VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation.

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

Cutaneous vasculitis occurring in the setting of systemic lupus erythematosus: a multicentre cohort study.

OBJECTIVES: To describe the clinical and pathological features of biopsy-proven cutaneous vasculitis (CV) associated with SLE, focusing on diagnosis classification and impact on overall SLE activity. METHODS: Retrospective multicentric cohort study including SLE patients with biopsy-proven CV identified by (i) data from pathology departments of three university hospitals and (ii) a national call for cases. SLE was defined according to 1997 revised ACR and/or 2019 ACR/EULAR criteria. CV diagnosis was confirmed histologically and classified by using the dermatological addendum of the Chapel Hill classification. SLE activity and flare severity at the time of CV diagnosis were assessed independently of vasculitis items with the SELENA-SLEDAI and SELENA-SLEDAI Flare Index. RESULTS: Overall, 39 patients were included; 35 (90%) were female. Cutaneous manifestations included mostly palpable purpura (n = 21; 54%) and urticarial lesions (n = 18; 46%); lower limbs were the most common location (n = 33; 85%). Eleven (28%) patients exhibited extracutaneous vasculitis. A higher prevalence of Sjögren's syndrome (51%) was found compared with SLE patients without CV from the French referral centre group (12%, P < 0.0001) and the Swiss SLE Cohort (11%, P < 0.0001). CV was mostly classified as urticarial vasculitis (n = 14, 36%) and cryoglobulinaemia (n = 13, 33%). Only 2 (5%) patients had no other cause than SLE to explain the CV. Sixty-one percent of patients had inactive SLE. CONCLUSION: SLE-related vasculitis seems very rare and other causes of vasculitis should be ruled out before considering this diagnosis. Moreover, in more than half of patients, CV was not associated with another sign of active SLE.

Superficial (nodular) thrombophlebitis as a heterogeneous entity with distinctive clinico-pathological aspects: Correlation with the underlying conditions.

BACKGROUND: Superficial (nodular) thrombophlebitis, referring to a thrombo-inflammatory disorder of dermal-subcutaneous veins, encompass a spectrum of nodular lesions often associated with inflammatory, infectious, neoplastic or thrombophilic diseases. OBJECTIVE: We postulate that distinct clinico-pathological features may correlate with the underlying conditions. METHODS: We conducted a retrospective monocentric study of all patients seen in our dermatology department for a superficial thrombophlebitis, completed with a literature review. Clinical and pathological data were extracted from the patient files and articles. RESULTS: A total of 108 cases of superficial thrombophlebitis was analysed. Forty-five percent manifested as elongated nodules clearly evoking vascular involvement, while the other 55% were presenting as nodules or plaques. The elongated phenotype was strongly associated with malignancy or thrombophilia if a pure thrombosis was demonstrated histopathologically, while tuberculosis was the main underlying condition if a granulomatous vasculitis was present. Panniculitis-like lesions were mainly corresponding to erythema-nodosum-like lesions of Behçet's disease, characterized by the distinctive feature of thrombotic veins with an associated leukocytoclastic vasculitis. LIMITATIONS: Retrospective design and risk of publication bias. CONCLUSION: Superficial (nodular) thrombophlebitis is a heterogeneous entity with a distinct clinico-pathological presentation that strongly points to the nature of the underlying medical condition, thus guiding the medical workup.

Human Co-Infections between Borrelia burgdorferi s.l. and Other Ixodes-Borne Microorganisms: A Systematic Review.

