François Chasset

Targeting interferons and their pathways in Systemic Lupus Erythematosus

Significant advances in the understanding of the molecular basis of innate immunity have led to the identification of interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of Systemic Lupus Erythematosus. Therefore, targeting of IFNs and of their downstream pathways has emerged as important developments for novel drug research in SLE. Based on this, several specific interferon blocking strategies using anti-IFN-α antibodies, anti-type I interferon receptor antibodies, Interferon-α-kinoid, or anti-IFN-γ antibodies have all been assessed in recent clinical trials. Alternative strategies targeting the plasmacytoid dendritic cells (pDCs), Toll-Like Receptors (TLRs)-7/9 or their downstream pathways such as the myeloid differentiation primary-response protein 88 (MYD88), spleen tyrosine kinase (Syk), Janus-kinases (JAKs), interleukin-1 receptor-associated kinase 4 (IRAK4), or the Tyrosine Kinase 2 (TYK2) are also investigated actively in SLE, at more preliminary clinical development stages, except for JAK inhibitors which have reached phase 2 studies. In a near future, in-depth and personalized functional characterization of IFN pathways may provide further guidance for the selection of the most relevant therapeutic strategy in SLE, tailored at the patient-level.

Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids

AbstractIpilimumab is an anti-CTLA-4 antibody which has recently been approved in Europe as a monotherapy in the treatment of metastatic melanoma.We report a single-center study among patients treated within a Temporary Authorization for Use (TAU) protocol.We also performed a review of the literature involving expanded access program studies with a focus on factors associated with overall survival (OS).Patients and methodsThis retrospective, observational study included patients between June 2010 and July 2011 with a diagnosis of non-resectable stage III or IV melanoma with at least one previous line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose of 3mg/kg every three weeks.Results45 patients were included, among whom23 (51%) had brain metastases. 33 (71%) of the patients completed the induction phase. The best overall response rate (BORR) was 13% and median overall survival (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with brain metastases at baseline and those without (p = 0.10), regardless of BRAF V600E status (p = 0.61). OS was poorer in patients who were being treated with corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008).ConclusionA subset of patients most likely to benefit from ipilimumab should be defined. In our series we found a negative association of baseline corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain metastases should not be barriers to the initiation of treatment.

Contact dermatitis due to ultrasound gel: A case report and published work review.

Adverse skin reactions with ultrasound gel are rare and related mostly to allergic contact dermatitis or contact urticaria. We report an allergic contact dermatitis with Doppler ultrasound gel applied in a 67‐year‐old man. The patient developed atypical purpuric cutaneous presentation located on vascular axes. Semi‐open test with ultrasound gel and patch test with phenoxyethanol were followed by the same clinical purpuric eruption which strongly suggested the accountability of this later component as allergen. Based on this observation, we present a review of published work with a focus on clinical features and allergens involved in ultrasound gel cutaneous reaction.

Cutaneous Manifestations of Medium- and Large-Vessel Vasculitis

Dermatologic manifestations are observed in almost all systemic vasculitides, even in large-and medium-vessel vasculitides, although such vessels are not found in the skin. Cutaneous manifestations may be related to a direct skin localization of the systemic vasculitis or a non-specific process associated with the vasculitis. According to the 2012 International Chapel Hill consensus, the two major variants of large-vessel vasculitides are Takayasu arteritis and giant-cell arteritis. In Europe and North America, acute inflammatory nodules or erythema nodosum-like lesions are the most commonly observed skin lesions with Takayasu arteritis. Medium-sized arteriole vasculitis of the dermis or subcutis but also septal or lobular panniculitis may be found during pathological examination. In Japan, widespread pyoderma gangrenosum-like lesions are more frequent. Cutaneous manifestations of giant-cell arteritis are rare; they are ischemic, linked to arterial occlusions, or non-ischemic, with various mechanisms. The two major medium-vessel vasculitides are Kawasaki disease and polyarteritis nodosa. Kawasaki disease is characterized by a mucocutaneous lymph node syndrome without skin vasculitis. Two subsets of polyarteritis nodosa with different skin manifestations are described, without transition from one to the other. In the systemic subset, the most frequent skin lesions are in the order of frequency purpura, livedo, and nodules. Cutaneous polyarteritis nodosa mainly features nodules, livedo racemosa, and ulcerations. Genetic screening and measurement of plasma levels of adenosine deaminase 2 should be considered for patients with uncommon systemic polyarteritis nodosa or early-onset cutaneous polyarteritis nodosa.

Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis

The antimalarials (AMs) hydroxychloroquine (HCQ) and chloroquine (CQ) have demonstrated variable cutaneous response rates in cutaneous lupus erythematosus (CLE).

