Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Urticaria exacerbations and adverse reactions in patients with chronic urticaria receiving COVID-19 vaccination: Results of the UCARE COVAC-CU study.

BACKGROUND: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy. OBJECTIVE: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination. METHODS: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters. RESULTS: Across 2769 COVID-19-vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination-induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination-induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine-related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions. CONCLUSIONS: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated.

Safety profile of immune checkpoint inhibitors according to cancer type.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment in recent years, but have led to the emergence of new so-called immune-related adverse events (irAE). The objective of this study was to determine whether cancer type is a potential predictive factor of irAEs. METHODS: This retrospective study included patients who had started an ICI treatment between 2019 and 2020 at the Grenoble Alpes University Hospital. A logistic regression model and a Fine and Gray survival model with death as a competing risk were used to identify variables associated with grade≥2 irAEs and grade≥2 irAEs-free survival. RESULTS: Of the 512 patients included, 160 (31.2%) had a grade≥2 irAE. Grade≥2 irAEs were less frequent in head and neck cancer compared to other cancers. Ipilimumab (odds ratio [OR]: 6.05; 95% confidence interval [CI]: 2.81-13.7), treatment duration (OR: 1.01; 95% CI: 1.01-1.02), and history of autoimmune disease (OR: 6.04; 95% CI: 2.45-16.5) were independently associated with grade≥2 irAEs. With death as a competing risk, grade≥2 irAEs-free survival was independently improved with treatment duration (subdistribution hazard ratio [sdHR]: 0.93; 95% CI: 0.92-0.94), ipilimumab (sdHR: 0.24; 95% CI: 0.1-0.59) and history of autoimmune disease (sdHR: 0.23; 95% CI: 0.08-0.69) whereas it was poorer for patients with performance status≥2 (sdHR: 2.04; 95% CI: 1.5-2.76) and an older age (sdHR: 1.02; 95% CI: 1.00-1.03). CONCLUSION: Ipilimumab and history of autoimmune disease were both associated with the presence of grade≥2 irAEs and grade≥2 irAEs-free survival. The different cancer groups were not.

Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients.

OBJECTIVE: A new adult-onset autoinflammatory syndrome has been described, named VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic). We aimed to compare the clinical characteristics, the laboratory features and the outcomes between idiopathic-relapsing polychondritis (I-RP) and VEXAS-relapsing polychondritis (VEXAS-RP). METHODS: Patients from French retrospective multicentre cohort of RP were separated into two groups: a VEXAS-RP and an I-RP. RESULTS: Compared with patients with I-RP (n=40), patients with VEXAS-RP (n=55) were men (96% vs 30%, p<0.001) and were older at diagnosis (66 vs 44 years, p<0.001). They had a greater prevalence of fever (60% vs 10%, p<0.001), of skin lesions (82% vs 20%, p<0.001), of ocular involvement (57% vs 28%, p=0.01), of pulmonary infiltrates (46% vs 0%, p<0.001), of heart involvement (11% vs 0%, p=0.0336) and with higher median C-reactive protein levels (64 mg/L vs 10 mg/L, p<0.001). Seventy-five per cent of the patients with VEXAS-RP had myelodysplastic syndrome (MDS) versus none in I-RP group. The glucocorticoids use, and the number of steroid sparing agents were similar in both groups, but patients with VEXAS-RP had more frequent refractory disease (remission obtained in 27% vs 90%, p<0001). VEXAS-RP was associated with higher risk of death: six patients (11%) died in the VEXAS-RP group after a median follow-up of 37 months and none in the I-RP group after a median follow-up of 92 months (p<0.05). CONCLUSION: We report the largest cohort of VEXAS-RP, characterised by high prevalence of male sex, fever, skin lesion, ocular involvement, pulmonary infiltration, heart involvement, older age and MDS association.

Effective Anti-SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders.

BACKGROUND: Mast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published. OBJECTIVE: To study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting. METHODS: Clinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti-SARS-CoV-2-specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies. RESULTS: Overall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2-specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2-specific, IFN-γ-producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden). CONCLUSIONS: Patients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.

Hereditary Angioedema with and Without C1-Inhibitor Deficiency in Postmenopausal Women.