When it comes to tick-borne diseases, co-infections are often mentioned. This concept includes several entities. On the one hand, tick vectors or vertebrate reservoir host can harbor several microorganisms that can be pathogenic for humans. On the other hand, human co-infections can also be understood in different ways, ranging from seropositivity without clinical symptoms to co-disease, i.e., the simultaneous clinical expression of infections by two tick-borne microorganisms. The latter, although regularly speculated, is not often reported. Hence, we conducted a systematic review on co-infections between B. burgdorferi s.l., the etiological agent of Lyme borreliosis, and other microorganisms potentially transmitted to humans by Ixodes spp. ticks. A total of 68 relevant articles were included, presenting 655 cases of possible co-infections. Most cases of co-infections corresponded to patients with one tick-borne disease and presenting antibody against another tick-borne microorganism. Co-disease was particularly frequent in two situations: patients with clinical symptoms of high fever and erythema migrans (EM), and patients with neurological symptoms linked to the TBEv or a neuroborreliosis. No impact on severity was evidenced. Further studies are needed to better appreciate the frequency and the impact of co-infections between several tick-borne microorganisms.

Significance of Sjögren's syndrome and anti-cN1A antibody in myositis patients.

OBJECTIVE: We recently recorded a high prevalence of inclusion body myositis (IBM) in patients with Sjögren's syndrome (SS). Whether myositis patients with SS differ from myositis patients without SS in terms of the characteristics of the myositis is currently unknown. Anti-cytosolic 5'-nucleotidase 1 A (cN1A) has recently been proposed as a biomarker for IBM but is also frequent in SS. Whether anti-cN1A is independently associated with IBM is still an open question. We aimed to assess the significance of SS and anti-cN1A in myositis patients. METHODS: Cumulative data on all myositis patients (EULAR/ACR 2017 criteria) screened for SS (ACR/EULAR 2016 criteria) in a single centre were analysed. Ninety-nine patients were included, covering the whole spectrum of EULAR/ACR 2017 myositis subgroups and with a median follow-up of 6 years (range 1.0-37.5). The 34 myositis patients with SS (myositis/SS+) were compared with the 65 myositis patients without SS (myositis/SS-). RESULTS: . IBM was present in 24% of the myositis/SS+ patients vs 6% of the myositis/SS- group (P = 0.020). None of the IBM patients responded to treatment, whether they had SS or not. Anti-cN1A was more frequent in myositis/SS+ patients (38% vs 6%, P = 0.0005), independently of the higher prevalence of IBM in this group (multivariate P value: 0.02). Anti-cN1A antibody specificity for IBM was 0.96 (95% CI: 0.87, 0.99) in the myositis/SS- group but dropped to 0.70 (95% CI: 0.48, 0.85) in the myositis/SS+ group. INTERPRETATION: In myositis patients, SS is associated with IBM and with anti-cN1A antibodies, independently of the IBM diagnosis. As a consequence, anti-cN1A has limited specificity for IBM in myositis patients with SS.

AESOP syndrome: a potential life-saving and early clue to the diagnosis of POEMS syndrome.

Adenopathy and an extensive skin patch overlying a plasmacytoma (AESOP) syndrome, first described 16 years ago, is characterized by a slowly expanding red or brown patch (classic variant) or plaque (morphea-like variant) overlying a solitary plasmacytoma of the bone. Early recognition can be life-saving, as it is an early presentation of polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome, which may be fatal. There are two forms: the classic variant, which presents as a smooth, shiny macule with abnormal visibility of skin vessels, and the morphea-like variant, which presents as a plaque where the skin is folded, giving a "peau d'orange" appearance. The locations are frequently above the rib cage, above the sternum, or the scalp. Seventy-five percent of the patients develop regional lymphadenopathy within a few months. Histopathologic study reveals a capillary proliferation in the dermis. The diagnosis relies on subsequent identification of the plasmacytoma. At the time of a presumptive diagnosis, only 40% of patients have fulfilled the diagnostic criteria of POEMS. Treatment depends on the final hematologic diagnosis, but radiation of the plasmacytoma is required.

Progressive multifocal leukoencephalopathy and sarcoidosis under interleukin 7: The price of healing.