Risk of thromboembolic events in patients treated with thalidomide for cutaneous lupus erythematosus: a multicenter-retrospective study

REFERENCES 1. Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol. 2000;84(8): 834-836. 2. Lowell FC, Carroll JM. A study of the occurrence of atopic traits in patients with keratoconus. J Allergy. 1970;46(1):32-39. 3. Copeman PW. Eczema and keratoconus. Br Med J. 1965; 2(5468):977-979. 4. Lee J, Lee JS, Park SH, et al. Cohort profile: the National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol. 2017;46(2):e15. 5. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327-349.

Efficacy and tolerance profile of thalidomide in cutaneous lupus erythematosus: A systematic review and meta-analysis

Background Thalidomide has shown excellent results for severe cutaneous lupus erythematosus (CLE), but its prescription is limited by potentially severe adverse events. Objective To assess the overall rate of response to thalidomide in CLE with respect to CLE subtypes and the occurrence rate of relevant adverse events on the basis of previously published studies. Methods We performed a systematic review and meta‐analysis of studies published in MEDLINE, Embase, and the Cochrane Library between 1965 and January 2017. The proportions of responders and rates of adverse events were extracted from individual studies and pooled using random effects or fixed models. Results Among 548 patients from 21 included studies, the overall rate of response to thalidomide was 90% (95% confidence interval [CI], 85‐94), with similar response rates between CLE subtypes. Conversely, the pooled rate of thalidomide withdrawal related to adverse events was 24% (95% CI, 14‐35) including confirmed peripheral neuropathy in 16% (95% CI, 9‐25) and thromboembolic events in 2% (95% CI, 1‐3). The pooled rate of relapse after thalidomide withdrawal was 71% (95% CI, 65‐77) compared with 34% (95% CI, 25‐44) with a maintenance dose. Limitations We found important statistical heterogeneity across included studies. Conclusion Considering the frequent occurrence of adverse events, prescription of thalidomide should be restricted to patients with severely refractory CLE or who are at high risk for severe scarring.

Autoimmune manifestations associated with lymphoma: characteristics and outcome in a multicenter retrospective cohort study

Abstract This French multicenter retrospective cohort study aimed to describe the autoimmune manifestations (AIMs) associated with lymphoma among patients hospitalized between 2005 and 2016 in three French University Hospitals. Among 2503 patients with lymphoma, 108 (4.3%) had AIMs, mostly autoimmune cytopenias (71.3%), neurological diseases (10.2%), kidney diseases (6.5%), systemic vasculitis (5.6%) and others. As compared with the 2395 lymphoma patients without AIMs, those with AIMs were older (p = .01), more frequently had B-cell chronic lymphocytic leukemia (p < .01) and less frequently diffuse large B-cell lymphomas (p = .01) and Hodgkin lymphoma (p = .01). The 5-year overall survival with lymphoma was 65% and 79% (p = .03) with and without AIMs. This large cohort study shows that various types of AIMs, mostly cytopenias, could be associated with lymphoma and affect the overall outcome with lymphoma, in particular for B-cell non-Hodgkin lymphoma (p = .01) and T-cell non-Hodgkin lymphoma (p = .01), with no survival difference noted for other types of lymphoma (p = .2).

Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: A multicenter observational study

Background: Changing from one antimalarial (AM) agent to another is often recommended in cutaneous lupus erythematosus (CLE) when the first AM agent is ineffective or poorly tolerated. Objective: To evaluate the effect on cutaneous response of a switch from hydroxychloroquine to chloroquine, or the reverse, after failure of the first AM agent. Methods: We conducted a retrospective observational study between 1997 and September 2015. The overall cutaneous response rate and reasons for failure of the switch were assessed for up to 48 months. Kaplan‐Meier survival curves were used to assess the risk for failure of the second AM agent. Results: A total of 64 patients with CLE (78% were women) were included; for 48 patients, the switch was for inefficacy, and for 16, it was for adverse events. Median follow‐up was 42 months (range, 3‐171). Of the patients changed because of inefficacy, 56% were responders at month 3; however, the response decreased over time, with a median duration before failure of the second AM agent of 9 months (95% confidence interval, 6‐24). For patients switched because of adverse events, the second AM agent was well tolerated in 69% of cases. Limitations: Retrospective design and subjective evaluation of cutaneous response. Conclusion: A change of AM agent should be considered in patients with CLE when the first AM agent is ineffective or poorly tolerated.

The 2018 pipeline of targeted therapies under clinical development for Systemic Lupus Erythematosus: a systematic review of trials

Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials. The search yielded a total of 1140 trials, from which we identified 74 targeted therapies for SLE. Those treatments target inflammatory cytokines, chemokines, or their receptors (n = 17), B cells or plasma cells (n = 17), intracellular signalling pathways (n = 10), T/B cells costimulation molecules (n = 8), interferons (n = 7), plasmacytoid dendritic cells (pDC) (n = 3), as well as various other targets (n = 12). Not all these candidate drugs will reach phase III, but the broad spectrum of drugs being investigated may satisfy the urgent need for improved lupus medications. The identification of biomarkers that would allow adequate prediction of response-to-therapy remains high, but when solved will allow a more rationale selection of the optimal pharmacological agent at the patient level.