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We retrospectively gathered data of 21 patients (13 male and 8 female; median age 65 years) diagnosed with immunoglobulin M (IgM)-related light-chain (AL) amyloidosis in Japan to investigate characteristics of IgM-AL amyloidosis and its optimal treatment strategy. Median IgM and difference free light chain (FLC) at diagnosis were 1257 mg/dl and 34.3 mg/l, respectively. Organ involvement was observed in the heart in 7 patients (33%), kidneys in 15 (71%), and lymph nodes in 5 (24%). Initial treatments were melphalan/dexamethasone in 7 patients, bortezomib/cyclophosphamide/dexamethasone in 3, autologous stem cell transplantation in 3, rituximab/bendamustine in 1, other in 3, and none in 4. Hematological responses among 15 evaluable patients were as follows: 3 reached complete response (CR), 4 partial response (PR), and 1 very good PR (VGPR), making the overall response rate of PR or better 40%. Median overall survival (OS) was 14.0 months and 1-year OS was 71.4%. Prognosis was significantly poorer in patients with cardiac involvement than those with non-cardiac involvement (1-year OS 27.8% vs. 85.7%, p = 0.0468). The involved FLC value was low in several patients and therapeutic response was difficult to assess. Further study is necessary to determine the optimal treatment for IgM-AL amyloidosis., (© 2023. Japanese Society of Hematology.)

The molecular pathogenesis of human amyloidosis has been elucidated greatly during the last 20 years. Based on the understanding of the molecular mechanisms of amyloid fibril formation and deposition, various kinds of new drugs and therapeutics have been emerging to improve the prognosis of amyloidosis and even cure this disease. In this review article, we first summarize the pathogenesis and state-of-the-art therapeutics of representative types of systemic human amyloidosis, that is, immunoglobulin light chain-related, transthyretin-related, amyloid A-associated and β 2 -microglobulin-related amyloidosis. Next, we describe the essential roles of pathological diagnosis, especially the typing diagnosis of amyloidosis to appropriately guide type-specific therapies of amyloidosis patients. Finally, we introduce the activities of the government-funded group for surveys and research of amyloidosis in Japan, especially the nation-wide pathology consultation system of amyloidosis, which started in April 2018. The nation-wide improvement of the typing diagnosis of amyloidosis is essential for the appropriate treatment and care of amyloidosis patients in Japan., (© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

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.

Amyloid light-chain amyloidosis (ALA) is a rare disease with poor prognosis and is often associated with monoclonal gammopathy of undetermined significance, multiple myeloma, or Waldenström macroglobulinemia. Only high-dose melphalan with auto-peripheral blood stem cell transplantation (PBSCT) has shown high long-term hematological response rates, but combinations with novel agents, including bortezomib or lenalidomide, have recently shown high hematological response rates for AL amyloidosis patients. In the present study, we treated eight Japanese patients with AL amyloidosis using bortezomib, cyclophosphamide, and dexamethasone (CyBorD). Overall response rate was 100 %; four patients (50 %) had complete remissions (CR), two (25 %) had very good partial responses, and two (25 %) had partial responses. Five of six patients (83 %) had organ responses in the heart and/or kidney. A relapsed patient repeatedly achieved CR with the CyBorD treatment. One patient died of sudden cardiac arrest a month after normalization of his serum free light chain level, which may be attributable to his spending the previous 6 months undergoing PBSCT collection and high-dose melphalan with auto-PBSCT. Altogether, the CyBorD regimen achieved high levels of hematological responses relatively quickly (within 2-3 months). The CyBorD regimen, rather than high-dose melphalan treatment, could serve as a first-line therapy for Japanese patients with ALA.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of β2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of β2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients., (© 2012 The Authors. Therapeutic Apheresis and Dialysis © 2012 International Society for Apheresis.)

Dialysis-related amyloidosis (DRA) is a serious complication in patients undergoing long-term dialysis treatment. Deposited β(2)-microglobulin-related amyloid induces various osteoarticular disorders. The pathogenetic interaction of DRA with chronic kidney disease-minenal bone disorder (CKD-MBD) is still unclear, while clinical managements for both osteoarticular disorder and DRA is commonly required in dialysis patients. Recently, practical guidelines for DRA are published in Japan. Those make possible to assess DRA with not only pathological examination but also clinical manifestations, such as carpal tunnel syndrome, destructive spondyloarthropathy, joint pains, and so on. Treatments for DRA include hemodialysis with biocompatible high-flux dialysis membrane and/or ultrapure dialysate, hemodiafiltration, and β(2)-microglobulin adsorbent column. Recent studies suggested that these treatments have efficacy on the onset and severity of DRA, even mean age in patients are getting older with long term dialysis treatment.

