bDMARD can prevent the progression of AA amyloidosis to end-stage renal disease.

INTRODUCTION: AA amyloidosis (AA) can be the consequence of any chronic inflammatory disease. AA is associated with chronic inflammatory diseases (cid+AA), autoinflammatory syndromes (auto+AA) or AA of unknown origin or idiopathic AA (idio+AA). The major organ manifestation is renal AA that can progress to end-stage renal disease (ESRD) and multiple organ failure. MATERIALS AND METHODS: This study is a monocentric retrospective analysis of the renal outcome and survival of patients with cid+AA (n=34), auto+AA (n=24) and idio+AA (n=25) who were treated with cytokine-inhibiting biological disease-modifying antirheumatic drugs (bDMARDs). RESULTS: 83 patients with renal AA were identified and followed for a mean observational period of 4.82 years. C reactive protein (CRP), serum amyloid alpha and proteinuria were significantly reduced with bDMARD therapy. Progression to ESRD was prevented in 60% (cid+AA), 88% (auto+AA) and 81% (idio+AA) of patients. Tocilizumab was given to 34 patients with cid+AA and idio+AA and was more effective in reducing CRP and progression to ESRD and death compared with other bDMARDs. CONCLUSIONS: bDMARDs reduce systemic inflammation in various diseases, leading to a reduction of proteinuria and prevention of ESRD. Importantly, tocilizumab was more effective than other bDMARDs in controlling systemic inflammation in patients with chronic inflammatory diseases and idiopathic AA, leading to better renal and overall survival.

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

OBJECTIVE: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). METHODS: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. RESULTS: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. CONCLUSION: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.

Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages.

Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages.

Autologous hematopoietic stem cell transplantation improves long-term survival-data from a national registry.

BACKGROUND: Current recommendations on the management of systemic sclerosis (SSc) suggest that autologous hematopoietic stem cell therapy (HSCT) can be a rescue therapy for patients with rapidly progressive SSc. OBJECTIVES: To assess the safety and efficacy of HSCT for patients with SSc and to compare these with non-HSCT patients in a control cohort with adjusted risk factors. METHODS: A retrospective analysis of data from the multicentric German network for systemic scleroderma (DNSS) with 5000 patients with SSc. Control groups consisted of all patients with diffuse cutaneous (dc)-SSc (group A) and an adjusted high-risk cohort of male patients with Scl70-positive dc-SSc (group B). RESULTS: Eighty SSc patients received an HSCT 4.1 ± 4.8 years after SSc diagnosis. Among them, 86.3% had dc-SSc, 43.5% were males, and 71.3% were positive for Scl70 antibodies. The control group A (n=1513) showed a significant underrepresentation of these risk factors for mortality. When the survival of the control group B (n=240) was compared with the HSCT group, a lower mortality of the latter was observed instead. Within 5 years after HSCT, we observed an improvement of the mRSS from 17.6 ± 11.5 to 11.0 ± 8.5 (p=0.001) and a stabilization of the DLCO. We did not see differences in transplant-related mortality between patients who received HSCT within 3 years after SSc diagnosis or later. CONCLUSION: Our analysis of real-life data show that the distribution of risk factors for mortality is critical when HSCT cohorts are compared with non-HSCT control groups.

Autologous Hematopoietic Stem Cell Transplantation for Behçet's Disease: A Retrospective Survey of Patients Treated in Europe, on Behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation.

Background: Behçet's Disease (BD) is an autoimmune disease mostly presenting with recurrent oral and genital aphthosis, and uveitis. Patients are rarely refractory to immunosuppressive treatments. Autologous hematopoietic stem cell transplantation (aHSCT) is a standard of care in other autoimmune diseases. Some patients with BD have been treated with aHSCT based on compassionate use. Objectives: Evaluate the outcome of aHSCT in adult patients with BD treated in member centers of the European Society for Blood and Marrow Transplantation (EBMT). Methods: Adults who received aHSCT primarily for BD were identified retrospectively in the EBMT registry and/or in published literature. Data were extracted from either medical records of the patient or from publications. Results: Eight out of 9 cases reported to the registry and extracted data of 2 further patients from literature were analyzed. Four were female, median age at onset of BD was 24y (range 9-50). Median age at aHSCT was 32y (27-51). Patients had received median 4 (2-11) previous lines of therapy (89% corticosteroids, 50% methotrexate, anti-TNFα therapy or cyclophosphamide). All patients had active disease before mobilization. Conditioning regimen was heterogeneous. Median follow-up was 48 months (range 6-240). No treatment-related mortality was reported. This procedure induced complete remission (CR) in 80%, partial remission in 10% and lack of response in 10% of the patients. Relapse rate was 30% (2 relapses in patients in CR and 1 relapse in the patient in PR) with panuveitis (n=1), aphthosis (n=2) and arthralgia (n=1). Six patients were in CR. No late complications were reported. Conclusion: aHSCT has an acceptable safety profile and represents a feasible and relatively effective procedure in severe and conventional treatment-resistant cases of BD and has the potential to stabilize BD in patients with life-threatening involvements.

