AA amyloidosis - Benefits and prospects of IL-6 inhibitors.

AA amyloidosis may develop in patients with active chronic inflammation. Serum amyloid A (SAA), the precursor of the AA protein, is strongly amplified in the liver under the stimulation of inflammation-associated cytokines, such as IL-6, TNF, and IL-1. Sustained inflammation, aging, and polymorphisms in the SAA1.3 genotype are dependent risk factors for the formation of AA amyloidosis. The most rational treatment strategy for AA amyloidosis is to inhibit the production of SAA. Treatments for AA amyloidosis involving biologics have recently been emphasized. TNF inhibitors and abatacept reduce SAA levels; however, complete normalization is not always achieved. IL-6 inhibitors may normalize SAA levels in most patients in whom a sufficient concentration of medication is maintained in the blood. Therefore, treatments with IL-6 inhibitors represent an excellent therapeutic strategy for AA amyloidosis and have been verified by recent studies.

Achieving simplified disease activity index remission in patients with active rheumatoid arthritis is associated with subsequent good functional and structural outcomes in a real-world clinical setting under a treat-to-target strategy.

OBJECTIVE: To verify predictive validity of simplified disease activity index (SDAI) remission for subsequent functional and structural outcomes in real-world clinical settings under a treat-to-target strategy (T2T). METHODS: In this multicenter, prospective cohort study, T2T was implemented in rheumatoid arthritis (RA) patients with moderate-to-high disease activity. SDAI or clinical disease activity index (CDAI) was assessed every 12 weeks, and treatment was adjusted to achieve clinical remission or low disease activity (LDA). Multivariate logistic regression models were used to examine the associations of SDAI remission (≤3.3) at week 24 with the health assessment questionnaire-disability index (HAQ-DI) ≤ 0.5 or with the delta van der Heijde-modified total Sharp score (ΔvdH-mTSS)

Study on the frequency and risk factors of moderate-to-severe sleep apnea syndrome in rheumatoid arthritis.

OBJECTIVES: We aimed to investigate the frequency of moderate-to-severe sleep apnea syndrome (SAS) that possibly influences long-term prognosis in patients with rheumatoid arthritis (RA), and to analyze the risk factors for this group. METHODS: We examined respiratory disturbance index (RDI) by polysomnography in 62 hospitalized RA patients. Risk factors of moderate-to-severe SAS (RDI ≥20) were analyzed using a multivariate logistic regression analysis. RESULTS: RA was complicated by moderate-to-severe SAS in 13/62 (20.9%) cases. The highest stage of temporomandibular joint abnormality (TMJA) and a high value of health assessment questionnaire-disability index (HAQ-DI) were significant risk factors, according to the results of the multivariate logistic regression analysis (p < 0.0001 and p = 0.010, respectively). Contrary to these results, RDI was not related to the disease activity indexes of RA and other clinical characteristics. CONCLUSION: We clarified that the highest TMJA stage and a high value of HAQ-DI are novel important risk factors for moderate-to-severe SAS in RA patients.

Comparison of the clinical utility of tocilizumab and anti-TNF therapy in AA amyloidosis complicating rheumatic diseases.

OBJECTIVES: Anti-cytokine therapy is reportedly useful in amyloid A (AA) amyloidosis complicating rheumatic diseases. However, to date no studies have directly compared the utility of tumour necrosis factor (TNF) inhibition to that of interleukin-6. The aim of our retrospective study was to compare the clinical utility of tocilizumab (TCZ) and anti-TNF (TNF inhibitor) therapy. METHODS: We studied 42 patients treated with anti-cytokine agents at our hospital: 31 had received a single agent, ten had received two agents and one had received three agents. Patients were divided into a TCZ group (22 patients) and a TNF inhibitor group (32 patients). The main parameters compared were treatment retention rate, serum amyloid A (SAA) profile, renal function profile and clinical disease activity index. RESULTS: The 5-year retention rates were 90.4 (TCZ group) and 34.3 % (TNF inhibitor group) (p = 0.0154, log-rank test). The median SAA fell from 219.2 µg/mL at treatment initiation to 5.0 µg/mL at last observation (TCZ), and from 143.6 to 38.1 µg/mL (TNF inhibitor) (p = 0.0194). Estimated glomerular filtration rate was improved in 72.7 (TCZ) and 34.4 % (TNF inhibitor) of patients (p = 0.0062). The rates of clinical remission or low disease activity at last observation for the TCZ and TNF inhibitor groups were 72.7 and 40.7 % (p = 0.0201), respectively. CONCLUSIONS: Based on these results, we conclude that TCZ was of greater clinical utility than anti-TNF therapy in our patients with AA amyloidosis complicating rheumatic diseases.

