Secondary Amyloid Research Articles

Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA

Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycans degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect. Among these strategies, gene therapy has shown a great potential though its clinical application is challenging. We have shown previously in an MPS-IIIA mouse model that the molecular tweezer (MT) CLR01, a potent, broad-spectrum anti-amyloid small molecule, inhibits secondary amyloid storage, facilitates amyloid clearance, and protects against neurodegeneration. Here we demonstrate that combining CLR01 with AAV-mediated gene therapy, targeting both the primary and secondary pathologic storage in MPS-IIIA mice, results in a synergistic effect improving multiple therapeutic outcomes compared to each monotherapy. Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application.

Renal AA Amyloidosis in Ankylosing Spondylitis: A Case Report

Ankylosing spondylitis (AS) is a chronic inflammatory joint disease of seronegative spondyloarthropathies (SpA). Secondary amyloid A amyloidosis (Amyloidosis AA) is an uncommon complication of ankylosing spondylitis (AS). Amyloidosis AA is a systemic disease characterized by amyloid deposition in many organs including kidneys. An amyloid fibril formation starts with inappropriate folding of amyloidogenic precursor proteins. The amyloid fibrils have a typical appearance on light microscope that could be easily identified. The classification of secondary amyloidosis is based on the precursor proteins that form amyloid fibrils along with systemic and local distribution of amyloid deposition. Renal involvement is most frequent in systemic amyloidosis. The clinical manifestation of renal amyloidosis differs depending on the type of amyloid protein with the location and amount of amyloid deposition. The treatment of amyloidosis should be focused on managing symptoms and stabilizing amyloid protein.

#2078 Study of spectrum of renal dysfunction in cancer patients on ICPI as mono or combination with conventional chemo in north India

Abstract Background and Aims Although use of ICPI's have revolutionized the treatment of cancer patient with significantly improving the longevity of these patients but it also is associated with various adverse reactions known as iRAE's related to its use, which in due course is being revealed gradually. Kidney related iRAE's are important and also limitation to therapy, which could be a detrimental factor for these patients availing the beneficial effects of these revolutionary medications. Previous literature on these therapeutics had the limitations of being retrospective, small case series and case reports and evaluating only one or two parameters of kidney dysfunction, also the criteria used for evaluations had the limitation of standardization. With this we aimed to study the spectrum of renal dysfunction in cancer patients, receiving ICPI with or without conventional chemotherapy using standard criteria. Method Study involved patients with malignancy who had received at least 1 dose of ICPI as mono or combination with conventional chemotherapy. The primary end-point was 6 month assess the clinical spectrum & outcome of renal dysfunction, and the secondary end-points were the patient-level risk factors for renal dysfunction, the impact of renal dysfunction on clinical outcomes. Results Conducted through October 2021-2022, enrolled N = 156 (66 male & 90 females) & followed up for 6 months. 109 (69.9%) subjects developed KDIGO–AKI—Stage I (51.4%) & Stage II (35.8%) & non required RRT. The median duration for onset of AKI was 131 days. Proteinuria was observed in n = 143 (91.67%). n = 116 (74.3%) developed new-onset proteinuria. n = 40 (25.6%) were proteinuric at the start of the study & 27/40 (67.5%) were observed to have >50% increase in proteinuria, qualifying for proteinuria with therapy. 92/143 proteinuric subjects (64.3%) developed >1 g/day proteinuria. On subcategorizing proteinuria it was observed that 82/92 (57.3%) had 1–3 g/day proteinuria and ≥3.0 g/day proteinuria was observed in 10/92 (7.0%). Definitive ICPI–AKI could be attributed to only 2 subjects, as they underwent kidney biopsy for their kidney dysfunction and significant proteinuria. Secondary amyloid deposits in the glomeruli and mesangium was found in 1 subject & the other subject showed acute tubulointerstitial deposits with granular cast. Proteinuria and kidney dysfunction resolved with stoppage of the ICPI and steroids administration, which was consistent with the limited literature available for the management of ICPI related amyloidosis & iRAE. n = 88 had partial recovery of kidney dysfunction following an AKI event & complete recovery was seen in n = 3 (2.7%). >50% recovery in eGFR was observed in n = 41 (37.6%). Electrolyte abnormality commonly observed were hyponatremia, hypokalemia & hypomagnesemia & was seen in distributed almost equally, followed by hypocalcemia. Hypernatremia, hyperkalemia, hypermagnesemia & hypercalcemia were less commonly reported. Lastly mortality was also observed in n = 16 (10.2%), but could not be directly attributed to ICPI use, kidney dysfunction, malignancy type, comorbid conditions & other concomitants medication use. Conclusion To conclude this present prospective cohort study is a comprehensive assessment of the spectrum of renal dysfunction in cancer patients, among recipients of ICPI with or without conventional chemotherapy using standard criteria to the best of our knowledge, which has been the limitation of previous literature. We have shown a vast spectrum of kidney dysfunction possibly attributed to the ICPI's in malignancy patients. Viewed in respect to better QoL with ICPI therapy in malignancy patients, kidney related iRAE's could limit the patients from their beneficial effects. A possible persistent immune injury might have led to partial recovery of kidney dysfunction in majority. An unusual finding of secondary amyloid deposits with pembrolizumab, which possible might have occurred due to persistence of high levels of inflammatory markers due to these drugs. Thus underscoring the need for a close follow-up and recommend kidney biopsy to better & definitively identify the glomerular pathology & treatment accordingly.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Renal manifestations in rheumatoid arthritis and spondylarthritis

