[IL-17A and IL-17F: from discovery to target of biologics - an illustrative example of translational research]. / IL-17A et IL-17F : de la découverte au ciblage thérapeutique - Un exemple de médecine translationnelle.

Interleukin (IL)-17A and then IL-17F have been discovered through their roles in chronic inflammatory diseases. These cytokines share 50% of sequence homology and bind to the same receptor made of the IL-17RA et IL-17RC chains. While they have rather similar pro-inflammatory effects, slight differences exist depending on the cell type considered or whether there is TNF or not. Indeed, there is a synergistic effect of TNF and IL-17A or IL-17F on many cell types. In addition, the interactions between immune and stromal cells also modulate their effects which vary according to stromal cell subtype. The identification of IL-17A and IL-17F roles in inflammatory diseases, as psoriasis, has led to the development of inhibitors of those cytokines. Anti-IL-17A, then anti-IL-17A/F and now anti-IL-17RA have been approved for different diseases and are particularly efficient in psoriasis. Their use is expending to other diseases like psoriatic arthritis and spondyloarthritis. Last, the recent understanding of the importance of stromal cells during chronic inflammation explains the relative inefficacy of such inhibitors in some other diseases.

Title: IL-17A et IL-17F : de la découverte au ciblage thérapeutique - Un exemple de médecine translationnelle. Abstract: L'interleukine (IL)-17A puis l'IL-17F ont été découvertes tour à tour pour leur rôle joué dans les maladies inflammatoires chroniques. Elles ont une homologie de séquence d'environ 50 % et partagent le même récepteur formé des chaînes IL-17RA et IL-17RC. Si elles ont des effets pro-inflammatoires assez similaires, il existe néanmoins quelques différences selon le type cellulaire considéré et selon la présence ou non de TNF, autre cytokine avec laquelle elles ont une synergie d'action. La troisième variable venant moduler leurs effets réside dans les interactions entre cellules immunes et cellules stromales, qui, là encore, varient selon le type de cellules stromales. La mise en évidence de leur rôle dans le psoriasis a notamment conduit au développement d'inhibiteurs de l'IL-17A, puis à la fois de l'IL-17A et de l'IL-17F et enfin d'un de leurs récepteurs. Ces inhibiteurs sont utilisés avec succès dans cette pathologie, et leur indication a été étendue progressivement au rhumatisme psoriasique et à certaines formes de spondylarthrite. Enfin, la récente compréhension de l'importance des cellules stromales dans la réaction inflammatoire chronique permet d'expliquer l'efficacité variable de ces biothérapies dans certaines pathologies.

Structural cell heterogeneity underlies the differential contribution of IL-17A, IL-17F and IL-23 to joint versus skin chronic inflammation.

The current therapeutic strategy used in immune-mediated inflammatory diseases (IMIDs) primarily targets immune cells or associated-pathways. However, recent evidence suggests that the microenvironment modulates immune cell development and responses. During inflammation, structural cells acquire a pathogenetic phenotype and the interactions with immune cells are often greatly modified. Understanding the importance of these tissue-specific interactions may allow to explain why some biologics are effective in some IMIDs but not in others. The differential effects of interleukin (IL)-17 A, IL-17F and IL-23 in joint versus skin inflammation depends on structural cell heterogeneity. In addition, the sometimes opposite effects of immune/structural cell interactions on the production of these cytokines illustrate the importance of these cells in chronic inflammation, using the examples of rheumatoid arthritis, psoriasis and spondyloarthritis. This review describes these concepts, shows their interests through clinical observations, and finally discusses strategies to optimize therapeutic strategies.

Neutralizing and enhancing monoclonal antibodies in SARS-CoV-2 convalescent patients: lessons from early variant infection and impact on shaping emerging variants.

