Abrocitinib effect on patient-reported outcomes in patients with moderate-to-severe atopic dermatitis: Results from phase 3 studies, including the long-term extension JADE EXTEND study.

BACKGROUND: Abrocitinib improved signs and symptoms of moderate-to-severe atopic dermatitis (AD) at Weeks 12 and 16 in phase 3 studies, with a manageable safety profile. Patient-reported outcomes with long-term abrocitinib treatment were not reported. OBJECTIVE: To evaluate patient-reported outcomes with long-term abrocitinib treatment in patients with moderate-to-severe AD. METHODS: JADE EXTEND (NCT03422822) is an ongoing, phase 3, long-term extension study that enrolled patients from previous abrocitinib AD trials. This analysis includes patients from the phase 3 trials JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) who completed the full treatment period of placebo or abrocitinib (200 or 100 mg once daily) and subsequently entered JADE EXTEND and were randomised to receive once-daily abrocitinib 200 or 100 mg. Patient-reported endpoints to Week 48 included the proportion of patients who achieved Dermatology Life Quality Index (DLQI) scores of 0/1 (no effect of AD on quality of life [QoL]) and a ≥4-point improvement in Patient-Oriented Eczema Measure (POEM) score (clinically meaningful improvement). Data cut-off: April 22, 2020. RESULTS: Baseline DLQI mean scores were 15.4 and 15.3 in the abrocitinib 200- and 100-mg groups, respectively, which corresponded to a 'very large effect' on QoL; at Week 48, mean DLQI scores were lower with abrocitinib 200 mg (4.6; 'small effect' on QoL) and abrocitinib 100 mg (5.9; 'moderate effect' on QoL). Baseline POEM mean scores were 20.4 and 20.5 in the abrocitinib 200- and 100-mg groups, respectively; at Week 48, mean POEM scores were 8.2 and 11.0. Week 48 patient-reported responses with abrocitinib 200 mg and abrocitinib 100 mg were 44% and 34% for DLQI 0/1, and 90% and 77% for a ≥4-point reduction in POEM score. CONCLUSION: In patients with moderate-to-severe AD, long-term abrocitinib treatment resulted in clinically meaningful improvement in patient-reported symptoms of AD, including QoL.

Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician-reported signs (Eczema Area and Severity Index, EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting. OBJECTIVES: To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long-term control and itch intensity. METHODS: A face-to-face consensus meeting was held in Tokyo, Japan (8-10 April 2019) including 75 participants (49 healthcare professionals/methodologists, 14 patients, 12 industry representatives) from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules. RESULTS: It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long-term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long-term control. The peak itch numerical rating scale (NRS)-11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. CONCLUSIONS: For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.

Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).

BACKGROUND: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. METHODS: In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. RESULTS: At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1-13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8-16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5-17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8-27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. CONCLUSIONS: Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

BACKGROUND: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late-stage development for adult patients with moderate-to-severe AD. OBJECTIVE: To report pooled safety data for baricitinib in patients with moderate-to-severe AD in the clinical development program including long-term extension (LTE) studies. METHODS: This analysis included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one phase 2 and five phase 3), one double-blinded, randomized, LTE study and one open-label LTE study, reported in three data sets: placebo-controlled, 2-mg - 4-mg extended and All-bari AD. Safety outcomes include treatment-emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. RESULTS: Data were collected for 2531 patients who were given baricitinib for 2247 patient-years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo-controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo-controlled period in baricitinib-treated patients. Frequency of herpes simplex was higher in the 4-mg group (6.1%) vs. the 2-mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2-mg IR = 9.6; 4-mg IR = 14.5) were lower vs. the placebo-controlled data set (2-mg IR = 12.4; 4-mg IR = 21.3). In the All-bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2-mg group): two venous thrombosis events (4-mg group) and one death. CONCLUSION: This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib.

Efficacy and safety of dupilumab in Japanese adults with moderate-to-severe atopic dermatitis: a subanalysis of three clinical trials.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin-4 and interleukin-13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate-to-severe AD. METHODS: We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16-week, phase IIb dose-finding trial (AD-1021; NCT01859988); a 16-week, phase III, placebo-controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52-week, phase III, placebo-controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). RESULTS: Twenty-seven, 106 and 117 Japanese patients were enrolled in AD-1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection-site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation-regulated chemokine and gradual IgE reductions. CONCLUSIONS: Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate-to-severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T-cell activation profiles have been observed. International clinical studies in adults with moderate-to-severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin-4 and interleukin-13, key molecules in type 2 inflammation. The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate-to-severe AD. The effects were comparable with those observed in the overall study population. Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.

Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema clinical trials. Previous consensus meetings have agreed upon preferred instruments for clinician-reported signs (Eczema Area and Severity Index - EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure - POEM). This paper reports consensus decisions from the HOME VII meeting. OBJECTIVE: To complete the core outcome set for atopic eczema by agreeing upon core outcome instruments for the domains of quality of life, long-term control and itch intensity. METHODS: Face-to-face consensus meeting held in Tokyo, Japan (8th to 10th April, 2019) including 74 participants (47 healthcare professionals/methodologists, 14 patients, 13 industry representatives), from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using pre-defined consensus rules. RESULTS: It was agreed by consensus that quality of life should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children's Dermatology Life Quality Index (CDLQI) for children, and the Infant's Dermatology Quality of Life Index (IDQoL) for infants. For long-term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long-term control. The peak itch numerical rating scale(NRS)-11 past 24 hours was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum. CONCLUSIONS: For now, the core outcome set for clinical trials in atopic eczema is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.

Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice.

BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.

Gerontodermatology: the fragility of the epidermis in older adults.

The proportion of adults over 60 years of age is rapidly increasing and is estimated to reach approximately one-sixth of the global population by 2030. An ageing population is a real challenge for healthcare resources, including dermatologists and geriatricians, as age-related changes in skin integrity and barrier function make older adults more susceptible to developing skin pathologies such as pruritus, dermatitis and infections. Fragile skin arises from several interlinked causes, including age-related changes in skin barrier integrity, previous and current lifestyle choices, skin pathologies and medical interventions. Dermo-cosmetics can play a key role in enhancing skin care regimens and preventing pathologies in this age group. In vitro studies, clinical, and in-daily clinical practice studies of dermo-cosmetics have shown them to be effective in many skin conditions in older adults, like xerosis and pruritus. Incontinence-associated dermatitis (IAD), a common condition arising from contact with irritants such as urine and faeces which can significantly impact the quality of life of sufferers, can also be improved with a barrier cream in incontinent patients aged 70 years and older. This supplement focuses on the increased fragility of older skin, the development of common skin pathologies and the efficacy and tolerance of dermo-cosmetic products in older adults.

Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis.

BACKGROUND: Continuous treatment is recommended for patients with moderate-to-severe psoriasis; however, treatment may need to be interrupted in routine clinical practice. OBJECTIVE: To assess outcomes in patients continuously treated with ixekizumab versus those who interrupted therapy and were subsequently retreated with ixekizumab (IXE). METHODS: This analysis used data pooled from two phase 3 trials, UNCOVER-1 and UNCOVER-2. Patients were randomized to placebo (PBO), IXE every 4 (Q4W) or IXE every 2 weeks (Q2W) for 12 weeks. Patients with a static Physician's Global Assessment (sPGA) 0, 1 at Week 12 were rerandomized to IXEQ4W, IXE every 12 weeks (not presented) or PBO. We examined outcomes in patients who were continuously treated (IXEQ2W/IXEQ4W; IXEQ4W/IXEQ4W) or withdrawn (IXEQ2W/PBO; IXEQ4W/PBO), and in patients who were withdrawn and retreated with IXEQ4W for 24 weeks after disease relapse (sPGA ≥3). RESULTS: A total of 1226 treated patients achieved an sPGA 0, 1 at Week 12 and entered the maintenance phase; of these patients, 402 and 416 were rerandomized to PBO and IXEQ4W, respectively. Among patients interrupting treatment, 157 (82.2%) of IXEQ4W/PBO and 176 (83.4%) of IXEQ2W/PBO had an sPGA ≥3 by Week 60; median time to relapse was approximately 20 weeks irrespective of induction dose. At Week 60, continuously treated patients maintained high levels of PASI and sPGA responses (90.0% PASI 75 IXEQ2W/IXEQ4W; 81.9% sPGA 0, 1 IXEQ2W/IXEQ4W, non-responder imputation). After 24 weeks of retreatment with IXEQ4W (IXEQ2W/PBO/IXEQ4W and IXEQ4W/PBO/IXEQ4W), 87.0% (107 of 123) and 95.1% (97 of 102) (observed), respectively, of patients recaptured PASI 75 and 70.7% (104 of 147) and 82.3% (107 of 130) (observed) recaptured an sPGA 0, 1. Overall, adverse events in continuously treated and retreated patients were comparable. CONCLUSION: High levels of response were sustained with continuous ixekizumab treatment through 60 weeks. Most patients who were withdrawn experienced disease relapse, and most of those patients recaptured response after 24 weeks of retreatment.

Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME).

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure.

Thymic stromal lymphopoietin expression is increased in the horny layer of patients with atopic dermatitis.

Thymic stromal lymphopoietin (TSLP) is known for its capacity to induce CD11c(+) myeloid dendritic cells to promote T helper type 2 (Th2)-skewed inflammatory responses. Although increased expression of TSLP was reported in the lesional skin of limited numbers of patients with atopic dermatitis (AD), the relationships between the degree of TSLP expression in the skin and the severity of AD, epidermal barrier function and eruption type remain to be elucidated. The aim of this study was to examine the relationships between the degree of TSLP expression in the skin and the severity of AD, eruption type and epidermal barrier function using a non-invasive method in a sizeable group of the patients. Stratum corneum tissue was obtained from AD patients by tape stripping, and the stratum corneum TSLP (scTSLP) expression level was evaluated using a TSLP-specific antibody followed by image analysis. The correlations between the scTSLP intensity and the severity scoring of AD (SCORAD) index and epidermal barrier function, such as stratum corneum hydration and transepidermal water loss (TEWL), were analysed. The changes in the scTSLP level induced by the application of moisturizer were also examined. The scTSLP expression level was increased in AD patients compared with healthy subjects and was correlated with SCORAD, especially with the dry skin score, and stratum corneum hydration. Moisturizer application resulted in reduced scTSLP levels. The scTSLP level can be used as a biomarker of AD severity and particularly epidermal barrier status.

