Protection from articular damage by passive or active anti-tumour necrosis factor (TNF)-α immunotherapy in human TNF-α transgenic mice depends on anti-TNF-α antibody levels.

Active anti-tumour necrosis factor (TNF)-α immunization with the kinoid of TNF-α (TNF-K) induces polyclonal anti-TNF-α antibodies and ameliorates arthritis in human TNF-α (hTNF-α) transgenic mice (TTg). We compared the efficacy of TNF-K to that of infliximab (IFX) and of TNF-K and IFX co-administration, and evaluated whether the titres of anti-hTNF-α antibodies induced by immunization were a determinant of TNF-K efficacy. Forty-eight TTg mice received one of the following treatments: TNF-K immunization (TNF-K group); weekly IFX throughout the study duration (IFXw0-15); TNF-K plus weekly IFX for 4 weeks (TNF-K + IFX); and weekly IFX for 4 weeks (IFXw0-4); PBS. Animals were killed at week 16. Anti-hTNF-α antibody titres and clinical and histological scores were compared. All TNF-K immunized mice (TNF-K and TNF-K + IFX) produced anti-hTNF-α antibodies. Titres were higher in TNF-K versus TNF-K + IFX (P < 0·001) and correlated inversely with histological inflammation (R = -0·78; P = 0·0001) and destruction (R = -0·67; P = 0·001). TNF-K + IFX had higher histological inflammation and destruction versus TNF-K (P < 0·05). A receiver operating characteristic (ROC) analysis of anti-hTNF-α antibody titres identified the criterion cut-off value to discriminate most effectively between the TNF-K and TNF-K + IFX groups. Mice with high versus low titres had less histological inflammation and destruction (P < 0·05). In a model of TNF-α-dependent arthritis, protection from articular damage by TNF-K correlates with the titres of induced anti-hTNF-α antibodies. The co-administration of TNF-K and a short course of infliximab does not result in less articular damage versus solely TNF-K, due probably to lower anti-hTNF-α antibody production. These results are relevant for future development of active anti-TNF-α immunization in human disease.

The impact of the Eurofever criteria and the new InFevers MEFV classification in real life: Results from a large international FMF cohort.

INTRODUCTION: New Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants. OBJECTIVES: To evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort. METHODS: Baseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients. RESULTS: Since November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC-). The majority of the EPCC- patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC- patients (69%, p < 0.0001), who were treated in a higher proportion with steroid or NSAID on demand (p = 0.003 and 0.008, respectively). Four percent of patients received Anti-IL-1 treatment. CONCLUSIONS: The combination of EPCC and the 2018 INSAID classification of MEFV variants is able to identify two distinct groups of patients, which differ in clinical characteristics, therapeutic approach and response to treatment. EPCC+ patients displayed the typical features of FMF, while EPCC- patients had a more variable phenotype with a lower percentage of response to colchicine.

[Diagnosis and classification of primary Sjögren syndrome. Comparison of 3 criteria sets in 219 cases]. / Diagnosi e classificazione della sindrome di Sjögren primitiva. Confronto fra tre gruppi di criteri in una casistica di 219 pazienti.

In spite of all recent years' international meetings, the question of diagnostic criteria of primary Sjögren's syndrome (pSS) is still under debate. The aim of our study is to define sensitivity, specificity and diagnostic accuracy of 3 sets of criteria: those of the European Community Study Group (ECSG), those proposed by Fox, and those proposed by Daniels. We considered 219 subjects complaining of dry mouth and/or dry eyes and/or parotid swelling, evaluated for pSS. The following parameters were considered golden standard for the diagnosis of pSS: focus score > or = 2 foci/mm2, double positivity for SSA and SSB antibodies, and a sialographic grade > or = 2. Our study demonstrates that ECSG criteria show a high sensitivity and a good specificity, resulting in a diagnostic accuracy similar, and sometimes higher, than that obtained with Fox and Daniels' criteria.

Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis.

OBJECTIVE: The rationale for blocking interleukin-6 (IL-6) in rheumatoid arthritis (RA) lies chiefly in the proinflammatory effect of this cytokine. Few studies have evaluated the consequences of anti-IL-6 receptor (IL-6R) antibody treatment on Treg cells. This study was undertaken to elucidate the mechanism of action of anti-IL-6R antibody treatment by studying the effects on Treg cells in an experimental arthritis model and in patients with RA. METHODS: Mice with collagen-induced arthritis (CIA) were treated with a mouse anti-IL-6R antibody (MR16-1), and changes in Treg, Th1, and Th17 cells were assessed at key time points during the course of the disease. Peripheral blood from 15 RA patients was collected on day 0 and after 3 months of tocilizumab treatment for flow cytometry analysis of Th17 and Treg cells. RESULTS: In MR16-1-treated mice, Th17 cell frequencies were unchanged, whereas Treg cell frequencies were increased. The Treg cell phenotype showed marked changes, with an increase in the frequency of CD39+ Treg cells in the lymph nodes and spleen. Interestingly, similar CD39+ Treg cell expansion was observed in RA patients who were tocilizumab responders at 3 months, with no change in Th17 cell frequency. Moreover, fluorescence-activated cell-sorted CD39+ Treg cells from responder RA patients were functionally able to suppress the proliferation of conventional T cells. CONCLUSION: In both CIA and RA, the frequency of functionally suppressive CD39+ Treg cells is increased as a result of anti-IL-6R treatment, whereas Th17 cells are unaffected. The modification of Treg cell frequency and phenotype may be one of the mechanisms involved in the therapeutic effect of IL-6 blockade in RA.

Screening for latent tuberculosis in anti-TNF-α candidate patients in a high tuberculosis incidence setting.

BACKGROUND: Screening for latent tuberculosis infection (LTBI) using a protocol comprising chest X-ray and tuberculin skin test (TST) interpreted with medical history, Sc1, reduces LTBI reactivation on treatment with anti-tumour necrosis factor-alpha (anti-TNF-α). In the district of Seine-Saint-Denis, France, where tuberculosis (TB) incidence ranges from 30 to >100/100 000 person-years, however, Sc1 might be insensitive as a screening tool. We adopted another protocol, Sc2, comprising Sc1 plus two additional tests: the QuantiFERON(®)-TB Gold In-Tube (QFT-GIT) and chest computed tomography (CT). METHODS: We screened 123 consecutive patients with inflammatory rheumatic diseases (IRDs), candidates for anti-TNF-α treatment, and evaluated the impact of Sc2 vs. Sc1 on the prescription of prophylactic anti-tuberculosis treatment. RESULTS: Sc2 led to a diagnosis of LTBI in 69 patients vs. 59 when using Sc1: eight were QFT-GIT-positive. Diagnosis was based on CT findings in two patients. QFT-GIT had higher diagnostic accuracy than TST, but no single diagnostic test could detect all patients at high risk for LTBI reactivation (respectively 30.2% and 37.5% of patients positive with only TST or QFT-GIT). CT detected TB sequelae in 3/46 rheumatoid arthritis patients who were negative to all tests. CONCLUSIONS: Testing with both TST and QFT-GIT seems the safest strategy for detecting LTBI in patients with IRD from populations with high incidence of TB. Systematic screening with CT warrants further evaluation.