Serological studies of COVID-19 convalescent patients have identified polyclonal lineage-specific and cross-reactive antibodies (Abs), with varying effector functions against virus variants. Individual specificities of anti-SARS-CoV-2 Abs and their impact on infectivity by other variants have been little investigated to date. Here, we dissected at a monoclonal level neutralizing and enhancing Abs elicited by early variants and how they affect infectivity of emerging variants. B cells from 13 convalescent patients originally infected by D614G or Alpha variants were immortalized to isolate 445 naturally-produced anti-SARS-CoV-2 Abs. Monoclonal antibodies (mAbs) were tested for their abilities to impact the cytopathic effect of D614G, Delta, and Omicron (BA.1) variants. Ninety-eight exhibited robust neutralization against at least one of the three variant types, while 309 showed minimal or no impact on infectivity. Thirty-eight mAbs enhanced infectivity of SARS-CoV-2. Infection with D614G/Alpha variants generated variant-specific (65 neutralizing Abs, 35 enhancing Abs) and cross-reactive (18 neutralizing Abs, 3 enhancing Abs) mAbs. Interestingly, among the neutralizing mAbs with cross-reactivity restricted to two of the three variants tested, none demonstrated specific neutralization of the Delta and Omicron variants. In contrast, cross-reactive mAbs enhancing infectivity (n = 3) were found exclusively specific to Delta and Omicron variants. Notably, two mAbs that amplified in vitro the cytopathic effect of the Delta variant also exhibited neutralization against Omicron. These findings shed light on functional diversity of cross-reactive Abs generated during SARS-CoV-2 infection and illustrate how the balance between neutralizing and enhancing Abs facilitate variant emergence.

Differential effects of interleukin-17A and 17F on cell interactions between immune cells and stromal cells from synovium or skin.

We compared the contribution of IL-17A and IL-17F in co-culture systems mimicking cell interactions as found in inflamed synovium and skin. Synoviocytes or skin fibroblasts were co-cultured with activated PBMC, with IL-17A, IL-17 A/F, IL-17F, IL-23, anti-IL-17A, anti-IL-17A/F or anti-IL-17F antibodies. IL-17A, IL-17F, IL-6 and IL-10 production was measured at 48 h. mRNA expression of receptor subunits for IL-23, IL-12 and IL-17 was assessed at 24 h. Both cell activation and interactions were needed for a high IL-17A secretion while IL-17F was stimulated by PHA activation alone and further increased in co-cultures. IL-17F levels were higher than IL-17A in both co-cultures (p < 0.05). IL-17F addition decreased IL-17A secretion (p < 0.05) but IL-17A addition had no effect on IL-17F secretion. Interestingly, IL-17A and IL-17F upregulated IL-17RA and IL-17RC mRNA expression in PBMC/skin fibroblast co-cultures (p < 0.05) while only IL-17F exerted this effect in synoviocytes (p < 0.05). Monocyte exclusion in both co-cultures increased IL-17A and IL-17F (twofold, p < 0.05) while decreasing IL-10 and IL-6 secretion (twofold, p < 0.05). IL-17A and F had differential effects on their receptor expression with a higher sensitivity for skin fibroblasts highlighting the differential contribution of IL-17A and F in joint vs. skin diseases.

Cryofibrinogen-Characteristics and Association with Cryoglobulin: A Retrospective Study Out of a Series of 1,712 Samples over 7 Years.

OBJECTIVE: Cryofibrinogens (CFs) and cryoglobulins (CGs) are cryoproteins responsible for obstructive vasculopathy and vasculitis. The aim of this study was to compare the characteristics of CF and CG, and to define the conditions of their association. METHODS AND RESULTS: This retrospective study was conducted at the Lyon University Hospitals, and included patients with at least one sample tested for CF and/or CG between September 2013 and April 2021. Serum and plasma samples were analyzed in very strict conditions of temperature. After cold precipitation, CF and CG were characterized and quantified in the cryoprecipitates. CRP and plasma fibrinogen levels were also investigated. Over this 7-year period, 1,712 samples for CF detection and 25,650 samples for CG detection were sent to the laboratory. Simultaneous testing of CF and CG was performed in 1,453/1,712 samples (85%). CF was less often positive than CG (8.3 vs. 13.5%, p < 0.0001). In positive CF samples, CG was associated in 28.9% of cases. In CF, fibrinogen was associated with fibronectin in 98/142 (69%) samples, especially in highly concentrated CF. CF concentration was independent of C-reactive protein and plasma fibrinogen concentrations. CONCLUSION: The simultaneous detection of CF and CG is essential for the diagnosis of vasculitis or thromboembolic events and their treatment.