[Significance of susceptibility-weighted angiography for endovascular thrombectomy of acute ischemic stroke].

Efficacy of intravenous systemic thrombolysis is limited in patients with large-vessel occlusion and for whom more than 4.5 hours have passed since onset. As such, mechanical thrombectomy has been the mainstay therapy for these patients. Localization of the intra-arterial clot prior to thrombectomy can be beneficial in cases of acute ischemic stroke. Here, we present 3 cases of acute ischemic stroke that were initially imaged with susceptibility-weighted angiography(SWAN)before endovascular thrombectomy(middle cerebral artery occlusion, internal carotid artery occlusion, basilar artery occlusion)was attempted. In all 3 cases, clot localization by SWAN was consistent with that by angiography, and recanalization was successful. Identifying clot location and composition may help determine the optimal treatment and predict successful recanalization.

Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis.

We report successful tocilizumab (TCZ) use in a patient with adult-onset Still's disease (AOSD) complicated by chronic hepatitis B (CHB) and AA amyloidosis (AAA). Treatments with corticosteroid and various types of immunosuppressants were unsuccessful. Aggravation of CHB ensued, and entecavir was started. Normalisation of liver function and hepatitis B virus (HBV) DNA were confirmed. TCZ was then started. His arthritis and AAA improved dramatically. TCZ is an excellent treatment for refractory AOSD and is feasible in an HBV-infected patient.

Rituximab used for simultaneous treatment of PR3-ANCA positive vasculitis associated with rheumatoid arthritis: A case report.

We treated PR3-ANCA positive vasculitis in a patient diagnosed with rheumatoid arthritis using rituximab. Monoclonal antibody therapy can be used to simultaneous treat more than one collagen disease in such patients. This suggests that shared pathogenic pathways exist between different collagen diseases.

Microsurgery of Spinal Dural Arteriovenous Fistula Using Indocyanine Green Video Angiography: 2-Dimensional Operative Video.

Spinal dural arteriovenous fistulas (SDAVF) develop by direct abnormal arteriovenous connection between both sides of the spinal dura matter. In this condition, there is no intervening nidus between a meningeal segmental artery and a radiculomedullary vein. Open microsurgery is one of the choices for patients with SDAVF. When the AVF is on the inner dural surface, we can easily block the radiculomedullary vein in a microscopic view. We herein report a 50-yr-old woman who presented with low back pain, was diagnosed with an SDAVF, and underwent surgical treatment under a microscopic view. The spinal angiography demonstrated abnormal arteriovenous connections between intercostal arteries at the level of Th11 to 12 and the intradural radiculomedullary vein. Operative indocyanine green (ICG) microangiography demonstrated the blood flow in meningeal vessels and their anastomoses between both sides of the dural surface. We easily identified the radiculomedullary vein fed by the surrounding meningeal feeding arteries and block completely under a direct microscopic view. We detected the change in hemodynamic during feeder ligation by Flow 800 (Zeiss Penteto Flow 800 microscope; Zeiss Corporation, Tokyo, Japan). After surgery, the patient's symptoms disappeared and no recurrence of the disease has been noted in the past 23 mo. We have received the informed consent of this patient for the publication of this case report.

First Nationwide Survey of 199 Patients with Amyloid A Amyloidosis in Japan.