Renal involvement is very common in AL amyloidosis. Our aim was to investigate associations between the clinical characteristics and renal pathology of patients with AL amyloidosis. The data of 11 adult Japanese patients with AL amyloidosis and renal involvement were analyzed retrospectively. To assess the difference based on the pattern of distribution of amyloid deposition, we divided the patients into a group with the capillary form and a group with the small vessel form, and compared the clinical characteristics of the two groups. Concerning AL amyloidosis, the small vessel form group was associated with cardiac involvement and left ventricular thickening compared with the capillary form group (p = 0.03). There were no significant differences between the groups in the rates of patient survival and renal survival. There was a negative correlation between grade of amyloid deposition and renal survival duration (p = 0.04, r² = 0.66). The degree of amyloid deposition was not correlated with the extent of proteinuria or renal function. These findings suggest that the vascular deposition pattern of amyloid in the kidney is important for determining patient survival and renal outcome.

Pathologic informatics is an analysis of mechanism of pathogenesis using various medical information. Biologic reactions by many reactants are studied on molecules, cells, organs, and individuals by using various methods. Themes of our laboratory are as follows: 1) to analyze of the pathogenesis of various diseases by using novel diagnostic methods, 2) to elucidate amyloid formation mechanism in amyloidosis and to develop novel therapies, 3) to develop the methods for tests and diagnosis for DIC, 4) to study on activation mechanism of ribosomal proteins in the tissues by the blood cell function, 5) to study on the expression and suppression of neogenesis of blood vessels by physical invasion in the organ failure, and 6) to develop the diagnostic methods for autonomic dysfunction and to analyze the pathogenesis.

The current understanding of dialysis-related amyloidosis has evolved over the past two decades. In the early 1980s, several researchers found amyloid deposits in the synovia of carpal tunnel syndrome (CTS), which have been recognized as a complication of chronic hemodialysis. The enigma was resolved in 1985, when beta2-microglobulin (beta2-m) with a molecular weight of 12,000 Da was identified as the major constitutional protein of this amyloid. Amyloid fibrils of this type that contain the sub-unit protein of human leukocyte antigens (HLA), beta2-m, deposit predominantly in osteoarticular tissues, inducing musculoskeletal symptoms such as CTS, polyarthralgia, bone cyst showing radiolucency at X-ray examination and destructive spondyloarthropathy. In addition, extra articular symptoms such as ischemic colitis, megaloglossia, and heart failure, that is, systemic involvement occasionally occur. We confirmed that the prevalence of CTS increases with duration of dialysis. Most patients with CTS associated with beta2-m amyloid deposits have undergone hemodialysis for 10 years or more. Up to 50% of patients had developed this complication after 20 years and the percentage was even higher after 25 years. General categories of therapeutic approaches for amyloidosis include prevention of onset or progression, symptomatic therapy (conservative treatment, orthopedic procedures, and physiotherapy), and renal transplantation. It is critical to elucidate the detail mechanisms of the amyloid fibril formation, and establish its radical treatment. It is also important to develop novel therapies such as cell implantation to compensate for normal kidney functions of uremic toxin protein metabolism.

It is well established that amyloidosis is a serious clinical complication that can influence the prognosis of patients with rheumatoid arthritis (RA). The purpose of the study was to obtain information on the survival and the hemodialysis (HD) of patients with amyloidosis. Eighty patients (9 men and 71 women) who were diagnosed with amyloidosis by biopsy and definite or classical RA were studied retrospectively. The average duration of RA prior to the diagnosis of amyloidosis was 15.4+/-9.4 years. The average period from the diagnosis of amyloidosis to death was 67.4 months. Forty-nine patients died of the disease (32 cases with HD and 17 cases without HD). Thirty-one patients lived (7 cases with HD and 24 cases without HD). Regarding the survival of these patients, 49 (61.3%) of the 80 patients have died. Survival rate at 28 months was 75%; at 67 months, it was 50%; and at 111 months, it was down to 25%. Mortality rate was 11.9% per year. Survival rate in dialysis at 9.8 months was 75%; at 60.6 months, it dropped to 50%; and at 100.0 months, to 25%. As for patients' survival, high onset age of amyloidosis was the major determining factor for poor survival in these patients (p<0.001). Furthermore, male patients also had poor survival (p=0.07). The long-term results were very encouraging to initiate HD in patients with end-stage renal disease due to reactive amyloidosis associated with RA.

