0.001). The sensitivity and specificity in the diagnosis of RA was 88.00% and 96.00% for anti-agalactosyl IgG antibodies, 90.00% and 99.00% for anti-CCP antibodies, and 91.00% and 95.00% for IgM-RF, respectively. The serum level of anti-agalactosyl IgG antibodies was significantly higher in RA than in SLE, SSc, and healthy controls. There was a good correlation between serum levels of anti-agalactosyl IgG antibodies, anti-CCP antibodies, and IgM-RF. These three tests had comparable sensitivity and specificity.     

Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA

The aim of this study was to evaluate serum and synovial levels of IL-17A by ELISA in rheumatoid arthritis (RA) and find out the correlations between IL-17A levels and various clinical, laboratory parameters and RA disease activity and severity indices. Group I consists of 30 adult active RA patients fulfilling the ARA 1987 revised criteria, with knee effusion and receiving basic therapy, and with a mean age of 41.47 ± 11.49 years and mean disease duration of 9.5 ± 4.16 years. Group II consisted of 13 healthy volunteers, age- and sex-matched, with a mean age of 39.08 ± 14.19 years. RA patients showed significantly higher mean serum IL-17A levels than controls (11.25 ± 9.67 vs. 0.6 ± 1.4 pg/mL, respectively, p = 0.0002). Synovial IL-17A levels showed a significant positive correlation with serum IL-17A levels (r = 0.5 and p = 0.005). RA patients with negative rheumatoid factor (RF) had non-significantly higher mean serum IL-17A levels (12 ± 9.86 pg/mL) compared to those with positive RF (10.82 ± 9.81 pg/mL); however, the mean synovial IL-17A levels were nearly the same. Significant positive correlations were found between both serum and synovial IL-17A levels and DAS-28 scores (r = 0.556, 0.392 and p = 0.001, 0.032, respectively). RA patients with class III functional status showed significantly higher mean serum IL-17A levels (17.53 ± 13.43 pg/mL) than classes I and II (8.97 ± 6.97 pg/mL, p = 0.009). These led us to conclude that the elevated serum and synovial IL-17A levels in RA patients parallel the degree of disease activity and severity. This may highlight the usefulness of IL-17 (especially serum level) as a possible marker for more aggressive joint involvement and damage.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

 Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20 pg/ml versus 61 ± 8 pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36 pg/ml versus 413 ± 49 pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258 pg/ml; HGF, 1500 ± 295 pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94 pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43 pg/ml; HGF, 1294 ± 224 pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients. Received: February 19, 2002 / Accepted: August 13, 2002 Acknowledgment We are grateful to Ms. Aki Nomura for assistance with the ELISA of VEGF and HGF.     

Amyloid A amyloidosis secondary to rheumatoid arthritis: pathophysiology and treatments

The introduction of biological therapies targeting specific inflammatory mediators revolutionised the treatment of rheumatoid arthritis (RA). Targeting key components of the immune system allows efficient suppression of the pathological inflammatory cascade that leads to RA symptoms and subsequent joint destruction. Reactive amyloid A (AA) amyloidosis, one of the most severe complications of RA, is a serious, potentially life-threatening disorder caused by deposition of AA amyloid fibrils in multiple organs. These AA amyloid fibrils derive from the circulatory acute-phase reactant serum amyloid A protein (SAA), and may be controlled by treatment. New biologics may permit AA amyloidosis secondary to RA to become a treatable, manageable disease. Rheumatologists, when diagnosing and treating patients with AA amyloidosis secondary to RA, must understand the pathophysiology and clinical factors related to development and progression of the disease, including genetic predisposition and biological versatility of SAA.     

Study on the safety and efficacy of tocilizumab,an anti-IL-6 receptor antibody,in patients with rheumatoid arthritis complicated with AA amyloidosis

Abstract

Objectives: Although treatment of rheumatoid arthritis (RA) has progressed by the use of biologics, amyloid A (AA) amyloidosis is still an intractable complication in patients with RA. In the present study, safety and efficacy of 1-year treatment with an anti-IL-6 receptor antibody tocilizumab (TCZ) on RA and AA amyloidosis were estimated.

