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1.
Blood ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578202

RESUMO

Bortezomib is a standard therapy in AL amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum free light chains (dFLC) less than 10mg/L (low-dFLC response) post-treatment predicts survival in AL patients with low presenting dFLC (20-50mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore impact of post-treatment dFLC<10mg/L (a 'stringent dFLC response') in all patients. 915 newly diagnosed AL patients treated with bortezomib in the UK and assessed at our centre were included. Haematologic responses, 6 month dFLC, organ responses, overall survival (OS) and time-to-next-treatment (TNT) were evaluated. Analysis of TNT excluded patients that died without starting second-line treatment. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low-dFLC response. The proportion of patients with a stringent dFLC response, dFLC 10-40mg/L and >40mg/L was 30%, 22% and 48%, respectively. Median OS was 72 months. 289 patients died without progressing to second-line treatment. Of the remaining patients, median TNT was not reached and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than those with lesser responses. 72% of CR patients did not progress to further treatment at 3 years, compared to 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared to lesser responses (45%), (p=0.005). Upfront bortezomib confers durable haematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

2.
J Invest Dermatol ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31539532

RESUMO

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.

3.
Br J Haematol ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31410841

RESUMO

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re-evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant-related mortality (TRM) and overall survival (OS) were analysed. The median OS post-ASCT was 87 months [95% confidence interval (CI): 77-106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29-55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35-2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19-3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994-2000: 18·8%; 2001-2006: 13·6%; 2007-2012: 6·2%; 2013-2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long-term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis.

4.
Haematologica ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31399529

RESUMO

Patients with systemic AL amyloidosis with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo Stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 µmol/L and mean left ventricular septal wall thickness, 10mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (N=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (p=<0.008, HR 3.180, CI=1.349-7.495) and cardiac involvement on magnetic resonance imaging (p=0.026, HR=5.360, CI=1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL amyloidosis may need to be redefined.

5.
Br J Haematol ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388995

RESUMO

Bortezomib is standard treatment in AL amyloidosis (AL), but is contraindicated in patients with significant neuropathy. Carfilzomib, a second-generation proteosomal inhibitor, results in a lower incidence of neuropathy than bortezomib, but data in AL is scant. We report a cohort of five AL patients treated with upfront carfilzomib. All had cardiac, peripheral and autonomic neuropathy at presentation. All achieved at least a very good partial haematological response. There was no worsening in cardiac function, peripheral or autonomic neuropathy. Carfilzomib is an effective upfront treatment option in AL patients with peripheral and/or autonomic neuropathy (without severe cardiac or renal involvement).

6.
Artigo em Inglês | MEDLINE | ID: mdl-31384939

RESUMO

OBJECTIVES: Hereditary systemic autoinflammatory diseases are rare genetic disorders, which if untreated, can be complicated by AA amyloidosis leading to renal failure and premature death. Our objective was to find a genetic cause in a British family with a dominantly inherited autoinflammatory disease complicated by AA amyloidosis. METHODS: The index patient and his sister underwent comprehensive clinical and laboratory assessment including the next-generation sequencing panel targeting autoinflammatory genes. Subsequently, other relatives underwent clinical evaluation and genetic testing. Screening of the SAA1 gene was performed in all symptomatic cases. RESULTS: The index case and his sister presented with proteinuria due to AA amyloidosis. They have been suffering from episodes of fever accompanied by severe abdominal and chest pain, arthritis and erythema since childhood. Their father died aged 52 years from complications following a cadaveric renal transplantation. The post-mortem examination demonstrated AA amyloidosis. The index case's grandmother, two paternal cousins and two of their children described similar symptoms. All symptomatic individuals had excellent responses to colchicine. Next-generation sequencing analysis identified a single MEFV p.P373L variant in the index case, his sister and subsequently, in symptomatic family members. Sequencing of the SAA1 gene revealed all cases were heterozygous for the SAA1.1 allele. CONCLUSION: Typically FMF is an autosomal recessive disorder; nonetheless rare cases of dominantly inherited disease have previously been described. Here we report a novel MEFV variant p.P373L, causing dominant FMF complicated by AA amyloidosis in four generations of a British family.

