TNF-alpha blockade in Primary Chronic Non-Bacterial Osteomyelitis of the Mandible.

OBJECTIVES: Primary chronic Non-Bacterial Osteomyelitis of the jaw is a rare auto-inflammatory disease of unknown aetiology that bears pathophysiological resemblance to both the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome in adults and chronic recurrent multifocal osteomyelitis (CRMO) in children. Both SAPHO and CRMO respond to TNF-alpha blockade. Previously reported treatment regimens in CNOM including non-steroidal anti-inflammatory drugs, corticosteroids, antibiotics, anti-resorptive therapy, and surgery all bear disappointing results. TNF- α blockade is suggested as a treatment option by some experts but this is not backed by any clinical data.We sought to retrospectively and exhaustively report our experience of anti-TNF alpha therapy in refractory CNOM. METHODS: Fifteen patients with refractory CNOM and high disease burden were referred to our centre. TNF- α blockade was attempted in 10 cases, given its efficacy in neighbouring diseases, its good tolerance profile and failure of previous treatment strategiesWe herein retrospectively report detailed outcomes for all patients having received anti-TNF alpha therapy for this indication in our centre. RESULTS: TNF-α-targeting therapy resulted in a rapid and sustained remission in a majority of patients with CNOM, without serious adverse events. Treatment was tapered and stopped without relapse in some patients despite a refractory course of several years. Male sex seems to be associated with a poorer outcome. CONCLUSION: Our results suggest that blocking TNF-α is efficient and safe in CNOM.

Risk of flare in patients with SLE in remission after hydroxychloroquine or chloroquine withdrawal.

OBJECTIVE: Previous studies have provided evidence that the discontinuation of hydroxychloroquine (HCQ), and chloroquine (CQ), in patients with systemic lupus erythematosus (SLE) is associated with an increased risk of disease flares, with limited information on the level of disease activity at the time of HCQ/CQ discontinuation. Here we aimed to describe the risk of SLE flare after withdrawal of HCQ or CQ in patients with SLE in remission. METHODS: Case-control study (1:2) comparing the evolution of patients with SLE after HCQ/CQ withdrawal for antimalarial retinopathy (cases) with patients with SLE matched for sex, antimalarial treatment duration and age at SLE diagnosis, whose antimalarial treatment was continued throughout the entire follow-up period (controls). To be included in the study, patients had to be in remission for at least one year according to the DORIS classification. The primary endpoint was the proportion of patient experiencing a flare according to the SELENA-SLEDAI Flare Index after a 36-month follow-up. RESULTS: We studied 48 cases and 96 controls. The proportion of patients experiencing a flare was significantly higher in the HCQ/CQ withdrawal group as compared to the maintenance group (15 [31.3%] patients versus 12 [12.5%]; OR 3.1 [95%CI 1.2-8.2], P=0.01). Withdrawal of HCQ/CQ was inferior with respect to occurrence of severe SLE flare (12 [25.0%] vs 11 [11.5%]; OR 2.5 [95%CI 0.9-6.9], P=0.053) and time to first flare (HR 6.3 [2.0-19.9], P<0.005). Elevated serum levels of anti-dsDNA antibodies were identified as a risk factor for SLE flare following HCQ/CQ discontinuation (HR 5.4 [1.5-18.7], P<0.01). CONCLUSION: Withdrawal of HCQ or CQ in patients with SLE in remission is associated with a 3-fold increased risk of relapse.

Identification of new risk factors for hydroxychloroquine and chloroquine retinopathy in systemic lupus erythematosus patients.

BACKGROUND: Long-term hydroxychloroquine (HCQ) or chloroquine (CQ) intake causes retinal toxicity in 0.3-8 % of patients with rheumatic diseases. Numerous risk factors have been described, eg, daily dose by weight, treatment duration, chronic kidney disease, concurrent tamoxifen therapy and pre-existing retinal or macular disease. However, those factors cannot explain the entire risk of developing antimalarial retinopathy. OBJECTIVE: This study was undertaken to identify new risk factors associated with HCQ or CQ retinopathy (QRNP) in systemic lupus erythematosus (SLE) patients. METHODS: This case-control (1:2) study compared SLE patients with QRNP (cases) to those without (controls). Controls were matched for sex and known QRNP risk factors: HCQ and/or CQ treatment duration (±1 year) and age (±5 year) at SLE diagnosis. RESULTS: Forty-eight cases were compared to 96 SLE controls. Multivariable logistic-regression analysis retained the following as independent determinants significantly associated with QRNP: concomitant selective serotonin-reuptake inhibitor (SSRI) or serotonin- and norepinephrine-reuptake inhibitor (SNRI) intake (OR [95 % confidence interval] 6.6 [1.2 to 40.9]; p < 0.01); antiphospholipid syndrome (OR=8.9 [2.2 to 41.4] p < 0.01); blood hydroxychloroquine/desethylchloroquine concentration ([HCQ]/[DCQ]) ratio <7.2 (OR 8.4 [2.7 to 30.8]; p < 0.01) or skin phototype ≥4 (OR 5.5 [1.4 to 26.5]; p = 0.02), but not daily HCQ dose, blood [HCQ] or body mass index. CONCLUSION: The results of this case-control study identified blood [HCQ]/[DCQ] ratio, concurrent SSRI/SNRI therapy, skin phototype ≥4 and antiphospholipid syndrome as new risk factors for QRNP.