Heterogeneous effects of S100 proteins during cell interactions between immune cells and stromal cells from synovium or skin.

Cell interactions represent an important mechanism involved in the pathogenesis of chronic inflammation. The key S100 proteins A8 and A9 have been studied in several models of chronic inflammatory diseases with highly heterogeneous conclusions. In this context, the aim of this study was to determine the role of cell interactions on S100 protein production and their effect on cytokine production during cell interactions, between immune and stromal cells from synovium or skin. Peripheral blood mononuclear cells (PBMC) were cultured alone or with synoviocytes or skin fibroblasts, with or without phytohemagglutinin, exogenous A8, A9, A8/A9 proteins or anti-A8/A9 antibody. Production of IL-6, IL-1ß, IL-17, TNF, A8, A9, and A8/A9 was measured by ELISA. Cell interactions with synoviocytes had no effect on A8, A9, or A8/A9 secretion, while cell interactions with skin fibroblasts decreased A8 production. This highlights the importance of stromal cell origin. The addition of S100 proteins in co-cultures with synoviocytes did not increase the production of IL-6, IL-17, or IL-1ß, except for an increase of IL-6 secretion with A8. The presence of anti-S100A8/A9 antibody did not show obvious effects. Low concentration or absence of serum in the culture medium decreased the production of IL-17, IL-6, and IL-1ß but despite these conditions, the addition of S100 proteins did not increase cytokine secretion. In conclusion, the role of A8/A9 in cell interactions during chronic inflammation appears complex and heterogeneous, depending on multiple factors, notably the origin of stromal cells that can affect their secretion.

Effects of pro-inflammatory cytokines and cell interactions on cell area and cytoskeleton of rheumatoid arthritis synoviocytes and immune cells.

Rheumatoid synovitis is infiltrated by immune cells that interact with synoviocytes, leading to the pannus formation. Inflammation or cell interaction effects are mainly evaluated with cytokine production, cell proliferation or migration. Few studies interest on cell morphology. Here, the purpose was to deepen some morphological changes of synoviocytes or immune cells under inflammatory conditions. Inflammatory cytokines, IL-17 and TNF that are largely involved in RA pathogenesis, induced a change in synoviocyte morphology, inducing a retracted cell with higher number of pseudopodia. Several morphological parameters decreased in inflammatory conditions: cell confluence, area and motility speed. The same impact on cell morphology was observed in co-culture of synoviocytes and immune cells in inflammatory/non-inflammatory conditions or with cell activation (miming the in vivo situation), affecting both cell types: synoviocytes were retracted and inversely immune cells proliferated, indicating that cell activation induced a morphological change of cells. In contrast, with RA but not control synoviocytes, cell interactions were not sufficient to affect PBMC and synoviocyte morphology. The morphological effect came only from the inflammatory environment. These findings reveal that the inflammatory environment or cell interactions induced massive changes in control synoviocytes, with cell retraction and increase of pseudopodia number, leading to better interactions with other cells. Except in the case of RA, the inflammatory environment was absolutely required for such changes.