As systemic diseases it is not uncommon for inflammatory rheumatic diseases to exhibit renal involvement. In contrast to connective tissue diseases and vasculitis, in rheumatoid arthritis and spondylarthritis direct inflammatory manifestations in the sense of glomerulonephritis (GN) and autoimmune interstitial nephritis are rare. In these groups of diseases renal biopsies usually show mesangial proliferative GN and IgA nephropathy or less commonly membranous GN. These and secondary amyloid A (AA) amyloidosis are regularly associated with longer lasting disease activity and a poor prognosis; however, clinically more frequent and more relevant are other sequelae of chronic systemic inflammation, namely endothelial function disorder and the premature development of atherosclerosis, resulting in progressive kidney failure. This is accompanied by the undesired effects of antirheumatic treatment and renal complications of comorbidities.

A197 COLONIC AMYLOIDOSIS: A CAUSE OF RECURRENT HYPOVOLEMIA

Abstract Background Systemic amyloidosis is a multi-organ disease characterized by abnormal extracellular protein deposition. The most common type is primary (AL) amyloid relating to underlying plasma cell dyscrasias. Other major variants include secondary (AA) amyloid from chronic inflammation, dialysis related amyloid (DRA) with β2-microglobulin, and heritable protein mutations. Management of the underlying disorder can limit further organ damage; however, no definitive treatment exists for familial causes. While uncommon, gastrointestinal involvement is variable and can cause asymptomatic infiltration, liver impairment, bleeding, or chronic diarrhea. Aims To discuss an unusual case of gastrointestinal amyloidosis as a cause of recurrent diarrhea and hypovolemic shock. Methods The patient records were examined, and a review of the literature was performed. Results An 87-year-old male with dementia, coronary artery disease and end stage renal disease from PCKD presented in hypovolemic shock. He had a two-week history of gradual onset, non-bloody, watery diarrhea with up to 20 bowel movements daily. He denied fever, sick contacts, travel, or recent antibiotic use. He had previously foregone endoscopy for a remote history of self-resolved hematochezia. Examination was notable for an uncomplicated inguinal hernia. Labs showed an anion-gap metabolic acidosis but no leukocytosis. He initially received iv hydration, vasopressors, and empiric antibiotics. CT showed diffuse wall thickening of the terminal ileum, colon and rectum with relative sigmoid sparing concerning for enterocolitis. Stool culture grew C. albicans, but C. difficile toxin and Ova and Parasite PCR were negative. He clinically improved with loperamide and was discharged only to be readmitted four days later with recurrent diarrhea and hypovolemia. Repeat cultures were negative. Endoscopy showed diffuse well-demarcated clean-based ulcers and colonic edema. Biopsies excluded viral causes but showed a classic appearance of apple-green birefringence on Congo red staining suggesting amyloid deposition. Raised light chain immunoglobulins and lysozyme on proteomic analysis indicated either AL or a heritable amyloid but excluded AA and DRA. Full diagnostic criteria for AL were not met as free light chain ratio was preserved without clear monoclonality. While his diarrhea again improved, next-of-kin opted for palliative care due to repeated admissions for delirium and generalized deterioration. Conclusions This case was indicative of atypical AL amyloidosis versus a rare lysozyme mutation involving renal and GI systems. AL amyloid has a classic appearance on special stains and mass spectrometry that distinguishes it from most subtypes, however, given elevated lysozyme levels further genetic analysis is needed to guide management. In the appropriate clinical context, gastrointestinal amyloidosis can be considered as a rare cause of recurrent unexplained diarrhea. Funding Agencies None