Objective To clarify the underlying diseases, clinical manifestations, and treatment strategies for Amyloid A (AA) amyloidosis (AAA) in Japanese patients. Methods We conducted a survey on Japanese patients with AAA treated between January 1, 2012, and December 31, 2014. Results A total of 199 patients with AAA were included in the present study. The underlying diseases of AAA were rheumatoid arthritis (60.3%), uncharacterized inflammatory disorders (11.1%), neoplasms (7.0%), other rheumatic diseases (6.5%), inflammatory bowel diseases (4.5%), chronic infection (4.5%), Castleman's disease (4.0%), and autoinflammatory diseases (2.0%). The clinical manifestations at the diagnosis of AAA were moderate to severe renal dysfunction (46.2%), moderate to severe proteinuria (30.7%), intractable diarrhea (32.2%), melena (4.5%), paralytic ileus (3.5%), heart failure (11.6%), cardiac conduction disturbances (10.1%), arrhythmia (5.5%), and hypothyroidism (11.6%). Diagnostic biopsies were performed most frequently in the gastrointestinal tract (66.3%), followed by the kidneys (22.1%), heart (5.5%), abdominal fat (4.0%), and others (3.0%). Biologics were used to treat 97 patients with AAA (48.7%). Tocilizumab (TCZ) was administered to 66 patients, with 95.5% showing good responses. Anti-TNF agents were administered to 27 patients, with 74.1% showing good responses. The treatment effects of TCZ were significantly superior to those of anti-TNF agents (p<0.007). Conclusion The most common underlying diseases of AAA were rheumatic diseases. Uncharacterized inflammatory disorders and neoplasms were also frequently observed in patients with AAA. Renal and gastrointestinal manifestations were common and important for the diagnosis of AAA, with cardiac manifestations also being of significance. Biologics, particularly TCZ, were effective therapeutic modalities.

The prevalence of endoscopic gastric mucosal damage in patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) patients often take non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids as supportive drugs. In this study, we investigated the prevalence of endoscopic gastric damage and their prescribed medications under an actual clinical condition. METHODS: We collected the data of 1704 RA patients who underwent upper gastrointestinal fiberscopy. Gastric mucosal erosion and ulcer were classified using modified LANZA score. We analyzed these data with a multiple regression analysis. RESULTS: The prevalence of endoscopic gastric mucosal damage in these RA patients was 16.7% (285 cases). A multiple regression analysis indicated that prednisolone (PSL), NSAIDs and proton pump inhibitors (PPIs) were independent risk factors associated with the modified LANZA score. PSL and NSAIDs were positively correlated with the score, while the administration of PPIs was inversely correlated with the score. The modified LANZA score in RA patients treated with both PSL and NSAIDs was significantly higher than that in those treated with PSL alone (no NSAIDs use). CONCLUSIONS: Our findings suggest that PSL and NSAIDs were exacerbating factors for gastric mucosal damage, while PPIs usage was a protective factor. And, the combined usage of corticosteroids and NSAIDs may induce the development of gastric ulcers.

Detection of AA76, a Common Form of Amyloid A Protein, as a Way of Diagnosing AA Amyloidosis.

Reactive amyloid deposits consist of amyloid A (AA) proteins, the degradation products of serum amyloid A (SAA). Since the most common species of AA is the amino terminal portion produced by cleavage between residues 76 and 77 of SAA (AA76), the presence of AA76 in tissues could be a consequence of AA amyloid deposition. This study assessed the diagnostic significance of the detection of AA76 for AA amyloidosis using two different approaches. Biopsy specimens (n=130 from 54 subjects) from gastroduodenal mucosa or abdominal fat (n=9 from 9 subjects) of patients who had already been diagnosed with or were suspected of having AA amyloidosis were used. Fixed mucosal sections were subjected to immunohistochemistry using a newly developed antibody recognizing the carboxyl terminal end of AA76 (anti-AA76). The non-fixed materials from gastroduodenal mucosa or abdominal fat were subjected to immunoblotting for detection of the size of AA76. Among the gastroduodenal specimens (n=115) from already diagnosed patients, the positive rates of Congo red staining, immunohistochemistry using anti-AA76, and immunoblotting were 68.4%, 73.0%, and 92.2%, respectively. The anti-AA76 did not stain the supposed SAA in the blood or leakage, which was stained by anti-SAA antibody. AA76 was not detected either by immunohistochemistry or by immunoblot in the materials from patients in whom AA amyloidosis had been ruled out. In the abdominal fat, the immunoblot detected AA76 in 8 materials from 8 already diagnosed patients and did not in 1 patient whose gastroduodenal mucosa was negative. In conclusion, the detection of AA76 may alter the ability to diagnose AA amyloidosis. In immunohistochemistry for fixed specimens, the new anti-AA76 antibody can improve the specificity. Immunoblot for non-fixed materials, which can considerably improve the sensitivity, should be beneficial for small materials like abdominal fat.