Phenotypes in antiphospholipid syndrome: A hierarchical cluster analysis based on two independent databases.

BACKGROUND: Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by thromboses at various sites and obstetric events associated with the persistent presence of antiphospholipid antibodies. The identification of clinical phenotypes in APS patients is a clinical need. In this study, we aimed to determine the clinical phenotypes of APS patients through an unsupervised analysis of two well-characterized cohorts of APS patients. PATIENTS AND METHODS: APS phenotypes were defined by an ascending hierarchical cluster analysis to identify preferential associations between 18 types of organ involvement and clinical characteristics. This analysis was performed on an initial multi-center cohort of 1000 patients, with validation in a replication cohort of 435 patients. RESULTS: The hierarchical analysis identified three APS phenotypes in both the initial and replication cohorts: an obstetric phenotype (n = 259 and n = 74 patients, respectively), a venous thrombosis phenotype, accounting for the largest number of patients (n = 461 and n = 297 patients, respectively), and a skin-central nervous system-heart phenotype (n = 280 and n = 64 patients, respectively). The clinical characteristics of the patients differed significantly between the three phenotypes, but there was no difference in antiphospholipid antibody profile between the groups. CONCLUSIONS: We identified three phenotypes of APS defined based on preferential associations of organ involvements and differences in presentation. These observations may help clinicians to detect organ involvement and to manage treatment.

Prognostic value of hypermetabolic bone sarcoidosis observed by 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: Sarcoidosis is a multisystemic granulomatosis diagnosed mainly in young adults.18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) is useful in sarcoidosis cases to search for a biopsiable site or assess disease activity.18F-FDG PET-CT can reveal bone hypermetabolism in sarcoidosis patients, even in the absence of osteoarticular symptoms. The aim of this study was to describe metabolic bone involvement in sarcoidosis patients and to evaluate its prognostic impact. METHODS: This was an observational, comparative, retrospective, monocentric study. Inclusion criteria were a confirmed diagnosis of sarcoidosis according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria and at least one 18F-FDG PET-CT scan during follow-up. Metabolic bone involvement of sarcoidosis was defined as focal bone hypermetabolism with no argument for a differential diagnosis of bone 18F-FDG uptake. Patients with and without bone involvement were compared. RESULTS: Among the 175 included patients, 32 (18%) had metabolic bone involvement of sarcoidosis. The metabolic bone involvement was mainly axial and mostly without bone abnormalities on CT. Metabolic bone involvement was associated with intrathoracic and extrathoracic lymph node involvement and with a higher number of organs involved. Patients with metabolic bone involvement more frequently received corticosteroids, methotrexate and tumor necrosis factor (TNF)-α inhibitors and a higher number of treatments. Relapse of sarcoidosis occurred sooner in patients with metabolic bone involvement. CONCLUSION: These results suggest that metabolic bone involvement is associated with more diffuse and more severe sarcoidosis.

Identification of natural killer markers associated with fatal outcome in COVID-19 patients.

Introduction: Increasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients. Methods: We enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells. Results: Here, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production. Discussion: These data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells.

Lower disease activity but higher risk of severe COVID-19 and herpes zoster in patients with systemic lupus erythematosus with pre-existing autoantibodies neutralising IFN-α.

OBJECTIVES: Type-I interferons (IFNs-I) have potent antiviral effects. IFNs-I are also overproduced in patients with systemic lupus erythematosus (SLE). Autoantibodies (AAbs) neutralising IFN-α, IFN-ß and/or IFN-ω subtypes are strong determinants of hypoxemic COVID-19 pneumonia, but their impact on inflammation remains unknown. METHODS: We retrospectively analysed a monocentric longitudinal cohort of 609 patients with SLE. Serum AAbs against IFN-α were quantified by ELISA and functionally assessed by abolishment of Madin-Darby bovine kidney cell protection by IFN-α2 against vesicular stomatitis virus challenge. Serum-neutralising activity against IFN-α2, IFN-ß and IFN-ω was also determined with a reporter luciferase activity assay. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns. RESULTS: Neutralising and non-neutralising anti-IFN-α antibodies are present at a frequency of 3.3% and 8.4%, respectively, in individuals with SLE. AAbs neutralising IFN-α, unlike non-neutralising AAbs, are associated with reduced IFN-α serum levels and a reduced likelihood to develop active disease. However, they predispose patients to an increased risk of herpes zoster and severe COVID-19 pneumonia. Severe COVID-19 pneumonia in patients with SLE is mostly associated with combined neutralisation of different IFNs-I. Finally, anti-IFN-α AAbs do not interfere with COVID-19 vaccine humoral immunogenicity. CONCLUSION: The production of non-neutralising and neutralising anti-IFN-I antibodies in SLE is likely to be a consequence of SLE-associated high IFN-I serum levels, with a beneficial effect on disease activity, yet a greater viral risk. This finding reinforces the recommendations for vaccination against SARS-CoV-2 in SLE.