Roles of Serum Amyloid A 1 Protein Isoforms in Rheumatoid Arthritis

Abstract Secondary amyloid A amyloidosis, a lethal complication, is induced when acute or chronic infection coexists with over-secretion of the serum amyloid A 1 (SAA1) protein and deposition in key internal organs. Previously, using the whole-exome sequencing method, we identified a novel deleterious mutation SAA1.2 in rheumatoid arthritis (RA) patients. However, the role of SAA1 in RA pathogenesis and its complications remains unknown. The purpose of this study was to determine the pathogenetic roles of SAA1 protein isoforms in RA progression. We modified an experimental adenovirus infection protocol to introduce SAA1.2 gene alleles into the knee joints of mice and used SAA1.3 and SAA1.5 as controls. Micro-computed tomography analysis was applied to determine changes in bone morphology and density. Immunohistochemical (IHC) analysis, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and real-time polymerase chain reaction (RT-PCR) were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone destruction. We found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood resulted in the stimulation of immune responses, leading to CD8+ T cell and pro-inflammatory cytokine elevation, such as interleukin (IL)-6, IL-22, matrix metalloproteinase (MMP)-3, MMP-9, with subsequent synovial inflammation and bone destruction. These findings indicate that SAA1 protein isoforms, particularly SAA1.2, play a significant role in the induction and progression of RA and may have potential value in the early diagnosis and severity prediction of RA.

SAA1 Protein Isoforms Induce Rheumatoid Arthritis

Background: Secondary amyloid A amyloidosis, a lethal complication, is induced when acute or chronic infection coexisted with over-secretion of the SAA1 protein and deposition of SAA1 in key internal organs. Previously, using the whole-exome sequencing method, we identified the novel deleterious mutation SAA1.2 in rheumatoid arthritis (RA) patients. However, the role of SAA1 in RA pathogenesis and its complications remains unknown, making early diagnosis and risk prevention difficult. Methods: We modified an experimental adenovirus infection protocol in order to successfully introduce SAA1.2, SAA1.3, SAA1.5 gene alleles into the rear knee joints of C57BL/6 mice. micro-CT analysis was applied to determine changes in bone morphology and density. IHC, flow cytometry, ELISA and real-time PCR were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone destruction. Findings: The pathogenetic functions of SAA1.2, SAA1.3 and SAA1.5 protein isoforms in promoting the initiation and progression of RA were determined. We established that SAA1.2 was the most aggressive factor in RA induction and progression. Mechanistically, we found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood results in stimulation of immune responses, leading to CD8 + T cell and pro-inflammatory cytokine elevation, with subsequent synovial inflammation and bone destruction. Interpretation: These findings indicate that SAA1 protein isoforms, particularly SAA1.2, play a significant role in the induction and progression of RA and may have potential value in the early diagnosis and severity prediction for RA. Funding Statement: This work was funded by The Science and Technology Development Fund, Macau SAR (file no. FDCT-FDCT-17-002-SKL). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the institutional committee for animal welfare.