Evaluation of the Performance of an Indirect Immunofluorescence Assay for the Detection of Anti-MDA5 Antibodies.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare systemic autoimmune disease; further, its prognosis can be rapidly fatal due to pulmonary involvement. The identification and quantification of anti-MDA5 Abs, which serve as a highly specific biomarker of the disease, is a critical step for the establishing of both the diagnosis and monitoring of the disease's activity. The development of a simple, fast, low-cost, and specific detection system of anti-MDA5 Ab is therefore highly desirable for the purposes of routine laboratory diagnosis. Here, we developed a human cell line that stably expresses MDA5 and evaluated its analytical performance in order to detect anti-MDA5 Abs by the utilization of indirect immunofluorescence (IIF). Serum samples from 23 anti-MDA5 DM patients and 22 anti-MDA5 Abs negative myositis readings, which were obtained at time of diagnosis, were analyzed by IIF on MDA5-transfected cells. The results were compared with those obtained with specific semi-quantitative (immunodot) and quantitative (ELISA) assays. A specific cytoplasmic pattern was found solely with the sera of anti-MDA5 DM patients. The sensitivity and specificity of IIF on MDA5-transfected cells were 96% and 100%, respectively, compared with ELISA. The anti-MDA5 Abs titers that were determined by this approach were consistent with the quantitative results obtained by ELISA. Baseline concentrations of anti-MDA5 Abs, either by ELISA or IIF, were not significantly different between surviving and deceased patients; further, they did not differ significantly according to clinical phenotypes. Overall, an IIF cell-based assay constitutes a simple, fast, and low-cost approach to identify and quantify anti-MDA5 Abs; moreover, it is as efficient as ELISA.

Morphological and Mechanical Characterization of Extracellular Vesicles and Parent Human Synoviocytes under Physiological and Inflammatory Conditions.

The morphology of fibroblast-like synoviocytes (FLS) issued from the synovial fluid (SF) of patients suffering from osteoarthritis (OA), rheumatoid arthritis (RA), or from healthy subjects (H), as well as the ultrastructure and mechanical properties of the FLS-secreted extracellular vesicles (EV), were analyzed by confocal microscopy, transmission electron microscopy, atomic force microscopy, and tribological tests. EV released under healthy conditions were constituted of several lipid bilayers surrounding a viscous inner core. This "gel-in" vesicular structure ensured high mechanical resistance of single vesicles and good tribological properties of the lubricant. RA, and to a lesser extent OA, synovial vesicles had altered morphology, corresponding to a "gel-out" situation with vesicles surrounded by a viscous gel, poor mechanical resistance, and poor lubricating qualities. When subjected to inflammatory conditions, healthy cells developed phenotypes similar to that of RA samples, which reinforces the importance of inflammatory processes in the loss of lubricating properties of SF.

Synovial Extracellular Vesicles: Structure and Role in Synovial Fluid Tribological Performances.

The quality of the lubricant between cartilaginous joint surfaces impacts the joint's mechanistic properties. In this study, we define the biochemical, ultrastructural, and tribological signatures of synovial fluids (SF) from patients with degenerative (osteoarthritis-OA) or inflammatory (rheumatoid arthritis-RA) joint pathologies in comparison with SF from healthy subjects. Phospholipid (PL) concentration in SF increased in pathological contexts, but the proportion PL relative to the overall lipids decreased. Subtle changes in PL chain composition were attributed to the inflammatory state. Transmission electron microscopy showed the occurrence of large multilamellar synovial extracellular vesicles (EV) filled with glycoprotein gel in healthy subjects. Synovial extracellular vesicle structure was altered in SF from OA and RA patients. RA samples systematically showed lower viscosity than healthy samples under a hydrodynamic lubricating regimen whereas OA samples showed higher viscosity. In turn, under a boundary regimen, cartilage surfaces in both pathological situations showed high wear and friction coefficients. Thus, we found a difference in the biochemical, tribological, and ultrastructural properties of synovial fluid in healthy people and patients with osteoarthritis and arthritis of the joints, and that large, multilamellar vesicles are essential for good boundary lubrication by ensuring a ball-bearing effect and limiting the destruction of lipid layers at the cartilage surface.

Synoviocytes and skin fibroblasts show opposite effects on IL-23 production and IL-23 receptor expression during cell interactions with immune cells.