Localized immunoglobulin light chain amyloidosis: Novel insights including prognostic factors for local progression.

In localized light chain amyloidosis (locAL), amyloidogenic light chains (aLC) are produced and deposited locally by a B-cell clone. We present 293 patients with immunohistochemically confirmed locAL. Lung (nodular pulmonary) with 63 patients was the most involved organ. The aLC was λ in 217 cases (κ:λ ratio 1:3). A local B-cell clone was identified in 30% of cases. Sixty-one (21%) had a concomitant autoimmune disorder (cAD). A monoclonal component (MC) were present in 101 (34%) patients and were more frequent in subjects with cAD (51% vs 34%; P = .03). Cigarette smoking was more prevalent in lung locAL (54% vs 37%; P = .018). After a median follow-up of 44 months, 16 patients died and 5- and 10-years locAL progression-free survival (PFS) were 62% and 44%. Interestingly, locAL-PFS was shorter among patients with an identified clonal infiltrate at amyloid deposition site (40 vs 109 months; P = .02) and multinuclear giant cells and/or an inflammatory infiltrate resulted in longer locAL-PFS in lung involvement (65 vs 42 months; P = .01). However, no differences in locAL PFS were observed in patients with cAD, a MC and involved organ site. Treatment was administered in 163 (54%) patients and was surgical in 135 (46%). Median locAL-PFS after first treatment was 56 months. Responders had longer locAL-PFS (78 vs 17 months; P < .001). Three patients with lung locAL and a MC were diagnosed as systemic AL amyloidosis at follow-up. In summary, locAL pathogenesis seems to be heterogeneous and the clonal infiltrate leads local progression.

Piperlongumine Acts as an Immunosuppressant by Exerting Prooxidative Effects in Human T Cells Resulting in Diminished TH17 but Enhanced Treg Differentiation.

Piperlongumine (PL), a natural small molecule derived from the Piper longum Linn plant, has received growing interest as a prooxidative drug with promising anticancer properties. Yet, the influence of PL on primary human T cells remained elusive. Knowledge of this is of crucial importance, however, since T cells in particular play a critical role in tumor control. Therefore, we investigated the effects of PL on the survival and function of primary human peripheral blood T cells (PBTs). While PL was not cytotoxic to PBTs, it interfered with several stages of T cell activation as it inhibited T cell/APC immune synapse formation, co-stimulation-induced upregulation of CD69 and CD25, T cell proliferation and the secretion of proinflammatory cytokines. PL-induced immune suppression was prevented in the presence of thiol-containing antioxidants. In line with this finding, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs. Diminished intracellular glutathione was accompanied by a decrease in S-glutathionylation on actin suggesting a global alteration of the antioxidant response. Gene expression analysis demonstrated that TH17-related genes were predominantly inhibited by PL. Consistently, the polarization of primary human naïve CD4+ T cells into TH17 subsets was significantly diminished while differentiation into Treg cells was substantially increased upon PL treatment. This opposed consequence for TH17 and Treg cells was again abolished by thiol-containing antioxidants. Taken together, PL may act as a promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished TH17 but enhanced Treg cell differentiation.

Activation of natural killer cells by rituximab in granulomatosis with polyangiitis.

OBJECTIVE: In the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab's mechanism of action in GPA. METHODS: B cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry. RESULTS: NK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions. CONCLUSION: B cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab's mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.

Idiopathic Pericarditis-an Autoinflammatory Disease?

PURPOSE OF THE REVIEW: Idiopathic acute and recurrent pericarditis are rare diseases of unknown origin. Here, we review trigger factors, pathomechanism, and treatment options for acute and recurrent pericarditis. RECENT FINDINGS: Acute pericarditis can be triggered by viral infections, myocardial ischemia, heart catheter interventions, cardiac surgery or seem to occur without any trigger. Earlier reports about viral nucleic acids in the effusion or myocardial autoantibodies in serum were detected only in a minority of patients. The current pathomechanistic concept focuses on the innate immune system. Clinical trials revealed that colchicine and anti-IL1ß-targeted medication were effective to control acute and recurrent attacks. Activation of the innate immune system in pericarditis suggests that autoinflammation contributes to acute and recurrent pericarditis. The efficacy of colchicine and anti-IL1ß-targeted medication in clinical trials indicates that acute and recurrent pericarditis should be regarded as an autoinflammatory disease. Therefore, idiopathic pericarditis should be considered as an autoinflammatory disease.

Reduced Right Ventricular Output Reserve in Patients With Systemic Sclerosis and Mildly Elevated Pulmonary Artery Pressure.

OBJECTIVE: This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH). METHODS: Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test. RESULTS: Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W). CONCLUSION: The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.

IL1-blocking therapy in colchicine-resistant familial Mediterranean fever.