Postischemic intraventricular administration of FGF-2 expressing adenoviral vectors improves neurologic outcome and reduces infarct volume after transient focal cerebral ischemia in rats.

Fibroblast growth factor (FGF)-2 is a potent neurotrophic and angiogenic peptide. To examine possible protective effects of FGF-2 gene expression against transient focal cerebral ischemia in rats, a replication defective, recombinant adenovirus vector expressing FGF-2, was injected intraventricularly 2 hours after middle cerebral artery occlusion (MCAO). The treatment group showed significant recovery compared with the vehicle-treated groups in terms of serial neurologic severity scores over the 35 days after MCAO. Further, 2,3,5-triphenyltetrazolium chloride staining showed that FGF-2 gene transfer decreased infarct volume by 44% as compared with that in the vehicle-treated groups at 2 days after MCAO. The same tendency of gene transfer effects on infarct volume was confirmed at 35 days after MCAO with hematoxylin/eosin staining. Enzyme-linked immunosorbent assay revealed that FGF-2 concentration was increased significantly at 2 days after MCAO, not only in cerebrospinal fluid but also in cerebral substance in the lesioned and treated animals. These results suggested that FGF-2 gene transfer using these adenoviral vectors might be a useful modality for the treatment of occlusive cerebrovascular disease even after the onset of stroke.

An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians.

Serum amyloid A1 (SAA1), one of the two isotypes of acute phase SAA, is the predominant precursor to amyloid A (AA) protein, the chief constituent of fibrillar deposits in reactive (AA) amyloidosis. Prolonged hyperexpression of SAA protein accompanying chronic inflammation is critical to, but seems not to be sufficient for, the development of AA amyloidosis. Several previous studies have investigated the possibility of linkage between SAA1 exon 3 polymorphisms and susceptibility to amyloidosis. While the SAA1.1 allele was found to have a negative association with amylodosis in Japanese subjects, it showed a positive association in Caucasians. Moriguchi and colleagues recently showed that a single nucleotide polymorphism (SNP) at position -13 in the SAA1 5' flanking region was more strongly associated with amyloidosis than was the exon 3 polymorphism. To test whether this SNP may be an amyloidogenic factor common to Japanese and Caucasians, we have analyzed the SAA1 gene in amyloid and non-amyloid patients of both ethnic groups for the presence of T or C at position -13 and for exon 3 polymorphisms (SAA1.1, 1.3 or 1.5). The frequency of the -13T allele was 0.708 and 0.521 in Japanese rheumatoid arthritis patients with and patients without AA amyloidosis, respectively, and 0.536 and 0.196 in American Caucasian patients with AA amyloidosis and control subjects, respectively. In Caucasians, the -13T allele had a stronger association with amyloidosis than did the SAA1.1 allele. These findings suggest that -13T is a genetic background for AA amyloidosis in both Japanese and Caucasians and the difference in prevalence of AA amyloidosis in the two ethnic groups may be due, at least in part, to a difference in the frequency of the -13T SAA1 allele.

Tocilizumab induced acquired factor XIII deficiency in patients with rheumatoid arthritis.

Factor XIII is one of the twelve coagulation factors and also known as a fibrin-stabilizing factor. In 2012, we encountered a male RA patient with hemorrhagic factor XIII deficiency who had been treated with tocilizumab for two years. There are few reports regarding the relationship between tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)) and factor XIII. We measured the factor XIII activity levels in the plasma of 40 RA patients (10 patients treated without biologics, 30 patients treated with biologics (15 patients treated with necrosis factor inhibitors and 15 patients treated with tocilizumab)) and 19 healthy controls. Consequently, the tocilizumab group exhibited lower levels than the other three groups according to the Steel-Dwass test (P<0.01). Furthermore, we compared the plasma factor XIII activity levels and the plasma factor XIII concentrations in the RA patients treated with biologics. Pearson's correlation test was used to assess the relationship between the factor XIII activity levels and the plasma factor XIII concentrations (r=0.449, P=0.019). According to the multiple regression analysis, the treatment with tocilizumab is an independent risk factor for plasma factor XIII reduction in RA patients. In conclusion, RA patients treated with tocilizumab, an IL-6R blocker, are at risk of developing acquired factor XIII deficiency. The mechanisms underlying the reduced factor XIII activity observed in RA patients treated with tocilizumab may result from the quantitative reduction in the plasma. These data imply that IL-6 plays an important role in maintaining the factor XIII activity level.