OBJECTIVE: To report the association of JC virus infection of the brain (progressive multifocal encephalopathy [PML]) during the course of sarcoidosis and the challenging balance between immune reconstitution under targeted cytokine interleukin 7 (IL7) therapy for PML and immunosuppression for sarcoidosis. METHODS: Original case report including deep sequencing (whole-exome sequencing) to exclude a primary immunodeficiency (PID) and review of the literature of cases of PML and sarcoidosis. RESULTS: We report and discuss here a challenging case of immune reconstitution with IL7 therapy for PML in sarcoidosis in a patient without evidence for underling PID or previous immunosuppressive therapy. CONCLUSIONS: New targeted therapies in immunology and infectiology open the doors of more specific and more specialized therapies for patients with immunodeficiencies, autoimmune diseases, or cancers. However, before instauration of these treatments, the risk of immune reconstitution inflammatory syndrome and potential exacerbation of an underlying disease must be considered. It is particularly true in case of autoimmune disease such as sarcoidosis or lupus.

Effects of topical corticosteroids and lidocaine on Borrelia burgdorferi sensu lato in mouse skin: potential impact to human clinical trials.

Lyme borreliosis is the most prevalent vector-borne disease in northern hemisphere. Borrelia burgdorferi sensu lato spirochetes are transmitted by Ixodes species ticks. During a blood meal, these spirochetes are inoculated into the skin where they multiply and often spread to various target organs: disseminated skin sites, the central nervous system, the heart and large joints. The usual diagnosis of this disease relies on serological tests. However, in patients presenting persistent clinical manifestations, this indirect diagnosis is not capable of detecting an active infection. If the serological tests are positive, it only proves that exposure of an individual to Lyme spirochetes had occurred. Although culture and quantitative PCR detect active infection, currently used tests are not sensitive enough for wide-ranging applications. Animal models have shown that B. burgdorferi persists in the skin. We present here our targeted proteomics results using infected mouse skin biopsies that facilitate detection of this pathogen. We have employed several novel approaches in this study. First, the effect of lidocaine, a local anesthetic used for human skin biopsy, on B. burgdorferi presence was measured. We further determined the impact of topical corticosteroids to reactivate Borrelia locally in the skin. This local immunosuppressive compound helps follow-up detection of spirochetes by proteomic analysis of Borrelia present in the skin. This approach could be developed as a novel diagnostic test for active Lyme borreliosis in patients presenting disseminated persistent infection. Although our results using topical corticosteroids in mice are highly promising for recovery of spirochetes, further optimization will be needed to translate this strategy for diagnosis of Lyme disease in patients.

Skin Interface, a Key Player for Borrelia Multiplication and Persistence in Lyme Borreliosis.

The skin plays a key role in vector-borne diseases because it is the site where the arthropod coinoculates pathogens and its saliva. Lyme borreliosis, particularly well investigated in this context, is a multisystemic infectious disease caused by Borrelia burgdorferi sensu lato and transmitted by the hard tick Ixodes. Numerous in vitro studies were conducted to better understand the role of specific skin cells and tick saliva in host defense, vector feeding, and pathogen transmission. The skin was also evidenced in various animal models as the site of bacterial multiplication and persistence. We present the achievements in this field as well as the gaps that impede comprehensive knowledge of the disease pathophysiology and the development of efficient diagnostic tools and vaccines in humans.

Correction to: Autoinflammatory diseases: why they should matter to the dermatologist.

This corrects the article DOI: 10.23736/S0392-0488.20.06778-4.

Multilocus sequence typing of clinical Borreliella afzelii strains: population structure and differential ability to disseminate in humans.