OBJECTIVE: Approximately 10%-20% of patients with familial Mediterranean fever (FMF) show an inadequate response to colchicine. In our cohort study, patients with FMF with or without amyloidosis and with an inadequate response to colchicine were treated with anakinra or canakinumab. METHODS: Clinical and laboratory parameters, Mediterranean fever (MEFV) mutations, and patient-reported outcomes were analyzed in 31 patients treated with anakinra or canakinumab. RESULTS: In a cohort of 250 adult patients with FMF, 31 patients were treated with anakinra (n=29) or canakinumab (n=2). The median Pras FMF severity score was 8 (range, 5-14) and correlated with the presence of high-penetrance MEFV mutations (p.Met-694-Val or p.Met-680-Ile). The FMF severity score was 11 in patients with two high-penetrance MEFV mutations (68%), 9 in those with a single high-penetrance MEFV mutation (19%), and 7.5 in those without high-penetrance MEFV mutations (13%, p=0.2). FMF-related amyloid A amyloidosis was diagnosed in 12 (39%) patients. Anakinra was used daily in 20 patients, thrice a week in 7, and upon demand during attacks in 2. Two patients were treated with canakinumab. IL-1-blocking treatment showed a rapid (2±3 days) and persistent suppression of FMF symptoms and inflammatory parameters. The frequency of FMF attacks was significantly reduced (p<0.003). Both patient- and physician-reported FMF activity significantly improved (p<0.0001). CONCLUSION: IL-1-blocking therapy was well tolerated over a median period of 2 years and reduced the frequency of FMF attacks in patients with colchicine-resistant FMF.

Sulforaphane Inhibits Inflammatory Responses of Primary Human T-Cells by Increasing ROS and Depleting Glutathione.

The activity and function of T-cells are influenced by the intra- and extracellular redox milieu. Oxidative stress induces hypo responsiveness of untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased levels of reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g., in rheumatoid arthritis. Therefore, balancing the T-cell redox milieu may represent a promising new option for therapeutic immune modulation. Here we show that sulforaphane (SFN), a compound derived from plants of the Brassicaceae family, e.g., broccoli, induces a pro-oxidative state in untransformed human T-cells of healthy donors or RA patients. This manifested as an increase of intracellular ROS and a marked decrease of GSH. Consistently, increased global cysteine sulfenylation was detected. Importantly, a major target for SFN-mediated protein oxidation was STAT3, a transcription factor involved in the regulation of TH17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the TH17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases. The inhibitory effects of SFN could be abolished by exogenously supplied GSH and by the GSH replenishing antioxidant N-acetylcysteine (NAC). Together, our study provides mechanistic insights into the mode of action of the natural substance SFN. It specifically exerts TH17 prone immunosuppressive effects on untransformed human T-cells by decreasing GSH and accumulation of ROS. Thus, SFN may offer novel clinical options for the treatment of TH17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis.

Extracellular Vesicle Subtypes Released From Activated or Apoptotic T-Lymphocytes Carry a Specific and Stimulus-Dependent Protein Cargo.

Extracellular vesicles (EVs) are released from nearly all mammalian cells and different EV populations have been described. Microvesicles represent large EVs (LEVs) released from the cellular surface, while exosomes are small EVs (SEVs) released from an intracellular compartment. As it is likely that different stimuli promote the release of distinct EV populations, we analyzed EVs from human lymphocytes considering the respective release stimuli (activation Vs. apoptosis induction). We could clearly separate two EV populations, namely SEVs (average diameter <200 nm) and LEVs (diameter range between 200 and 1000 nm). Morphology and size were analyzed by electron microscopy and nanoparticle tracking analysis. Apoptosis induction caused a massive release of LEVs, while activated T-cells released SEVs and LEVs in considerably lower amounts. The release of SEVs from apoptotic T-cells was comparable with LEV release from activated ones. LEVs contained signaling proteins and proteins of the actin-myosin cytoskeleton. SEVs carried cytoplasmic/endosomal proteins like the 70-kDa heat shock protein 70 (HSP70) or tumor susceptibility 101 (TSG101), microtubule-associated proteins, and ubiquitinated proteins. The protein expression profile of SEVs and LEVs changed substantially after the induction of apoptosis. After apoptosis induction, HSP70 and TSG101 (often used as exosome markers) were highly expressed within LEVs. Interestingly, in contrast to HSP70 and TSG101, gelsolin and eps15 homology domain-containing protein 3 (EHD3) turned out to be specific for SEVs irrespective of the stimulus causing the EV release. Finally, we detected several subunits of the proteasome (PSMB9, PSMB10) as well as the danger signal HMGB1 exclusively within apoptotic cell-released LEVs. Thus, we were able to identify new marker proteins that can be useful to discriminate between distinct LEV subpopulations. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD009074.

Obesity is a significant susceptibility factor for idiopathic AA amyloidosis.

BACKGROUND: To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis. METHODS: Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease. FINDINGS: Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n = 111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n = 37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30 µg/l were detected in 18% of FMF/rheumatic + AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p = .018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease. CONCLUSIONS: Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.

Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS).

Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.