BACKGROUND: The IL-23/IL-17 axis is involved in inflammatory diseases including arthritis and psoriasis. However, the response to IL-23 or IL-17 inhibitors is different depending on the disease. The aim was to compare the effects of interactions between immune and stromal cells on the IL-23 axis to understand these differences. METHODS: Peripheral blood mononuclear cells were co-cultured with RA synoviocytes or Pso skin fibroblasts, with or without phytohemagglutinin, IL-23, or anti-IL-23 antibody. Production of IL-6, IL-1ß, IL-23, IL-17, IL-12, and IFNγ was measured by ELISA. IL-23 and cytokine receptor gene expression (IL-17RA, IL-17RC, IL-12Rß1, IL-12Rß2, and IL-23R) was analyzed by RT-qPCR. IL-12Rß1 and IL-23R subunits were analyzed by flow cytometry. RESULTS: The production of IL-6, IL-1ß, IL-17, IL-12, and IFNγ with synoviocytes or skin fibroblasts was rather similar, and cell interactions with immune cells increased their production, specifically that of IL-17. A major difference was observed for IL-23. Interactions with synoviocytes but not with skin fibroblasts decreased IL-23 secretion while mRNA level was increased, mainly with synoviocytes, reflecting a major consumption difference. IL-23 addition had only one effect, the increase of IL-17 secretion. Cell activation induced similar effects on cytokine receptor gene expression in co-cultures with synoviocytes or skin fibroblasts. The key difference was the cell interaction effects depending on the stromal cell origin. Interactions with synoviocytes increased the expression of both IL-23 receptor subunits at mRNA levels and IL-23R at the surface expression level while interactions with skin fibroblasts decreased their expression at the mRNA level and had no effect at the surface expression level. CONCLUSION: Interactions between immune and stromal cells are crucial in cytokine production and their receptor expression. The origin of stromal cells had a major influence on the production of IL-23 and its receptor expression. Such differences may explain part of the heterogeneity in treatment response.

Monoclonal antibodies from B cells of patients with anti-MDA5 antibody-positive dermatomyositis directly stimulate interferon gamma production.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) positive dermatomyositis (anti-MDA5 DM) is a rare entity associated with poor prognosis and multiple immunologic abnormalities. These include the presence of autoAbs and deleterious interferon (IFN)-gamma production in the severe form of the disease. Here, we show that the autoAbs profile differs between patients, depending on disease severity, and that autoAbs from B cells of patients directly stimulate IFN-gamma production by peripheral blood cells. Serum of 29 anti-MDA5 DM patients were analyzed by indirect immunofluorescence (IIF) on Hep-2 cells, to identify patterns associated with poor outcome. Seventeen (59%) serum gave a specific cytoplasmic MDA5 pattern on Hep-2 cells, while 12 (41%) gave an unspecific pattern. Specific MDA5 pattern was associated with a higher risk to develop interstitial lung disease (p = 0.003). Monoclonal autoAbs were generated from B cell clones of two patients with extreme clinical presentation, one who developed a lethal form of the disease, and the other with a favorable outcome. Supernatants of the autoreactive B cell clones that gave an IIF cytoplasmic pattern were tested for their abilities to stimulate IFN-gamma production by peripheral blood cells. Out of 120,000 B cell clones analyzed, 12 produced monoclonal Abs that triggered direct IFN-gamma secretion by peripheral blood cells, by a monocyte-dependent mechanism. None of them was directed against the MDA5 antigen. Altogether, these findings demonstrated that autoAbs other than the highly specific anti-MDA5 Ab are direct contributors of the IFN-gamma upregulation that is linked to the severity of the disease.

The role of B cells and their interactions with stromal cells in the context of inflammatory autoimmune diseases.