2751 Endoscopic Folie à Deux: Atypical Manifestations of Gastric Amyloid in Concurrent Cases

INTRODUCTION: Gastrointestinal amyloidosis is rare with variable, nonspecific presentations, signs, and endoscopic findings. We describe two cases featuring unusual endoscopic findings produced by histologically confirmed gastric amyloid. CASE DESCRIPTION/METHODS: Case 1: A 60 year old man with Child B cirrhosis due to chronic hepatitis C virus (HCV) infection, hidradenitis suppurativa, and end-stage renal disease from biopsy-proven amyloidosis on hemodialysis presented with melena and severe anemia. EGD showed diffuse gastric hemorrhagic, fibrinous exudates (Figure 1). On biopsy, Congo red stain showed apple green birefringence with plane polarized light microscopy consistent with amyloid. Four months later, after recurrent melena and bloody diarrhea, along with severe hypotension due to newly diagnosed adrenal insufficiency, the patient died while on comfort care. Case 2: A 63 year old man with Child C cirrhosis from chronic HCV, end-stage renal disease on hemodialysis, and prior intravenous drug use presented with hyperkalemia after missing his scheduled dialysis session. During his hospitalization, he developed melena and underwent an EGD, which showed scattered patchy moderate submucosal hemorrhages in a partially ringed pattern throughout the gastric body (Figure 2). On biopsy, Congo red stain showed apple green birefringence with plane polarized light microscopy; protein identification showed AA-type amyloid (Figure 3). Three months later, and to-date, the patient is hospitalized in the ICU for altered mental status, septic shock, and respiratory failure, with his hospital course complicated by repeated episodes of GI bleeding. DISCUSSION: These two cases of melena had distinctive, initially puzzling endoscopic findings, with biopsy results indicating gastric amyloid, a rare and atypical presentation of systemic amyloidosis. It is interesting that both patients in these cases had HCV infection. While AA-type, secondary amyloid can be caused by a chronic infectious state, there are no studies thus far that establish a causal link between HCV and amyloidosis. The patients in these two cases also carry other risk factors for amyloidosis, including hidradenitis suppurativa, end-stage renal disease, and intravenous drug use. Thus, while gastric amyloid is rare, endoscopists should keep it in the differential and note its potential for causing GI bleeding, especially in patients with risk factors, as it is a difficult condition to treat and its endoscopic findings can be dramatic.