Methods: TCZ (8 mg/kg every 4 weeks) was administered to five RA patients complicated with AA amyloidosis. The primary end point was improvement in renal dysfunction and the secondary end point was CDAI at 1 year after the treatment.

Results: An improvement in the renal dysfunction, including urinary protein secretion, was found, in four patients including two patients who were refractory to etanercept, with a remarkable decrease of SAA concentration, and the progression of organ dysfunction was prevented at 1 year in all patients treated with TCZ. The mean clinical disease activity index decreased from 33.9 to 4.7 (p = 0.012) in five patients treated with TCZ for 1 year. Three non-serious adverse events were observed in two patients.

Conclusions: TCZ ameliorates renal dysfunction in RA patients complicated with AA amyloidosis who are refractory to conventional therapies, thereby suggesting that TCZ has a potential to regulate AA amyloidosis.     

Native LDL-Cholesterol Mediated Monocyte Adhesion Molecule Overexpression is Blocked by Simvastatin

Aim of the study  This study sought to evaluate the effect of nLDL concentrations on monocyte adhesion molecule expression in hypercholesterolemic patients with stable coronary artery disease (CAD) and to determine whether lipid-lowering therapy with simvastatin would change this effect. Methods  Blood samples from patients with hypercholesterolemia (mean LDL 152 mg/dL) and CAD (HC, n = 23) were collected before and after a 12-week treatment with 40 mg of simvastatin. Healthy individuals (mean LDL 111 mg/dL) were used as controls (CT, n = 15). Isolated nLDL, at a fixed concentration of 100 mg/dL, was added to monocyte suspensions obtained before and after the simvastatin treatment. Monocyte activation was determined by changes in cellular adhesion molecule expression. Results  In response to nLDL, CD11b and CD14 adhesion molecule expression was higher in HC patients than in CT patients before treatment (174.2 ± 8.4 vs 102.2 ± 6.3, P < 0.03 and 140.4 ± 5.0 vs 90.4 ± 6.7, P < 0.04). After simvastatin treatment, CD11b expression decreased to 116.9 ± 12.5 (P < 0.03) and CD14 expression to 107.5 ± 6.2 (P < 0.04). Alternatively, L-selectin expression was lower in HC patients than in CT patients before therapy (46.0 ± 3.5 vs 62.1 ± 5.5, P < 0.04), and it increased markedly after lipid reduction to 58.7 ± 5.0 (P < 0.04 vs baseline). After simvastatin treatment, LDL was reduced to mean 101.5 mg/dL. Conclusions  These data demonstrate that monocytes from HC patients are more prone to marked nLDL-mediated changes of adhesion molecule expression than monocytes from controls. Simvastatin is capable of inhibiting such nLDL effects. This proinflammatory response to nLDL may have a role in the early onset of atherosclerosis.     

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.     

A case with rheumatoid arthritis and systemic reactive AA amyloidosis showing rapid regression of amyloid deposition on gastroduodenal mucosa after a combined therapy of corticosteroid and etanercept

Systemic reactive amyloid A (AA) amyloidosis is one of the critical complications associated with rheumatoid arthritis (RA). Recently, there are several useful reports of anti-tumor necrosis factor therapy for RA-related systemic reactive AA amyloidosis patients. However, the time-kinetic transition between effective anti-inflammatory therapies and regression of AA amyloid deposits remains uncertain. Here, we report a RA patient with systemic reactive AA amyloidosis who was successfully treated with prednisolone and etanercept, showing marked regression of gastroduodenal mucosal amyloid deposits within only 4 months. This is the first case report of RA-related systemic reactive AA amyloidosis histopathologically demonstrating rapid regression of amyloid deposits on gastroduodenal mucosa after adequate suppression of the underlying inflammatory condition.