BACKGROUND: Lyme borreliosis in humans results in a range of clinical manifestations, thought to be partly due to differences in the pathogenicity of the infecting strain. This study compared European human clinical strains of Borreliella afzelii (previously named Borrelia afzelii) using multilocus sequence typing (MLST) to determine their spatial distribution across Europe and to establish whether there are associations between B. afzelii genotypes and specific clinical manifestations of Lyme borreliosis. For this purpose, typing was performed on 63 strains, and data on a further 245 strains were accessed from the literature. RESULTS: All 308 strains were categorized into 149 sequence types (STs), 27 of which are described here for the first time. Phylogenetic and goeBURST analyses showed short evolutionary distances between strains. Although the main STs differed among the countries with the largest number of strains of interest (Germany, the Netherlands, France and Slovenia), the B. afzelii clinical strains were less genetically structured than those previously observed in the European tick population. Two STs were found significantly more frequently in strains associated with clinical manifestations involving erythema migrans, whereas another ST was found significantly more frequently in strains associated with disseminated manifestations, especially neuroborreliosis. CONCLUSIONS: The MLST profiles showed low genetic differentiation between B. afzelii strains isolated from patients with Lyme borreliosis in Europe. Also, clinical data analysis suggests the existence of lineages with differential dissemination properties in humans.

Clinical and Therapeutic Aspects of Linear Psoriasis: A Study of 30 Cases.

BACKGROUND: Psoriasis affects 2-4% of the population, with the most common clinical type being plaque psoriasis. The linear form of psoriasis is very rare. The literature on linear psoriasis (LP) consists of only case reports, and data are few. OBJECTIVE: This study aimed to better understand LP in a large-scale study. PATIENTS AND METHODS: We retrospectively retrieved the medical records from 14 French medical centers of patients newly diagnosed clinically with LP, with or without the support of histology, between 1 February and 31 July 2015. For each case, we assessed the clinical features, treatments and treatment efficacy. RESULTS: In total, 30 cases of LP (mean age 26.8 years, 13 males) were reported. Mean age at onset of LP was 20.0 years, with 18 developing LP in childhood. Ten patients had a family history of psoriasis, and two had psoriatic arthritis. A total of 19 cases were linear at onset, with concomitant classical psoriasis; these were termed "superimposed" LP. The remaining 11 cases were not associated with classical psoriasis and were termed "isolated" LP. In four of the superimposed cases, LP developed when the patient was receiving systemic treatment: methotrexate (n = 2), etanercept (n = 1) or infliximab (n = 1). Topical steroids were effective in 76% of cases in which they were used, and systemic treatment was effective in < 66%. Treatments were less effective in LP than in classical psoriasis. DISCUSSION: We identified a wide range of LP, with two profiles: isolated LP and superimposed LP. Topical treatment usually evoked clinical response, with relative resistance to systemic therapy. Methotrexate and anti-tumor necrosis factor (TNF)-α therapies can possibly unmask LP.

The ABC of Hidradenitis Suppurativa: A Validated Glossary on how to Name Lesions.

BACKGROUND: The precise clinical description of skin lesions observed in some patients with hidradenitis suppurativa (HS) can be extremely difficult. OBJECTIVE: Establishing a validated glossary of terms allowing the best possible description of lesions observed in HS patients. MATERIAL AND METHODS: Five international experts of HS were to assess a series of 25 photos representing typical lesions of this disorder. For each photo, the experts were asked whether naming of the lesions was possible or not and, if yes, by using which noun. Agreement of their responses was calculated using Fleiss's kappa index. Using a Delphi strategy, photos with disagreement were discussed, and photos were reevaluated on the next day. In case of agreement on the impossibility of naming some clinical situations, new terms, to be included into the glossary, were agreed upon. RESULTS: After the first round of photos, agreement between the experts was poor with a kappa index of only 0.33 (95% CI 0.22-0.46). After extensive discussion of cases with disagreement, the kappa index increased on day 2 to 0.75 (95% CI 0.60-0.87), allowing to conclude on good interobserver agreement on terminology. Furthermore, a few clinical situations were identified in which naming with established semantics is so far not possible. For these situations, the terms 'multicord', 'multipore', 'multitunnel' and 'retraction' were defined. DISCUSSION: This is the first validation of clinical terms used to describe lesions in patients with HS. This should be helpful in better defining the clinical phenotypes observed in this disorder.