No established treatments for systemic AL amyloidosis have been determined, and only four reports have described allogeneic stem cell transplantation for this disease. We report the case of a patient with orthostatic hypotension, diarrhea, nephrotic syndrome, and cardiac amyloidosis due to systemic AL amyloidosis. Reduced intensity allogeneic stem cell transplantation (RIST) was performed using a conditioning regimen comprising fludarabine 125 mg/m2 and melphalan 90 mg/m2. Hematologically complete remission and symptomatic improvement were obtained without severe transplantation-related complications. RIST may thus offer a useful treatment strategy for systemic AL amyloidosis complicated by cardiac amyloidosis., (Copyright 2006 Wiley-Liss, Inc.)

Objective: Immunoglobulin-related free light chains (FLCs) in serum have recently become quantitatively detectable using the nephelometric assay in plasma cell disorders, including multiple myeloma and AL amyloidosis. To investigate whether FLCs are useful as a diagnostic and therapeutic marker in Japanese patients with primary systemic AL amyloidosis, we determined these values in serum before and after chemotherapy., Patients and Methods: The serum FLC analysis was carried out in 25 patients with primary systemic AL amyloidosis (mean age, 60.1+/-8.4 years). All of the patients were shown to have either ALkappa- or ALlambda-immunoreactive amyloid deposits on biopsied tissues. Thirteen patients were treated with VAD (vincristine, doxorubicin and dexamethasone) alone (n=6) or VAD and subsequent high-dose melphalan followed by autologous stem cell support (n=7), and serum FLCs were serially determined before and after the chemotherapy., Results: Before chemotherapy the amyloidogenic FLC was elevated in serum with or without abnormal e/e ratios in 24 patients, including 5 with undetectable M-protein in both serum and urine on immunofixation. After chemotherapy the amyloidogenic FLC in serum was significantly decreased irrespective of high-dose melphalan (p<0.05), and all the patients with normalized kappa/lambda ratios showed a good prognosis., Conclusions: With respect to sensitivity and quantification serum FLCs will be a key marker for diagnosis and therapeutic effects in primary systemic AL amyloidosis. The prognosis of patients with this disease may be improved if the kappa/lambda ratio in serum can be normalized by intensive chemotherapy.

Portuguese-type amyloidosis (transthyretin amyloidosis, ATTR V30M) is the most common form of systemic hereditary amyloidosis, inherited in autosomal dominant mode. The disease, also called familial amyloid polyneuropathy type I (FAP-I), is caused by a mutant transthyretin (TTR) protein, which is synthesized by the liver. A single amino acid substitution of methionine for valine at position 30 of the TTR molecule (TTR V30M) was found in Portuguese patients. The clinical disease usually manifests as a peripheral sensory, motor and autonomic neuropathy starting in the 3rd or 4th decade of life. Renal manifestations of ATTR V30M, like other amyloidoses, are different levels of proteinuria and renal insufficiency. In ATTR V30M a large amyloid deposition in the medullary zone of the kidney and tubules is characteristic. A more extensive glomerular and vascular involvement is present only in patients with renal manifestations. A prospective survey in the north of Portugal showed that a stage of microalbuminuria (MA) could precede nephropathy and neurological disease. Nephropathy in FAP-I is present in one-third of affected patients and tends to aggregate in families. The progression towards end-stage renal disease (ESRD) affects 10% of the patients, and the survival after initiation of dialysis is a mean of 21 months. Patients who progress to ESRD have a late onset of neuropathy and lower prevalence of clinical disease in their families. Liver transplantation is a widely accepted treatment for FAP-I, and combined liver-kidney transplantation is also an option for selected patients with FAP-I and ESRD.

Effectiveness of various therapeutic modalities was analyzed among 1,196 patients entered in the registry of the Japanese Society for Dialysis Therapy who were on hemopurification therapy as of the end of 1998 and developed dialysis-related amyloidosis during 1999. In the investigation, the effectiveness of various hemopurification modalities on the dialysis-related amyloidosis was ranked as exacerbation, unchanged, or alleviation, so as to analyze the possible relationship between the hemopurification modality and its effectiveness. The analysis was performed using a logistic regression approach, and the results were shown as "the risk of a worse therapeutic ranking" among the hemopurification modalities. The smaller "the risk of a worse therapeutic effect" was, the more effective the treatment modality. When the risk of a worse therapeutic effect for the hemodialysis patients treated by a regular membrane was put at 1.0, the risk for hemodialysis patients using high-flux membrane was 0.489, the off-line hemodiafiltration risk was 0.117, the on-line hemodiafiltration risk was 0.013, and the risk of push/pull hemodiafiltration was 0.017. For hemodialysis with a beta(2)-microglobulin adsorption column, a low risk of 0.054 was found. The results indicated that hemodiafiltration therapy and simultaneous hemodialysis with beta(2)-microglobulin adsorption therapy were more effective treatment for dialysis-related amyloidosis.