Interactions between B cells and stromal cells have essential functions in immune cell development and responses. During chronic inflammation, the pro-inflammatory microenvironment leads to changes in stromal cells, which acquire a pathogenic phenotype specific to each organ and disease. B cells are recruited to the site of inflammation and interact with these pathogenic stromal cells contributing to the disease's severity. In addition to producing autoantibodies, B cells contribute to the pathogenesis of autoimmune inflammatory diseases by serving as professional antigen-presenting cells, producing cytokines, and through additional mechanisms. This review describes the role of B cells and their interactions with stromal cells in chronic inflammation, with a focus on human disease, using three selected autoimmune inflammatory diseases: rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. Understanding B cells roles and their interaction with stromal cells will help develop new therapeutic options for the treatment of autoimmune diseases.

The Th17 Pathway in Vascular Inflammation: Culprit or Consort?

The involvement of IL-17A in autoimmune and inflammatory diseases has prompted the development of therapeutic strategies to block the Th17 pathway. Promising results came from their use in psoriasis and in ankylosing spondylitis. IL-17A acts on various cell types and has both local and systemic effects. Considering the premature mortality observed during chronic inflammatory diseases, IL-17A action on vascular cells was studied. Both in vitro and in vivo results suggest that this cytokine favors inflammation, coagulation and thrombosis and promotes the occurrence of cardiovascular events. These observations led to study the role of IL-17A in diseases characterized by vascular inflammation, namely allograft rejection and vasculitis. Increased circulating levels of IL-17A and histological staining reveal that the Th17 pathway is involved in the pathogenesis of these diseases. Vasculitis treatment faces challenges while the use of steroids has many side effects. Regarding results obtained in giant cell arteritis with IL-6 inhibitors, a cytokine involved in Th17 differentiation, the use of anti-IL-17 is a promising strategy. However, lessons from rheumatoid arthritis and multiple sclerosis must be learnt before targeting IL-17 in vasculitis, which may be culprit, consort or both of them.

Synoviocytes from pigmented villonodular synovitis are less sensitive to cadmium-induced cell death than synoviocytes from rheumatoid arthritis.

Pigmented villonodular synovitis (PVNS) is a rare inflammatory articular disease sharing common characteristics with rheumatoid arthritis (RA), notably hyperplasia of the synovium due to a hyperproliferation of synoviocytes, and with cancer owing to mutations of the CSF1/M-CCSF gene. Targeting synovium hyperplasia by the local delivery of Cadmium (Cd) has been already tested in vitro and in vivo models of RA and could be applied to PVNS. PVNS and RA synoviocytes were exposed to low doses of Cd. After different culture time points, a qualitative analysis was done by microscopy and quantitative measurements of apoptosis, cell viability and IL-6 production were carried. IL-6 production by PVNS synovial tissue was also quantified after Cd treatment with or without the presence of pro-inflammatory cytokines (IL-17 + TNF). Addition of Cd induced cell death in both PVNS (1 ppm) and RA (0.1 ppm) synoviocytes, which increased with time and Cd concentrations. Cd increased the percentage of apoptotic cells and decreased cell viability and IL-6 production. In all these experiments, PVNS synoviocytes were tenfold less sensitive to Cd than RA synoviocytes. Cd decreased IL-6 production by PVNS synovial tissue and its effect was enhanced with pro-inflammatory cytokines. In summary, PVNS synoviocytes show resistance to Cd-induced cell death and decreased inflammation. Intra-articular use of Cd could represent a potential therapeutic tool in PVNS.

Update on Tenosynovial Giant Cell Tumor, an Inflammatory Arthritis With Neoplastic Features.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction and bone erosion. Even if many treatments were developed with success in the last decades, some patients fail to respond, and disease chronicity is still a burden. Mechanisms involved in such resistance may include molecular changes in stromal cells. Other explanations can come from observations of tenosynovial giant cell tumor (TGCT), first considered as an inflammatory arthritis, but with unusual neoplastic features. TGCT leads to synovium hypertrophy and hyperplasia with hemosiderin deposition. It affects young adults, resulting in secondary osteoarthritis and increased morbidity. TGCT shows clinical, histological and genetic similarities with RA but affecting a single joint. However, the monoclonality of some synoviocytes, the presence of translocations and rare metastases also suggest a neoplastic disease, with some features common with sarcoma. TGCT is more probably in an intermediate situation between an inflammatory and a neoplastic process, with a main involvement of the proinflammatory cytokine CSF-1/CSF1R signaling axis. The key treatment option is surgery. New treatments, derived from the RA and sarcoma fields, are emerging. The tyrosine kinase inhibitor pexidartinib was recently FDA-approved as the first drug for severe TGCT where surgery is not an option. Options directly targeting the excessive proliferation of synoviocytes are at a preclinical stage.