PURPOSE: Most types of hereditary angioedema (HAE) are worsened by endogenous or exogenous estrogens. Conversely, androgens can improve HAE with abnormal C1-Inhibitor (C1-INH) by increasing C1-INH concentrations. Menopause is associated with an extinction of ovarian estrogenic and androgenic secretion. There is currently insufficient information on postmenopausal women with HAE. The objective of this study was to describe the activity of HAE in postmenopausal women. METHODS: This was a French retrospective, multicenter study in postmenopausal women with HAE with or without C1-INH deficiency/dysfunction. The patients were classified before and after menopause with a previously validated HAE disease severity score. RESULTS: We included 65 women from 13 centers in France. The mean age was 62.7± 9.2 years, and the mean time between menopause and inclusion was 12.5± 9.1 years. HAE was associated with C1-INH deficiencyin 88% (n = 57) of the patients, a mutation of factor 12 in 8% (n = 5), a mutation in plasminogen gene in one, and unknown HAE for two. The HAE course was not different after menopause in 46.1% (n = 30), improved in 38.5% (n = 25), and worsened in 15.4% (n = 10). Improvement was correlated with estrogen sensitivity of angioedema before menopause (p = 0.06 for improvement vs no effect or worsening). In addition, we observed that only ten women received treatment (transdermal or oral estradiol+ progestogen) for their menopause symptoms. Among them, only 3 experienced worsening of symptoms (2 on transdermal and 1 on oral estradiol). CONCLUSION: Following menopause, most women with HAE remain stable but some worsen. Improvement was mainly observed in patients with previous estrogen sensitivity. More research is required in menopausal women with HAE to better understand how to manage climacteric symptoms.

Exogenous hormones and hereditary angioedema.

Gonadal hormones, estrogen and androgen are strongly involved in the control of the bradykinin production. Estrogen may worsen whereas androgen can be part of the long-term prophylactic treatment. In this review, we will describe the potential impact of estrogen in the pathophysiology of hereditary angioedema (HAE). Then we will review the different hormone treatments and their implication on the course of HAE in women and men: contraception, Assisted Reproductive Technology (ART), menopause, hormone dependent cancers in women and men, treatment of hyperandrogenism in women.

Hypereosinophilia: Biological investigations and etiologies in a French metropolitan university hospital, and proposed approach for diagnostic evaluation.

OBJECTIVES: We aimed to evaluate the usefulness of biological investigations in cases of eosinophilia in our area (French Alps). METHODS: We retrospectively included all adult patients attending the infectious disease and internal medicine units between 2009 and 2015 with eosinophilia ≥1 G/l. RESULTS: We identified 298 cases (129 women and 169 men). In 139 patients, eosinophilia had not been addressed. In the 159 others, the cause of eosinophilia was identified in 118 (74.2%). The main identified causes at the time were drug reactions (24.5%, mostly ß-lactams and allopurinol), infectious diseases (17.0%), vasculitis (8.2%), autoimmune diseases (6.9%), and malignant diseases (6.2%). In patients with a skin rash, eosinophilia was significantly more often investigated, and a diagnosis significantly more often made. Helminthosis were mainly diagnosed in tropical travelers (18/24) excepting toxocariasis (3 non-travelers). Stool examination for helminthosis was positive in 5/76 patients (6.6%) (all tropical travelers); 391 helminth serologies were performed in 91 patients, with 7.9% being positive (all but 3 positive cases were travelers). Anti-neutrophil cytoplasmic antibodies (ANCA) were positive in 26/112 patients (23.2%), with 9 cases of vasculitis identified. CONCLUSIONS: Drug-related eosinophilia is the main etiology. Search for helminthosis is not recommended among non-travelers (excepting toxocariasis). ANCA should be performed early so as not to overlook vasculitis.

Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study.

OBJECTIVES: To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). METHODS: We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. RESULTS: This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs. CONCLUSIONS: This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.