Implementation of the HOME core outcome set for clinical trials of atopic eczema-barriers and opportunities: the HOME IX meeting report.

The Harmonising Outcome Measures for Eczema (HOME) initiative established a core outcome set (COS) for atopic eczema (AE) clinical trials in 2019. This set encompasses four core outcome domains and corresponding measurement instruments: clinical signs (EASI), patient-reported symptoms (POEM and NRS 11 point for worst itch over the last 24 h), quality of life (DLQI/CDLQI/IDQoLI), and long-term control (Recap or ADCT). Following its roadmap, the HOME initiative is now focused on supporting implementation of the COS. To identify barriers and facilitators to implementation of the COS, and to guide the effort to promote COS uptake, a virtual consensus meeting was held over 2 days (September 25-26, 2021) attended by 55 participants (26 healthcare professionals, 16 methodologists, 5 patients, 4 industry representatives, and 4 students). Implementation themes were identified by a pre-meeting survey distributed to HOME members, presentations, and whole-group discussion. Participants were divided into five multi-professional small groups which ranked their top 3 most important themes, followed by whole-group discussion and anonymous consensus voting (consensus criteria: < 30% disagreement). Three most important implementation themes were identified and agreed upon: (1) awareness and stakeholder engagement, (2) universal applicability of the COS, and (3) ensuring minimum administrative burden. Working groups to address these issues are now a priority for the HOME initiative. The results from this meeting will inform the development of a HOME Implementation Roadmap in an effort to support other COS groups planning for effective implementation of their core sets.

Increased plasma LIGHT levels in patients with atopic dermatitis.

LIGHT [the name of which is derived from 'homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator (HVEM), and expressed by T lymphocytes'], is a member of the tumour necrosis factor superfamily that is involved in various inflammatory diseases. We aimed to estimate the relevance of plasma LIGHT levels as a biomarker for atopic dermatitis (AD). In order to understand the putative role of LIGHT in AD pathogenesis, we also investigate the effects of LIGHT on a monocytic cell line, human acute monocytic leukaemia cell line (THP-1). We examined plasma LIGHT levels, total serum IgE, serum value of CCL17 and peripheral blood eosinophil counts in patients with AD and healthy subjects. The effects of LIGHT on activation and apoptosis in THP-1 cells were also investigated. The plasma concentrations of LIGHT in AD patients were significantly higher than those in healthy individuals and the concentrations decreased as the symptoms were improved by treatment. The LIGHT plasma concentrations correlated with IgE levels and the Severity Scoring of AD (SCORAD) index. In addition, LIGHT stimulation increased expression of CD86 and induced production of interleukin-1ß in THP-1 cells. Apoptosis was inhibited, the Bcl-2 level increased and the caspase-3 level decreased in THP-1 cells stimulated with LIGHT, compared to unstimulated control cells. These results suggest that plasma LIGHT levels may be one of the promising biomarkers for AD.

Peripheral nerve involvement in primary systemic AL amyloidosis: a clinical and electrophysiological study.

BACKGROUND: Involvement of visceral organs usually dominates the clinical picture of primary systemic AL amyloidosis, but some patients suffer from serious peripheral neuropathy. The aim of this study is to clinically and electrophysiologically investigate peripheral nerve involvement in AL amyloidosis patients. PATIENTS AND METHODS: We reviewed clinical manifestations, electrophysiological findings including nerve conduction velocities and treatments in 43 consecutive patients. Twenty age-matched healthy subjects were employed as controls. RESULTS: Fifteen patients (34.9%) showed apparent neuropathic symptoms, which consisted of polyneuropathy in 11 (25.6%), bilateral carpal tunnel syndrome in 4 (9.3%), and autonomic dysfunction in 8 (18.6%). Polyneuropathy in this disease was characterized by symmetrical and sensory-dominant impairment, early involvement of the lower limbs, loss of all sensations, rarity of motor weakness, and painful paresthesia in the legs predominant at an early stage. Autonomic dysfunction including orthostatic hypotension was frequently associated with polyneuropathy at an advanced stage. On electrophysiological studies, motor conduction velocity and compound muscle action potential of both median and tibial nerves were significantly decreased in the patients with polyneuropathy but also in those without any signs of neuropathy. Only four of 15 patients with neuropathy were able to receive intensive but promising chemotherapy with a large dose of melphalan for plasma cell dyscrasia. CONCLUSIONS: Peripheral nerves in primary systemic AL amyloidosis patients seem to be involved more extensively than clinical manifestations might suggest. The clinical picture of polyneuropathy in this disease closely resembles that in transthyretin-type familial amyloid polyneuropathy patients with a late age at onset, particularly those originating from sporadic kindreds.