19. Fever, dyspnoea and a raised CRP: just another chest sepsis?

IntroductionAutoinflammatory conditions can arise in patients presenting on the medical take. Patients presenting with an inflammatory response, fever and organ dysfunction are usually (and appropriately) managed as sepsis until proven otherwise. However, a suspicion should be maintained for alternative diagnoses when there is no improvement with conventional antimicrobial therapy.We present a case of a young woman presenting with polyserositis with a wide differential diagnosis including infection, autoimmunity and malignancy. She was treated successfully with colchicine. Subsequent genetic analysis at the Royal Free hospital for fever syndromes has not found a pre-described genetic polymorphism.Case descriptionA 39-year-old woman presented to A&E with dyspnoea, night sweats, lethargy and right upper quadrant pain. Her past medical history included hypothyroidism and two years of intermittent diarrhoea. This diarrhoea was associated with a raised faecal calprotectin. Subsequent investigation with colonoscopy and MRI small bowel were normal. Other past history included pleurisy felt to be secondary to a lower respiratory tract infection aged 38 and a right knee effusion aged 15. She was born in the UK but had a Greek mother.Examination revealed reduced breath sounds in the bases which were dull to percuss, normal heart sounds and mild abdominal distension. There was no peripheral oedema. Observations showed oxygen saturations of 90% on air, BP 90/50, HR 120 and a pyrexia of 38°C. Blood results showed a raised ALT of 100 and CRP 40. She was initially treated with antibiotics for a working diagnosis of atypical pneumonia.Her respiratory failure deteriorated and a CTPA two days later showed bilateral pleural effusions, a massive pericardial effusion with impending tamponade and a right upper lobe PE. A CT CAP show moderate ascites but no evidence of malignancy or lymphoma.Pericardiocentesis showed a reactive picture with no organisms grown and normal cytopathology of the fluid. Pleural and ascitic fluid were also drained and she was commenced on LMWH for the PE. Virology, microbiological and autoimmune screens were unremarkable. CRP at this stage had risen to 78 as had the ALT to 1400.6 days after admission, antibiotics were stopped she was commenced on colchicine 1mg bd. Within 48 hours she rapidly improved both clinically and biochemically.DiscussionSince the index admission genetic analysis has shown she is HLA B51 negative and she has no recognised genetic polymorphism associated with a periodic fever syndrome.20 months since admission she has made a good recovery and is stable on colchicine 1mg od with no recurrence of the pleural and pericardial effusions. She has had one further episode of diarrhoea for 2 weeks associated with a raised faecal calprotectin and red macular rashes on her torso. Anticoagulation for the PE has been stopped.Polyserositis in the absence of infection or malignancy is uncommon and autoinflammatory and autoimmune aetiologies should be considered. This case highlights the importance of keeping a broad mind in patients presenting in an unusual way or when they do not respond to initial treatment.Autoinflammatory conditions are characterised by marked inflammation affecting the skin, serosal surfaces and synovium among others. Her history of colitis is intriguing. There are case reports of patients with familial Mediterranean fever presenting with serositis but she was negative for FMF on further genetic testing. Similarly she did not prove to have any of the genes that have so far been recognised as causing a periodic fever syndrome.We did consider Behçet’s but she denied a history of recurrent oral or genital ulceration or iritis and there was no family history. However Behçet’s can lead to inflammatory bowel disease and this remains an intriguing possibility.The dramatic response to colchicine was remarkable. Within 48 hours a re-accumulated pericardial effusion causing right ventricular strain had disappeared as had clinically apparent ascites. Most autoimmune, infective or malignant aetiologies would not be expected to respond in such a way and a yet undiscovered autoinflammatory syndrome remains a tantalising possibility.Key learning pointsMain learning points so far: Maintain a wide differential in patients presenting with polyserositis, especially when there is a poor response to typical management approaches. Consider autoinflammatory disease and take a detailed past medical and family history.Colchicine is cheap and generally well tolerated at lower doses. Colchicine is first line therapy for recurrent pericarditis.Learning points from the conference: What’s her risk of developing secondary amyloid or other secondary sequelae? How long will she need treatment for and how/ when you would you wean the colchicine? Is her partial Greek genetic heritage relevant? How common are wild type genetic polymorphisms occurring in autoinflammatory conditions? How frequently is colitis a feature of autoinflammatory diseases? If she becomes unwell again what would your second line therapy be?Conflicts of interestThe authors have declared no conflicts of interest.

PF639 IMMUNE ELECTRON MICROSCOPY AND MASS SPECTROMETRY FOR CLASSIFICATION OF AMYLOID DEPOSITS

Background:Amyloidosis is a shared name for a number of rare, complex and serious disease entities with an annual incidence in Denmark of about 2 per 100,000. Amyloidosis is caused by extra‐cellular deposits of amyloid substance created by accumulation of different misfolded proteins. Accurate characterization of the amyloid protein is essential. Amyloid light chain (AL) amyloidosis is a plasma cell dyscrasia that can be treated with chemotherapy, whereas transthyretin (ATTR) and secondary Amyloid A (AA) amyloidosis are other entities that are not treated within haematology. It is generally recognized that conventional immunohistochemistry has limitations, particular due to unspecific staining. Immune electron microscopy (IEM) and laser dissection microscopy followed by tandem mass spectrometry (LDM‐MS) are the new gold standards. It has not been established if one of the methods is superior; each method have some strengths and weaknesses. At Odense Amyloidosis Center, IEM and LDM‐MS have been established for standard diagnostics in 2017.Aims:To compare the sensitivity and specificity of IEM and MS for sybtyping amyloid deposits in different organsMethods:We performed a retrospective study of 106 Congo red positive biopsies from a number of different involved organs; heart, kidney, lung, gut mucosa, subcutaneous fat, bone marrow. IEM was performed with gold‐labeled antibodies against kappa, lambda, transthyretin and amyloid A.Results:IEM identified specific staining of amyloid fibrils in 91.6% of the biopsies; in 6 biopsies amyloid fibrils were not identified, and in 2 biopsies the subtype of the amyloid fibrils could not be established. MS identified an amyloigenic protein signature in 104/106 biopsies but in 9 of the biopsies the amyloid subtype could not be clearly identified. Protein subtype was established in 95 biopsies (89.6%). The concordance of the results ranged from 89.6–100% for the different subtypes. Importantly, the combined use of both methods increased the diagnostic sensitivity to 100%. Some variety in performances of the methods was observed on organ level.Summary/Conclusion:In conclusion, we demonstrate that both IEM and LDM‐MS are sensitive and specific methods for the identification of amyloidogenic proteins in amyloid deposits in biopsies from various organs.