Practical Details for the Detection and Interpretation of Cryoglobulins.

BACKGROUND: Cryoglobulins are immunoglobulins that precipitate at low temperature. Strict preanalytical and analytical conditions are critical for the detection of cryoglobulins. CONTENT: This review will focus on practical recommendations for detection and characterization of cryoglobulins and the technical problems that may be encountered. A laboratory report format is proposed for presentation of these results that includes the parameters necessary for an optimal interpretation by clinicians. The first step of detection of cryoglobulins can be performed in any laboratory that has a 37 °C incubator and temperature-controlled centrifuge. The second step is the characterization of cryoglobulins, and this often must be performed in more specialized laboratories. Characterization includes immunoglobulin typing, for the classification of cryoglobulins and potential underlying disease(s); quantification of immunoglobulins and rheumatoid factor in the cryoprecipitate to define the pathogenicity; and quantification of serum complement, which is useful for diagnosis. SUMMARY: These practical recommendations will be useful for the accurate detection of cryoglobulins, an essential step for the diagnosis of cryoglobulinemic vasculitis, a rare but severe clinical manifestation of cryoglobulins.

Gastroenterological safety of IL-17 inhibitors: a systematic literature review.

INTRODUCTION: Interleukin 17 is a proinflammatory cytokine considered to play a significant role in the immunopathogenesis of many chronic immune-mediated disorders. Interleukin 17 inhibitors provide an excellent treatment option for patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. However, Interleukin 17 inhibitors have been suspected of worsening or triggering new-onset inflammatory bowel disease. AREAS COVERED: A literature search was conducted until March 2021 to investigate reporting prevalence, and characteristics of all gastroenterological adverse events in patients treated with Interleukin 17 inhibitors. One hundred and six clinical randomized trials were included, involving 40,053 patients. Inflammatory bowel disease cases were reported in 0.4% of patients exposed to Interleukin 17 inhibitors. The most frequent other gastrointestinal adverse events were diarrhea (2.5%), nausea or vomiting (0.7%), and gastroenteritis (0.2%). Sixty-one uncontrolled or retrospective studies were included, involving 16,791 patients. Sixty (0.36%) inflammatory bowel disease cases were reported, 0.6% of patients reported other gastrointestinal adverse events. EXPERT OPINION: Interleukin 17 inhibitors are safe and effective in the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Low incidence rate of developing new-onset inflammatory bowel disease or exacerbating preexisting inflammatory bowel disease with anti-IL-17 agents has been reported. Clinicians should be aware of the possibility of these concerns when considering this therapy.

Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at 1 Year in Active Rheumatoid Arthritis.

Objectives: This study aims to investigate if addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA). Methods: Active RA patients with a knee needle synovial biopsy at baseline and finished 1-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31, and CD90 were scored semiquantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to 1 year. Results: Among 150 recruited RA patients, 123 (82%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells, and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and paucicellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, p = 0.011), together with the lowest rate of Boolean remission at 3, 6, and 12 months. Baseline synovial myeloid-stromal pathotype independently predicted radiographic progression at 1 year (adjusted OR: 3.199, 95% confidence interval (95% CI): 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA. Conclusions: This novel fibroblast-based myeloid-stromal pathotype could predict radiographic progression at 1 year in active RA patients which may contribute to the shift of therapeutic decision in RA.