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Helen J Lachmann

Publications and source records attributed to Helen J Lachmann.

16 recordsLinked to original sources
PubMed2006

Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis.

High-dose melphalan with stem-cell transplantation is believed to be the most effective treatment for systemic light-chain (AL) amyloidosis, but many patients are ineligible because of the extent of their disease, and treatment-related mortality (TRM) remains substantial. We report the use of a risk-adapted oral regimen of cyclophosphamide, thalidomide, and dexamethasone (CTD) or attenuated CTD (CTDa) in 75 patients with advanced AL amyloidosis, including 44 patients with clonal relapse after prior therapy. Fifty-one (68%) patients received CTD and 24 (32%) received CTDa. A hematologic response occurred in 48 (74%) of 65 evaluable patients, including complete responses in 14 (21%) and partial responses in 34 (53%) cases. Median estimated overall survival (OS) from commencement of treatment was 41 months, and from diagnosis median was not reached with a median follow-up of 22 months. Three-year estimated OS was 100% and 82% among complete and partial hematologic responders, respectively. Toxicity necessitating cessation of therapy occurred in 8% and was at least grade 2 in 52% of patients. TRM was 4%. The clonal response rates to CTD reported here are higher than any previously reported nontransplantation regimen in AL amyloidosis, and risk adaptation allows its use in poorer risk patients. CTD merits prospective randomized study.

Administration, Oral↗
PubMed2006

Outcome of autologous stem cell transplantation for AL amyloidosis in the UK.

High-dose chemotherapy with autologous stem cell transplantation (SCT) is widely used as a treatment for systemic AL amyloidosis, but its efficacy has not been proved and it has substantial toxicity in this setting. We report here the outcome of 92 patients evaluated at the UK National Amyloidosis Centre who underwent SCT for AL amyloidosis between 1994 and 2004 in various British centres. Median age was 53 years and median of two organs were affected by amyloidosis. All-cause day 100 mortality [treatment-related mortality (TRM)] was 23% for the entire cohort, although this was substantially greater for patients treated from 1994 to 1998 (15/47, 32%) than subsequently (6/45, 13%). Independent factors significantly associated with TRM on multivariate analysis were: number of affected organs, performance status, serum albumin and age. Response of the underlying clonal disease, defined by > or = 50% reduction in the aberrant serum-free light chain concentration, occurred in 83% of evaluable patients. Overall median survival was 5.3 years, and was 8.5 years among patients who survived beyond day 100. Despite recent refinements in patient selection, TRM remains substantial during SCT for systemic AL amyloidosis, and its place in the therapeutic armamentarium for this disease needs to be defined in randomised controlled clinical studies.

Aged↗
PubMed2006

Systemic amyloidosis.

Amyloidosis describes a heterogeneous group of diseases in which normally soluble plasma proteins are deposited in the extracellular space in an abnormal insoluble fibrillar form. These diseases can affect virtually any organ system and often present a major diagnostic and management challenge. Current therapies centre on reducing the supply of the respective amyloid fibril precursor protein, combined with supportive treatment. Better understanding of the mechanisms underlying amyloid formation has led to the development of novel treatment strategies aimed at inhibiting fibrillogenesis or destabilizing existing amyloid deposits. It is hoped that some of these developments might contribute to effective treatment not only of systemic amyloidosis, which is relatively rare, but also of the much more common type II diabetes and Alzheimer's disease, in which local amyloid formation is thought to play a role.

Amyloidosis↗
PubMed2006

Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations.

OBJECTIVE: To characterize the multisystem chronic inflammatory phenotype, dermatopathologic features, and response to therapy with interleukin 1 receptor antagonist (anakinra) in patients with mutations in the CIAS-1/NALP3 gene. DESIGN: Retrospective review of medical records and evaluation of histologic findings. SETTING: The National Amyloidosis Centre, London, and a tertiary referral clinic for urticaria. PATIENTS: Twenty-two individuals from 13 families with autoinflammatory disease associated with CIAS-1/NALP3 mutations. MAIN OUTCOME MEASURES: Phenotype, genotype, skin histologic findings, and response to treatment with anakinra. RESULTS: Five heterozygous missense mutations were identified in CIAS-1/NALP3. Skin histologic findings revealed marked vascular dilatation and neutrophilic infiltration involving small vessels and eccrine glands. Serologic evidence of intense inflammation was present in untreated patients, with median serum amyloid A protein and C-reactive protein levels of 141 and 38 mg/L, respectively. Fifteen patients received anakinra for up to 39 months, all of whom achieved serologic remission and complete resolution of fever, rash, conjunctivitis, and rheumatic symptoms, without any adverse effects. Six patients had AA (reactive systemic) amyloidosis, 2 of whom died of renal failure complications before interleukin 1-inhibiting therapy was available; 1 patient underwent renal transplantation and remains clinically well taking anakinra, and in the remaining 3 patients, anakinra therapy resulted in remission of their nephrotic syndrome. CONCLUSIONS: Anakinra therapy was well tolerated and has sustained efficacy on dermatologic and rheumatic manifestations in these patients with CIAS-1/NALP3 mutations. This treatment also resulted in resolution of AA amyloidosis-associated nephrotic syndrome in all affected patients.