AA amyloid quantification in biopsy samples from the stomach.

Amyloidosis is usually diagnosed through the histological examination of biopsy samples. However, its quantitative evaluation can be difficult. In this study, we immunochemically measured amyloid A (AA) proteins in biopsy samples taken from the stomachs of patients with AA amyloidosis. Samples were treated with guanidine and were subjected to an enzyme immunoassay for serum amyloid A. The results were compared with histological findings. All patients who tested negative for amyloid deposits had low values that clearly distinguished them from amyloid-positive patients. Among the amyloid-positive patients, the AA values correlated significantly with histological findings. This method may be useful for the quantitative evaluation of AA amyloidosis.

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

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.

Differential affinity of serum amyloid A1 isotypes for high-density lipoprotein.

Serum amyloid A (SAA), a precursor of reactive amyloid deposits, is a multigene product. SAA1, predominant both as an amyloid precursor and in plasma, consists of three allelic variants (SAA1.1, SAA1.3, and SAA1.5). Several investigations have shown that the SAA1.3 allele is associated with susceptibility to AA-amyloidosis in Japanese, and the SAA1.5 allele is related with higher serum concentrations of SAA. However, these results have not been interpreted functionally. This study assessed the affinity of SAA isotypes for high-density lipoprotein (HDL), to which SAA binds in plasma. Using a surface plasmon resonance-based apparatus (BIAcore), the affinity between immobilized recombinant human SAAs and HDL was determined. The SAA concentration was measured in fractions after ultracentrifugation (d = 1.23) of sera from patients with rheumatoid arthritis, whose SAA1 genotypes were determined. In the BIAcore analysis, as the dissociation reaction under the conditions used was too rapid to fit the typical kinetic model, the steady-state affinity model was used. The affinity (kd) of SAA1.1, SAA1.3, and SAA1.5 for HDL was 1.4 x 10(-5), 1.8 x 10(-5), and 3.7 x 10(-6), respectively. rSAA1.5 showed significantly (p < 0.05) stronger affinity than the other two. The fraction of lipid-free SAA in serum was significantly (p < 0.001) lower in the patients with larger numbers of the 1.5 allele at the SAA1 locus. These results suggest that the relatively high affinity of SAA1.5 may cause the high serum concentration and may be related to the low susceptibility to amyloidosis.

Review of tocilizumab in the treatment of rheumatoid arthritis.

Constitutively overproduced in proliferating synovial tissues, interleukin-6 (IL-6) is deeply involved in the pathology of rheumatoid arthritis (RA). Tocilizumab is a humanized anti-human IL-6 receptor antibody that binds to soluble and membrane-bound IL-6 receptor, and at detectable levels in blood, tocilizumab is capable of almost completely blocking the transmembrane signaling of IL-6. In clinical trials for patients with RA in Japan, tocilizumab monotherapy has shown clinical efficacy equaling that of tumor necrosis factor (TNF) inhibitor in combination with methotrexate, and in an extension study in patients who responded to tocilizumab, almost no patients showed a decrease in the efficacy of tocilizumab. Evidence obtained in a phase III study in Japan demonstrated that tocilizumab monotherapy had a sig-nificant inhibitory effect on the progression of structural joint damage compared with that of conventional disease modifying antirheumatic drugs (DMARDs). Furthermore it has been shown that tocilizumab has an excellent ability to suppress serum amyloid A levels and could therefore be an important therapeutic strategy in amyloid A amyloidosis secondary to rheumatic diseases. The safety profile of tocilizumab appears to be satisfactory. However, several serious infections were also reported, and careful monitoring is therefore important during use.