7.
Arthritis Rheumatol ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31268627

RESUMO

OBJECTIVE: To assess the prevalence of the MYD88 L265P mutation and variants within NLRP3 and evaluate the status of oligoclonal hematopoiesis in 30 patients with Schnitzler syndrome (SchS). METHODS: Thirty patients with SchS were recruited from 3 clinical centers. Six patients with known acquired cryopyrin-associated periodic syndromes (aCAPS) were included as controls. Allele-specific oligonucleotide-polymerase chain reaction was used for the detection of the MYD88 L265P variant, next-generation sequencing was applied to analyze NLRP3 and 28 genes associated with myelodysplastic syndrome, and gene scanning was performed for the detection of X chromosome inactivation. RESULTS: Activating NLRP3 mutations were not present in 11 SchS patients who had not been sequenced for this gene previously. The MYD88 L265P variant was present in 9 of 30 SchS patients, and somatic mutations associated with clonal hematopoiesis were identified in 1 of 30 patients with SchS and 1 of 6 patients with aCAPS. Evidence of nonrandom X chromosome inactivation was detected in 1 female patient with SchS and 1 female patient with aCAPS. CONCLUSION: A shared molecular mechanism accounting for the pathogenesis of inflammation in SchS remains elusive. Clonal hematopoiesis is not associated with other somatic mutations found in individuals with SchS or aCAPS.

8.
Pediatr Rheumatol Online J ; 17(1): 36, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31287007

RESUMO

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is a rare autoinflammatory disease, caused by gain of function mutation in NLRP3 resulting in excess production of interleukin-1 (IL-1). Canakinumab is a human monoclonal antibody against Interleukin-1 beta (IL-1ß), licensed for the treatment of CAPS. The objective of the study was to describe the feasibility and cost-effectiveness of a canakinumab vial-sharing programme for paediatric patients with CAPS. METHOD: Retrospective case series and clinical service description of a national specially commissioned CAPS clinic at Great Ormond Street Hospital (GOSH). Effectiveness was assessed using a CAPS disease activity score (DAS) and serum amyloid A protein (SAA). Adverse events were collected to determine safety. The number of canakinumab vials saved was considered when investigating the cost-effectiveness of vial-sharing. RESULTS: Nineteen/20 (95%) of our paediatric patients achieved minimally active clinical disease activity with canakinumab monotherapy; and 75% achieved both minimally active clinical disease and serological remission using a pre-specified definition based on the CAPS DAS and SAA level. Canakinumab was well tolerated, with only one child developing an infection requiring hospitalisation during the study. Canakinumab vial sharing resulted in 117 vials of canakinumab saved over a 24-month period, equating to a direct drug-related cost saving of £1,385,821, and a conservative estimated 5-year cost-saving of £3,464,552.50. CONCLUSION: We provide further evidence for the effectiveness and safety of canakinumab in children with CAPS, and highlight the cost-effectiveness of a vial-sharing programme for this high cost medicine. We suggest that this could have important implications for the delivery of other high cost medicines used in paediatric practice.

9.
Arthritis Rheumatol ; 71(11): 1955-1963, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31161734

RESUMO

OBJECTIVE: To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS). METHODS: CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. RESULTS: Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy. CONCLUSION: Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31202744

RESUMO

OBJECTIVES: This study aimed to assess the diagnostic use of native T1 to detect cardiac amyloidosis (CA) in a large prospective cohort of patients referred for suspected systemic amyloidosis. BACKGROUND: CA is a progressive and fatal underdiagnosed cause of heart failure. Cardiovascular magnetic resonance (CMR) has emerged as an extremely useful test for the non-invasive diagnosis of CA, but administration of contrast is still required to make a diagnosis. METHODS: In this study, 868 patients with suspected CA referred between 2015 and 2017 underwent CMR with late gadolinium enhancement (LGE), T1 mapping, and an array of clinical investigations. RESULTS: The final diagnosis was cardiac light-chain (AL) amyloidosis in 222, cardiac transthyretin (ATTR) amyloidosis in 214, and no cardiac involvement in 427 cases. T1 was significantly elevated in both types of CA and this was associated with high diagnostic accuracy in the overall population (area under the curve, 0.93). A native T1 <1,036 ms was associated with 98% negative predictive value for CA whereas a native T1 >1,164 ms was associated with 98% positive predictive value for CA. We propose the use of these cut-offs to exclude or confirm CA and to restrict the administration of contrast only to patients with intermediate probability (native T1 between 1,036 and 1,164 ms), 58% of patients in this population. CONCLUSIONS: Native myocardial T1 enables diagnosis of CA to be made without need for gadolinium contrast in a large proportion of patients with suspected systemic amyloidosis. We propose a diagnostic algorithm for non-contrast CMR applicable to patients with suspected amyloidosis.

