Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

European consensus statement on phenotypes of pustular psoriasis.

Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [Saurat Dermatologie 2016, Rook's Dermatology 2016, Fitzpatrick's 2012 and Braun-Falco 2012], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized pustular psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (>3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV.

The quest for psoriasis susceptibility genes in the postgenome-wide association studies era: charting the road ahead.

The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, organized its inaugural genetics workshop in Montreal, on 12 October 2011. The presentations included a summary of the remarkable progress achieved through the implementation of genome-wide association studies, which have highlighted key pathogenic pathways for psoriasis. Ongoing meta-analyses are identifying further susceptibility genes, bringing the number of known loci close to 40. The functional characterization of low-risk alleles is proving problematic, but next-generation sequencing approaches are expected to identify rare deleterious variants, which will be easier to investigate. Elucidating the genetic architecture of psoriasis will have major implications in terms of understanding disease mechanisms and predicting response to treatment.

Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes.

Psoriasis is an immune-mediated skin disorder, which is inherited as a complex trait. Genome-wide linkage and association studies have identified a major disease susceptibility locus on chromosome 6p21, as well as a number of genetic determinants of smaller effect. Our group has also documented a significant association between psoriasis and CDKAL1, a gene previously implicated in the pathogenesis of Crohn's disease (CD) and type II diabetes (TIID). With this study, we validate this association, through the analysis of CDKAL1 single nucleotide polymorphism (SNP) rs6908425 in an independently ascertained psoriasis dataset (replication sample: 1323 cases vs 1368 controls, P=0.00012, odds ratio (OR): 1.28; combined sample: 2579 cases vs 4306 controls, P=4 x 10(-6), OR: 1.26). We also show that the association with psoriasis and CD is completely independent from that with TIID. Finally, we report the results of expression studies demonstrating that CDKAL1 transcripts are virtually absent from skin keratinocytes, but are abundantly expressed in immune cells, especially in CD4+ and CD19+ lymphocytes. It is to be noted that our data indicate that CDKAL1 becomes markedly downregulated when immune cells are activated with proliferating signals. Taken together, our results document the presence of allelic heterogeneity at the CDKAL1 locus and suggest that CDKAL1 alleles may confer susceptibility to clinically distinct disorders through differential effects on disease-specific cell types.

Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease.

BACKGROUND: Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage analyses have clearly mapped a primary disease susceptibility locus to the major histocompatibility complex (MHC) region on chromosome 6p21. More recently, whole-genome association studies have identified two non-MHC disease genes (IL12B and IL23R), both of which also confer susceptibility to Crohn disease (CD). OBJECTIVE AND METHODS: To ascertain the genetic overlap between these two inflammatory conditions further, we investigated 15 CD-associated loci in a psoriasis case-control dataset. RESULTS: The analysis of 1256 patients and 2938 unrelated controls found significant associations for loci mapping to chromosomes 1q24 (rs12035082, p = 0.009), 6p22 (rs6908425, p = 0.00015) and 21q22 (rs2836754, p = 0.0003). Notably, the marker showing the strongest phenotypic effect (rs6908425) maps to CDKAL1, a gene also associated with type 2 diabetes. CONCLUSIONS: These results substantiate emerging evidence for a pleiotropic role for s genes that contribute to the pathogenesis of immune-mediated disorders.

Searching for psoriasis susceptibility genes in Italy: genome scan and evidence for a new locus on chromosome 1.

Psoriasis is a chronic inflammatory dermatitis, affecting approximately 2% of the population. Major clinical features include red, scaly patches on scalp, elbows, and knees, with or without severe arthritis. Several putative susceptibility loci have been mapped by parametric and non-parametric linkage analysis to chromosome regions 2p, 4q, 6p, 8q, 16q, 17q, and 20p; however, the most significant results and confirmation of linkage are only available for the 17q and 6p chromosome regions at present. In this study, 22 multiplex Italian families were investigated for linkage to 6p and 17q susceptibility regions, using a set of four microsatellites. These analyses failed to detect significant linkage with any of the examined markers. A genome-wide scan was then performed on one of the largest pedigrees, searching for an additional susceptibility locus. This study disclosed a putative linkage to chromosome 1cen-q21 markers. When these microsatellites were analyzed in the remaining families of the sample, a significant linkage was observed using both parametric and non-parametric methods. The highest two-point lod score value was obtained with D1S305 marker (3.75 at 0 = 0.05). Non-parametric analysis at this locus also demonstrated a significant excess of allele sharing (p = 0.0001).

Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21.

Psoriasis is a chronic skin disorder affecting approximately 2% of the Caucasian population. Family clustering of the disease is well established and nonparametric linkage analyzes have mapped disease susceptibility loci on chromosomes 6p (PSORS1) and 17q (PSORS2). Nonconfirmed evidence for linkage is also available for chromosomes 2q 3q, 4q (PSORS3), 8q, 16q, and 20p. We mapped an additional susceptibility locus on chromosome 1q21 (PSORS4). In this study, we have carried out a linkage disequilibrium analysis, in order to achieve a finer localization. We recruited 79 triads from continental Italy and typed them at five loci spanning the 1.6 Mb region generating the highest multipoint LOD scores in our previous linkage study. We observed significant evidence for association with D1S2346 marker (p = 0.004). Results consistent with this data were obtained by typing an independent sample that included 28 patients and 56 controls, originating from Sardinia. In fact, p values of 0.02 were observed with both D1S2346 and D1S2715 markers. We sought further confirmation of our results by typing both samples with two novel markers (140J1C and 140J1D) flanking D1S2346. Marker 140J1D generated a p value of 0.003 in the continental Italy sample where a D1S2346/140J1D haplotype was found with a higher frequency among patients' chromosomes. Altogether our data indicate that the 1q21 susceptibility gene may be localized in the genomic interval spanned by D1S2346 and 140J1D. This report provides evidence supporting the refinement of a non-HLA psoriasis susceptibility locus.

Fine mapping of a distinctive autosomal dominant vacuolar neuromyopathy using 11 novel microsatellite markers from chromosome band 19p13.3.

We previously mapped a distinctive autosomal dominant vacuolar neuromyopathy on human chromosome 19p13 in an 8cM region, delimited by D19S209 and D19S177 markers. We now report the fine mapping of the disease locus within an interval of 250 Kb by haplotype analysis performed using a set of 11 novel microsatellite markers isolated from the candidate region.

Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26.

Hearing impairment is the most common inherited human sensory defect. Nonsyndromic Hearing Impairment (NSHI) is the most genetically heterogeneous trait known. Over 70 loci have been mapped and a total of 19 genes have been identified. We report here a novel locus (DFNA 30) for autosomal dominant NSHI that we mapped to chromosome 15q25-26 in an Italian four-generation family. The haplotype analysis has identified a critical interval of 18 cM between markers D15S151 and D15S130. This region does not overlap with DFNB16 locus but partially coincides with the otosclerosis (OTS) locus. Localisation of the locus DFNA30 is a first step towards the identification of the gene.

Expression and activation of pro-gelatinase A by human melanoma cell lines with different tumorigenic potential.

The production of various proteolytic enzymes by tumor cells facilitate the invasion of solid tumors into surrounding tissues. We examined three cell lines (M1Dor, M4Be and M3Da) derived from malignant melanoma which exhibited different abilities to grow in nude mice following subcutaneous grafting. By in vitro invasion assay using Boyden-chambers technique, we found that none of those cell lines were able to invade the Matrigel. Several studies have substantiated the role of matrix metalloproteinases (MMP), mainly gelatinases MMP-9 and MMP-2, in melanoma cell invasion. Each cell line constitutively produced MMP-2 (but not MMP-9) in its latent form only, with stronger production for the most tumorigenic cell line in vivo (M3Da). Integrity of the MMP-2 activation process was studied since MMP-2 was also recovered as zymogen at the cell plasma membrane. All cell lines secreted TIMP-1 and TIMP-2 in a constitutive manner and again, but TIMP-2 production as well as MT1-MMP expression were found inversely related to their tumorigenic potential. Plating cells onto type I or type IV collagen did not trigger pro-MMP-2 activation; on the contrary, conversion of pro-MMP-2 to its active form could be evidenced when melanoma cell lines were seeded in a three dimensional type I collagen lattice.