Adolescent↗
PubMed2006

AA amyloidosis complicating hyperimmunoglobulinemia D with periodic fever syndrome: a report of two cases.

AA amyloidosis is the most serious potential complication of the inherited autoinflammatory syndromes and frequently results in end-stage renal failure. Although this complication is well recognized in familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and Muckle-Wells syndrome, there is only 1 previous published report of its occurrence in hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). We report 2 further cases of patients with AA amyloidosis in HIDS, both of whom developed dialysis-dependent renal failure, and we describe the outcome of the first renal transplant in this setting.

Adult↗
PubMed2005

Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis.

Extensive cardiac amyloid deposition in systemic AL amyloidosis is associated with a grave prognosis. Heart transplantation is rarely performed because of the systemic and progressive nature of the disease. Patients with severe cardiac amyloid infiltration are ineligible for the preferred treatment of melphalan chemotherapy with stem cell transplantation (SCT) rescue because of the high risk for treatment-related mortality. Heart transplantation followed by SCT was performed in 5 patients with AL amyloidosis and predominant cardiomyopathy. Patients were followed up for a median of 95 months (range, 37-118 months) from diagnosis. At censor, 3 of 5 patients were well without evidence of intracardiac or extracardiac amyloid accumulation, and median overall survival by Kaplan-Meier estimate was not reached. Two patients died of progressive amyloidosis 33 and 90 months after heart transplantation after relapse of their underlying plasma cell dyscrasia. Heart transplantation followed by SCT is feasible in selected patients with cardiac AL amyloidosis and may confer substantial survival benefit.

Adult↗
PubMed2005

Hypercalcemia in a patient with common variable immunodeficiency and renal granulomas.

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency. A granulomatous form of the condition is recognized. Renal involvement is rare. The authors present the first case of CVID with biopsy-proven noncaseating renal granulomas, in association with hypercalcemia. The mechanism of hypercalcemia in granulomatous disorders, and the difficulty of differentiating granulomatous CVID from sarcoidosis, are discussed.

Common Variable Immunodeficiency↗
PubMed2004

Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra.

OBJECTIVE: Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. Molecular studies suggest that NALP3 is involved in the processing of interleukin-1beta (IL-1beta), prompting us to investigate whether IL-1 blockade may be therapeutic in patients with MWS. METHODS: We reviewed the clinical features of 3 members of a family, all of whom had MWS associated with the NALP3 variant V200M (also designated V198M), and evaluated the response of their inflammatory disease to treatment with the recombinant human IL-1 receptor antagonist anakinra. The subjects kept a diary of symptoms and underwent fortnightly clinical and laboratory assessments, including measurement of the serum amyloid A protein concentration. RESULTS: Each subject had fever, rashes, arthralgia, conjunctivitis, sensorineural deafness, and an intense acute-phase response characteristic of MWS. However, additional features were identified, including exacerbation of their disease by cold and neurologic manifestations, that have hitherto been described only in FCAS and NOMID, respectively. Clinical and serologic evidence of active inflammatory disease resolved rapidly and completely during treatment with anakinra. CONCLUSION: The remarkable response of MWS to anakinra suggests that IL-1beta has a fundamental role in the pathogenesis of inflammation associated with mutations in the NALP3 gene, and supports study of IL-1 inhibition in patients with NOMID/CINCA syndrome or FCAS. The clinical features of the various syndromes associated with mutations in the NALP3 gene may overlap to a greater extent than has previously been recognized.

Acute-Phase Reaction↗
PubMed2004

Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American-Finnish families.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder associated with more than 80 different transthyretin (TTR) mutations. The clinical features of FAP are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timming of treatment by orthotopic liver transplantation. FAP in association with TTR Gly47Glu has been described previously in an Italian kindred, and we report here its phenotype in 7 additional patients from Dutch, British, and American (Finnish) families. Characteristic clinical features included amyloid cardiomyopathy and autonomic failure but, unusually, moderate to severe renal failure was present in more than half of the cases. Only four patients were deemed to be sufficiently fit to undergo orthotopic liver transplantation, and clinical deterioration was generally rapid. These observations support early intervention with orthotopic liver transplantation in patients with FAP associated with TTR Gly47Glu.