11.
Br J Haematol ; 186(3): 460-470, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124579

RESUMO

Systemic AL amyloidosis is a cause of type 5 cardiorenal syndrome. Response to treatment is currently reported according to organ-specific amyloidosis consensus criteria (ACC), which are not validated in cardiorenal AL amyloidosis. Of 1000 patients prospectively enrolled into the UK ALchemy study, 318 (32%) had combined cardiac and renal amyloidotic organ dysfunction at diagnosis, among whom 199 (63%) died; median survival by Kaplan-Meier analysis was 18·5 months. Fifty (16%) patients required renal replacement therapy (RRT). At diagnosis, independent predictors of death and dialysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP) >8500 ng/l (hazard ratio [HR] 3·30, P < 0·001; HR 3·00, P < 0·001), and estimated glomerular filtration rate (eGFR) < 30 ml/min/1·73 m2 (HR 1·89, P = 0·011; HR 6·37, P < 0·001). At 6 months, an increase in NT-proBNP of >30% and a reduction in eGFR of ≥25% were independent predictors of death (HR 2·17, P = 0·009) and dialysis (HR 3·07, P = 0·002), respectively. At 12 months, an increase in NT-proBNP >30% was highly predictive of death (HR 3·67, P < 0·001) and dialysis (HR 2·85, P = 0·010), whereas ACC renal response was predictive of neither. Cardiorenal AL amyloidosis is associated with high early mortality. Outcomes are dictated by NT-proBNP and eGFR at diagnosis rather than proteinuria, and thereafter predominantly by changes in NT-proBNP concentration.

12.
Circulation ; 140(1): 16-26, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31109193

RESUMO

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. METHODS: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. RESULTS: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9-27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P<0.001) and had worse measures of cardiac disease ( P<0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P<0.001) in comparison with the other subgroups. CONCLUSIONS: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.

13.
Ann Rheum Dis ; 78(8): 1025-1032, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31018962

RESUMO

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

15.
J Pathol Clin Res ; 5(3): 145-153, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30740936

RESUMO

The tissue diagnosis of amyloidosis and confirmation of fibril protein type, which are crucial for clinical management, have traditionally relied on Congo red (CR) staining followed by immunohistochemistry (IHC) using fibril protein specific antibodies. However, amyloid IHC is qualitative, non-standardised, requires operator expertise, and not infrequently fails to produce definitive results. More recently, laser dissection mass spectrometry (LDMS) has been developed as an alternative method to characterise amyloid in tissue sections. We sought to compare these techniques in a real world setting. During 2017, we performed LDMS on 640 formalin-fixed biopsies containing amyloid (CR+ve) comprising all 320 cases that could not be typed by IHC (IHC-ve) and 320 randomly selected CR+ve samples that had been typed (IHC+ve). In addition, we studied 60 biopsies from patients in whom there was a strong suspicion of amyloidosis, but in whom histology was non-diagnostic (CR-ve). Comprehensive clinical assessments were conducted in 532 (76%) of cases. Among the 640 CR+ve samples, 602 (94%) contained ≥2 of 3 amyloid signature proteins (ASPs) on LDMS (ASP+ve) supporting the presence of amyloid. A total of 49 of the 60 CR-ve samples were ASP-ve; 7 of 11 that were ASP+ve were glomerular. The amyloid fibril protein was identified by LDMS in 255 of 320 (80%) of the IHC-ve samples and in a total of 545 of 640 (85%) cases overall. The LDMS and IHC techniques yielded discordant results in only 7 of 320 (2%) cases. CR histology and LDMS are corroborative for diagnosis of amyloid, but LDMS is superior to IHC for confirming amyloid type.

16.
Presse Med ; 48(1 Pt 2): e49-e59, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30665783

RESUMO

The systemic autoinflammatory disorders (SAIDs) are associated with dysregulation of the innate immune system, affecting pro-inflammatory cytokines and apoptosis pathways. The spectrum of SAIDs continues to grow with over 30 different disorders identified to date. The main indication for genetic referral is when a patient presents with clinical symptoms consistent with one or more of the SAIDs. Thus, in making a referral for DNA screening, clinical information that supports the choice for screening of one or more SAIDs genes is required. Many of the SAIDs can display overlapping, partial or atypical symptoms, which makes the differential diagnosis extremely difficult and thus heavily dependent on genetic testing. Various attempts have been aimed at improving the efficiency of SAIDs diagnosis by proposing a set of clinical criteria to guide the genetic analysis of the SAIDs. In the last decade, due to application of the next-generation sequencing (NGS) the genetic diagnosis in patients with SAIDs have greatly improved; novel diseases and disease-associated genes have been identified and remarkable progress has been made in the genetic characterization of the undiagnosed patients and the sporadic cases. To date more than 800 variants have been recorded on the Infevers database, an online repository for DNA changes in genes associated with SAIDs (http://fmf.igh.cnrs.fr/ISSAID/infevers/). Recently, it has been updated with the new guidelines for classification of genetic variants pathogenicity in the in four most recognised SAIDs genes: MEFV, TNFRSF1A, NLRP3 and MVK.


Assuntos
Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Bases de Dados Genéticas , Diagnóstico Diferencial , Previsões , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas de Diagnóstico Molecular
18.
Nat Rev Nephrol ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510265

RESUMO

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

19.
J Rheumatol ; 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385706

RESUMO

OBJECTIVE: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. METHODS: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. RESULTS: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. CONCLUSION: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

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