A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13.

OBJECTIVE: To characterize a kindred with a distinctive autosomal dominant neuromuscular disorder. BACKGROUND: The authors studied a large Italian family affected by a progressive neuromyopathy. Ten individuals over three generations were affected. The disease was characterized by onset from the late teens to early 50s with distal leg weakness and atrophy, development of generalized muscle weakness with distal-to-proximal progression sparing facial and ocular muscles, dysphonia and dysphagia, pes cavus and areflexia, variable clinical expression ranging from subclinical myopathy to severely disabling weakness, and mixed neurogenic and myopathic abnormalities on electromyography. METHODS: Morphologic, immunocytochemical, and ultrastructural studies were performed in muscle biopsies from three affected patients. A genomewide linkage analysis through the genotyping of 292 microsatellite markers spanning the 22 autosomes was undertaken to map the disorder segregating in this family. RESULTS: All muscle biopsies showed variation of fiber size, panesterase-positive angular fibers, mild to severe fibrosis, and numerous "rimmed vacuoles." Electron microscopy failed to demonstrate the nuclear or cytoplasmic filamentous inclusions specific of inclusion-body myopathies and, accordingly, immunohistochemistry did not show any positivity with SMI-31 antibodies detecting hyperphosphorylated tau. Preliminary analysis of 292 microsatellite markers provided evidence for linkage to chromosome 19p13. CONCLUSIONS: This distinctive autosomal dominant disorder is characterized by a vacuolar neuromyopathy. Localization to chromosome 19p13 will allow the genetic relationship between this disease and inherited myopathies with rimmed vacuoles, in particular autosomal dominant inclusion-body myopathies, to be defined.

Discordant clinical outcome in type III spinal muscular atrophy sibships showing the same deletion pattern.

Three type III spinal muscular atrophy (SMA) families are described in which the same deletion pattern for SMN gene and flanking loci is apparent in both affected and unaffected siblings. Deletions extending to include the NAIP gene are reported in one sibship. All three individuals in which SMN and/or NAIP deletions were detected showed the same haplotypes for SMA linked microsatellite markers as their affected sibs. The three index cases had a SMA III with early onset (1.5-2 yr) and became chairbound at the age 4, 5 and 20 yr. The three haploidentical sibs were given a clinical severity score. One of them showed no sign of the disease at the age of 4 yr and was considered "unaffected"; a 35-yr-old female, who had no symptoms but showed tongue fasciculations and hand tremor was considered "asymptomatic"; a 34-yr-old female, who had mild muscular weakness since the age of 24, was rated "mild". These observations demonstrate the presence of a continuum of clinical variability within SMA III families. These data suggest that, in these three families at least, the SMA phenotype is caused or influenced by another gene(s) additional to SMN.

A single strand conformation polymorphism-based carrier test for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with a newborn prevalence of 1 in 10,000, and a carrier frequency of 1 in 40-60 individuals. The SMA locus has been mapped to chromosome 5q11.2-13. The disease is caused by a deletion of the SMN gene, often encompassing other genes and microsatellite markers. The SMN gene is present in two highly homologous copies, SMN1 and SMN2, differing at five nucleotide positions. Only homozygous SMN1 mutations cause the disease. The sequence similarity between the SMN1 and SMN2 genes can make molecular diagnosis and carrier identification difficult. We developed a sensitive and reliable molecular test for SMN1 carrier identification, by setting up a nonradioactive single strand conformation polymorphism (SSCP)-based method, which allows for the quantification of the amount of the SMN1 gene product with respect to a control gene. The assay was validated in 56 obligate (ascertained) carriers and 20 (ascertained) noncarriers. The sensitivity of the test is 96.4%, and its specificity, 98%. In addition, 6 of 7 SMA patients without homozygous deletions presented with a heterozygous deletion, suggesting a concomitant undetected point mutation on the nondeleted SMN1 allele. Therefore, the present test is effective for detecting compound hemizygote patients, for testing carriers in SMA families, and for screening for SMA heterozygotes in the general population.