Aged↗
PubMed2003

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.

OBJECTIVE: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. METHODS: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. RESULTS: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. CONCLUSION: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.

Antigens, CD↗
PubMed2003

Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy.

Monoclonal immunoglobulin light chains are deposited as amyloid fibrils in systemic AL (primary) amyloidosis, but the underlying plasma cell dyscrasias are often difficult to detect or unquantifiable. The relationships between circulating monoclonal light chains, amyloid load and clinical outcome, and the relative efficacies of chemotherapy regimens aimed at suppressing monoclonal immunoglobulin production, have not been determined. Circulating free immunoglobulin light chain (FLC) concentration was measured with a sensitive nephelometric immunoassay in 262 patients with AL amyloidosis, and followed serially in 137 patients who received either high-dose chemotherapy or one of two intermediate-dose cytotoxic regimens. Amyloid load was quantified by serum amyloid P component scintigraphy. A monoclonal excess of FLC was identified at diagnosis in 98% of patients. Among 86 patients whose abnormal FLC concentration fell by more than 50% following chemotherapy, 5-year survival was 88% compared with only 39% among those whose FLC did not fall by half (P < 0.0001). Amyloid deposits regressed in 58 patients. The magnitude and duration of the FLC responses to intermediate- and high-dose chemotherapy regimens were similar. The FLC assay enabled the circulating fibril precursor protein in AL amyloidosis to be quantified and monitored in most patients. Reduction of the amyloidogenic FLC by more than 50% was associated with substantial survival benefit, regardless of the type of chemotherapy used. Clinical improvement following chemotherapy in AL amyloidosis is delayed, but treatment strategies can be guided by their early effect on serum FLC concentration.

Adult↗
PubMed2003

Novel pharmacological strategies in amyloidosis.

Amyloidosis is a disorder of protein folding in which normally soluble plasma proteins are deposited as insoluble fibrils that disrupt tissue structure. Over 20 unrelated proteins form amyloid in vivo, with fibrils sharing a cross-beta-sheet structure composed of non-covalently associated protein or peptide subunits. Glycosaminoglycans and serum amyloid P component are universal non-fibrillar constituents of amyloid, contributing to fibrillogenesis and the stability of amyloid deposits. Amyloidosis may be acquired or hereditary and local or systemic, and is classified according to the precursor protein. Current treatment consists of support or replacement of impaired organ function and measures to reduce the production of amyloidogenic precursor proteins. Potential novel therapeutic strategies include stabilisation of the native fold of precursor proteins, reversion of misfolded proteins to their native state, inhibition of fibril propagation and enhancement of amyloid clearance either through immunotherapy or by reducing the stability of deposits through depletion of serum amyloid P component.

Amyloidosis↗
PubMed2002

Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.

BACKGROUND: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A alpha-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history. METHODS: We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations. RESULTS: Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent), most often in the genes encoding fibrinogen A alpha-chain (18 patients) and transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary amyloidosis was confirmed by additional investigations. A low-grade monoclonal gammopathy was detected in 8 of the 34 patients (24 percent). CONCLUSIONS: A genetic cause should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained.

Adult↗
PubMed2002

Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.

OBJECTIVE: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively. METHODS: Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA). RESULTS: Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA. CONCLUSION: These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Adult↗
PubMed2002

Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis.

Systemic monoclonal immunoglobulin light chain amyloidosis (AL) is associated with clonal plasma cell dyscrasias that are often subtle and non-proliferating. AL shares numerical chromosomal changes with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Illegitimate translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and deletions of the long arm of chromosome 13, [del(13q)], commonly occur in MM, MGUS and plasma cell leukaemia. In AL IGH rearrangements have been identified but, to date, there are no reports of del(13q). In this study of 32 patients with AL, 24 with systemic and eight with localized disease, translocations involving IGH and del(13q) were found using dual-colour interphase fluorescence in situ hybridization (FISH). IGH translocations were observed in 11 patients (37% overall and in 46% with systemic disease), of which nine had the IGH/CCND1 fusion from t(11;14)(q13;q32). Two showed IGH translocations other than the t(11;14) or t(4;14)(p16;q32). In one of these patients a breakpoint within the constant region of IGH between Calpha1 and Calpha2 was indicated. In the second a deletion covering Calpha1 and Calpha2 accompanied the translocation. Ten patients (27% overall and 33% of those with systemic disease) showed del(13q). The gain or loss of IGH and CCND1 signals provided evidence of numerical chromosomal changes in three patients.

Adult↗