Rituximab Therapy in Renal Amyloidosis Secondary to Rheumatoid Arthritis.

Secondary amyloid A (AA) amyloidosis is a late and serious complication of poorly controlled, chronic inflammatory diseases. Rheumatoid arthritis (RA) patients with poorly controlled, longstanding disease and those with extra-articular manifestations are under risk for the development of AA amyloidosis. Although new drugs have proven to be significantly effective in the treatment of secondary AA amyloidosis, no treatment modality has proven to be ideal. To date, only in small case series preliminary clinical improvement have been shown with rituximab therapy for AA amyloidosis secondary to RA that is refractory to TNF-α inhibitors (TNF-i) therapy. In these case series, we assessed the efficacy and safety of rituximab therapy for patients with RA and secondary amyloidosis. Hacettepe University Biologic Registry was developed at 2005. The data of the RA patients who were prescribed a biological drug were recorded regularly. Patients with biopsy proven AA amyloidosis patients were screened. Of 1022 RA patients under biologic therapy, 0.7% patients had clinically apparent histologically confirmed amyloidosis. Four of seven patients who were prescribed rituximab at least one infusion enrolled to those case series. Two of four patients showed significant clinical improvement and one of them also had decrease in proteinuria and the other one had stable renal function and proteinuria. The main goal for the treatment of AA amyloidosis is to control the activity of the underlying disorder. In this study, we showed that rituximab may be an effective treatment in RA patients with amyloidosis who were unresponsive to conventional disease modifying anti-rheumatic drugs (DMARDs) and/or TNFi.

Amyloid Goiter Secondary to Ulcerative Colitis.

Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

Chronic Hepatitis C Virus and Its Relation to Secondary Amyloid Nephropathy: Case Series and Literature Review

Chronic Hepatitis C Virus and Its Relation to Secondary Amyloid Nephropathy: Case Series and Literature Review

Coexistence of AA and AL Cardiac Amyloidosis in a Patient with Ankylosing Spondylitis Accompanying Monoclonal Gammopathy of Undetermined Significance

Amyloidosis is a clinical disorder caused by extracellular deposition of proteinaceous insoluble fibrils in various tissues, resulting in organ compromise. Amyloid L (AL) amyloidosis is the most common type of systemic amyloidosis, which occurs in association with multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). Secondary amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions, such as rheumatoid arthritis or ankylosing spondylitis. We report a case of a 49-year-old manwith a 11-year history of ankylosing spondylitis, who was recently diagnosed with MGUS presented with cardiac amyloidosis of both the AA and AL types. We report this case along with a review of relevant literature.