Autoantibodies Targeting Ficolin-2 in Systemic Lupus Erythematosus Patients With Active Nephritis.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease characterized by the production of various autoantibodies. The aim of this study was to investigate the presence of anti-ficolin-2 antibodies in SLE patients and to evaluate the association between the levels of these autoantibodies, clinical manifestations, and disease activity. METHODS: This is a comparative study using a cohort of 165 SLE patients and 48 healthy subjects. SLE patients were further divided into 2 groups (low disease activity [SLE Disease Activity Index (SLEDAI) score ≤4, n = 88] and high disease activity [SLEDAI score >4, n = 77]). Clinical manifestations were defined according to the physician in charge. Active lupus nephritis (LN) was documented by kidney biopsy. Detection of anti-ficolin-2 antibodies was performed by enzyme-linked immunosorbent assay. RESULTS: Levels of anti-ficolin-2 autoantibodies were significantly higher in SLE patients as compared to healthy subjects and associated with SLEDAI score. They were found to be positive in 61 of 165 SLE patients (37%). The presence of anti-ficolin-2 antibodies was significantly related only to renal involvement, with a very high prevalence (86%) of anti-ficolin-2 antibodies in SLE patients with active LN. Patients with active proliferative LN had significantly more positive anti-ficolin-2 antibodies than those with nonproliferative LN. The combination of anti-ficolin-2, anti-ficolin-3, and anti-C1q demonstrated a very high specificity (98%) for the diagnosis of active LN. CONCLUSION: Our results support the usefulness of anti-ficolin-2 as a complementary serologic biomarker for the diagnosis of active lupus with renal manifestations.

Biologics in myelodysplastic syndrome-related systemic inflammatory and autoimmune diseases: French multicenter retrospective study of 29 patients.

BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified. METHODS: In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics. RESULTS: We included 29 patients (median age 67years [interquartile range 62-76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3-4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial) was shown in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection. CONCLUSION: This nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.

Efficacy and Tolerance of Anti-Tumor Necrosis Factor α Agents in Cutaneous Sarcoidosis: A French Study of 46 Cases.

Importance: Evidence for the long-term efficacy and safety of anti-tumor necrosis factor α agents (anti-TNF) in treating cutaneous sarcoidosis is lacking. Objective: To determine the efficacy and safety of anti-TNF in treating cutaneous sarcoidosis in a large observational study. Design, Setting, and Participants: STAT (Sarcoidosis Treated with Anti-TNF) is a French retrospective and prospective multicenter observational database that receives data from teaching hospitals and referral centers, as well as several pneumology, dermatology, and internal medicine departments. Included patients had histologically proven sarcoidosis and received anti-TNF between January 2004 and January 2016. We extracted data for patients with skin involvement at anti-TNF initiation. Main Outcomes and Measures: Response to treatment was evaluated for skin and visceral involvement using the ePOST (extra-pulmonary Physician Organ Severity Tool) severity score (from 0 [not affected] to 6 [very severe involvement]). Epidemiological and cutaneous features at baseline, efficacy, steroid-sparing, safety, and relapses were recorded. The overall cutaneous response rate (OCRR) was defined as complete (final cutaneous ePOST score of 0 or 1) or partial response (ePOST drop ≥2 points from baseline but >1 at last follow-up). Results: Among 140 patients in the STAT database, 46 had skin involvement. The most frequent lesions were lupus pernio (n = 21 [46%]) and nodules (n = 20 [43%]). The median cutaneous severity score was 5 and/or 6 at baseline. Twenty-one patients were treated for skin involvement and 25 patients for visceral involvement. Reasons for initiating anti-TNF were failure or adverse effects of previous therapy in 42 patients (93%). Most patients received infliximab (n = 40 [87%]), with systemic steroids in 28 cases (61%) and immunosuppressants in 32 cases (69.5%). The median (range) follow-up was 45 (3-103) months. Of the 46 patients with sarcoidosis and skin involvement who were treated with anti-TNF were included, median (range) age was 50 (14-78) years, and 33 patients (72%) were women. The OCRR was 24% after 3 months, 46% after 6 months, and 79% after 12 months. Steroid sparing was significant. Treatment was discontinued because of adverse events in 11 patients (24%), and 21 infectious events occurred in 14 patients (30%). Infections were more frequent in patients treated for visceral involvement than in those treated for skin involvement (n = 12 of 25 [48%] vs n = 2 of 21 [9.5%], respectively; P = .02). The relapse rate was 44% 18 months after discontinuation of treatment. Relapses during treatment occurred in 35% of cases, mostly during anti-TNF or concomitant treatment tapering. Conclusions and Relevance: Anti-TNF agents are effective but suspensive in cutaneous sarcoidosis. The risk of infectious events must be considered.