Secondary amyloid deposition in a melanocytic nevus

Secondary amyloid deposition in a melanocytic nevus

Interaction of serum amyloid A with human cystatin C—assessment of amino acid residues crucial for hCC–SAA formation (part II)

Secondary amyloid A (AA) amyloidosis is an important complication of some chronic inflammatory diseases, primarily rheumatoid arthritis (RA). It is a serious, potentially life-threatening disorder caused by the deposition of AA fibrils, which are derived from the circulatory, acute-phase-reactant, serum amyloid A protein (SAA). Recently, a specific interaction between SAA and the ubiquitous inhibitor of cysteine proteases--human cystatin C (hCC)--has been proved. Using a combination of selective proteolytic excision and high-resolution mass spectrometry, the binding sites in the SAA and hCC sequences were assessed as SAA(86-104) and hCC(96-102), respectively. Here, we report further details concerning the hCC-SAA interaction. With the use of affinity tests and florescent ELISA-like assays, the amino acid residues crucial for the protein interaction were determined. It was shown that all amino acid residues in the SAA sequence, essential for the formation of the protein complex, are basic ones, which suggests an electrostatic interaction character. The idea is corroborated by the fact that the most important residues in the hCC sequence are Ser-98 and Tyr-102; these residues are able to form hydrogen bonds via their hydroxyl groups. The molecular details of hCC-SAA complex formation might be helpful for the design of new compounds modulating the biological role of both proteins.

Plasmacytoma of the larynx

Amyloid is an extracellular proteinaceous low-molecular-weight fibril. In the larynx, amyloid deposits usually represent a benign localized disease. Although laryngeal amyloidosis is an indolent lesion, amyloid deposition in the larynx may actually result from a lymphoproliferative disorder and not isolated amyloidosis. In this case report, we describe a patient referred for laryngeal amyloidosis who was subsequently diagnosed with extramedullary plasmacytoma of the larynx. The report discusses the presentation, diagnosis, and treatment provided. The importance of systemic workup and accurate tissue diagnosis in differentiating primary amyloidosis and secondary amyloid deposition will be highlighted.

Acne inversa (Hidradenitis suppurativa): A review with a focus on pathogenesis and treatment

Acne inversa (AI) is a disabilitating chronic inflammatory disease with major negative impact on quality of life and significant co-morbidities. This is an important link to insights into immune dysfunction, which stimulated therapeutic approaches like tumor necrosis-α inhibitor therapy. This new off-label drug treatment is particularly beneficial when used in combination with wide excision of inflamed skin and subcutaneous tissue. Retinoids have been reported to be helpful in secondary prevention. The standard of therapy in advanced cases is surgery with wide excisions and healing by secondary intention. This treatment results in significant reduction of complaints and achieves satisfactory body contouring.

Pathogenic Serum Amyloid A 1.1 Shows a Long Oligomer-rich Fibrillation Lag Phase Contrary to the Highly Amyloidogenic Non-pathogenic SAA2.2

Serum amyloid A (SAA) is best known for being the main component of amyloid in the inflammation-related disease amyloid A (AA) amyloidosis. Despite the high sequence identity among different SAA isoforms, not all SAA proteins are pathogenic. In most mouse strains, the AA deposits mostly consist of SAA1.1. Conversely, the CE/J type mouse expresses a single non-pathogenic SAA2.2 protein that is 94% identical to SAA1.1. Here we show that SAA1.1 and SAA2.2 differ in their quaternary structure, fibrillation kinetics, prefibrillar oligomers, and fibril morphology. At 37 °C and inflammation-related SAA concentrations, SAA1.1 exhibits an oligomer-rich fibrillation lag phase of a few days, whereas SAA2.2 shows virtually no lag phase and forms small fibrils within a few hours. Deep UV resonance Raman, far UV-circular dichroism, atomic force microscopy, and fibrillation cross-seeding experiments suggest that SAA1.1 and SAA2.2 fibrils possess different morphology. Both the long-lived oligomers of pathogenic SAA1.1 and the fleeting prefibrillar oligomers of non-pathogenic SAA2.2, but not their respective amyloid fibrils, permeabilized synthetic bilayer membranes in vitro. This study represents the first comprehensive comparison between the biophysical properties of SAA isoforms with distinct pathogenicities, and the results suggest that structural and kinetic differences in the oligomerization-fibrillation of SAA1.1 and SAA2.2, more than their intrinsic amyloidogenicity, may contribute to their diverse pathogenicity.