The abnormal signaling of the B cell receptor and co-receptors of lupus B cells.

It is easily understood that studying the physiology and pathophysiology of the BCRtriggered cascade is of importance, particularly in such diseases as systemic lupus erythematosus (SLE) that are considered by many as a "B cell disease". Even though B cells are not considered as the only players in lupus pathogenesis, and other immune and non-immune cells are certainly involved, it is the success of recent B cell-targeting treatment strategies that ascribe a critical role to the lupus B cell.

Treating Autoimmune-Related Interstitial Lung Disease With B Cell Depletion.

Autoimmune rheumatic diseases may affect vital organs with lung involvement being severe and difficult to treat manifestation. Systemic sclerosis (SSc) commonly affects the lung in the form of interstitial lung disease (ILD). ILD may be also seen in patients with rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), inflammatory myositis (IM), antisynthetase syndrome (AS), and the ANCA-associated vasculitides (AAV). Rituximab (RTX) is an anti-CD20 B lymphocyte depleting mAb, often administered in the treatment of autoimmune rheumatic diseases. Although RTX is an off-label treatment for CTD-ILD, there are numerous reports providing data that is effective in improving both pulmonary function tests (PFTs) and chest computed tomography findings consistent with ILD. There are retrospective uncontrolled studies that assess RTX as a treatment of ILD in autoimmune diseases. These studies, apart from one, do not include patients with AAV-ILD. In SSc-ILD, in particular, there are both controlled and uncontrolled studies displaying encouraging results following B cell depletion. In addition, a number of retrospective uncontrolled studies and fewer prospective studies evaluate RTX in connective tissue diseases CTD-ILD. Although RTX is an approved treatment for AAV there are scarce only data focusing on patients with AAV-ILD specifically. The results of a handful of studies comparing treatment of CTD-ILD with RTX to treatment with other agents are in favor of RTX. Results from large, still ongoing controlled trials are awaited to ascertain RTX effects in ILD encountered in autoimmune rheumatic diseases. We review herein the results of the different RTX trials in patients with autoimmune disease-associated with ILD. Despite the heterogeneity of these studies, RTX may be considered an alternative and safe but still off-label treatment for patients with refractory CTD-ILD.

The Role of B Cells in Scleroderma Lung Disease Pathogenesis.

Systemic sclerosis (SSc) is a chronic, autoimmune, multisystem disease characterized by tissue fibrosis that, apart from the skin, may affect the lungs among other organs. B cells have been found in tissue lymphocytic infiltrates; in the lungs are encountered in lymphoid aggregates. The abnormal and hyperreactive B cell in SSc may initiate and perpetuate the fibrotic process via incompletely understood mechanisms. Studies in animal models of SSc have demonstrated that B cell dysregulation is an early event in disease pathogenesis. Functional disturbances of BCR signaling such as decreased inhibitory CD22 signal transduction or augmented CD19-mediated signaling result in prolonged B cell activation. Antagonism of BAFF, a cytokine known for his central role in B cell survival and maturation, not only suppresses the production of fibrogenic cytokines such as IL-6 and IL-10, but also amplifies antifibrogenic cytokine secretion such as IFN-γ and it finally contributes to skin fibrosis attenuation. B cells subsets in SSc patients display several abnormalities. Naïve B cells are increased, in contrast to switched memory B cells that are not only decreased but also activated. Disturbances in the expression of molecules that are involved in B cell tuning have also been described. Interestingly, a distinct B cell population characterized by anergy and exhaustion has been found to be increased in patients with SSc-ILD. Another B cell subset, the CD30+GM-Beff, is capable to differentiate monocytes to dendritic cells and is increased in SSc patients with ILD. Of note, patients with SSc-ILD exhibit increased expression of the inhibitory receptor FcγRIIB on naïve and double negative B cells aiming perhaps to counterbalance the abnormal B cell activation. Studies of B cell targeted treatments have demonstrated promising clinical efficacy. Therefore, B cell eliminating therapies could be integrated into the therapeutic armamentarium of patients suffering from SSc-ILD aiming to at least stabilize the fibrotic lung process.

B Cell Depletion Treatment in Resistant Systemic Sclerosis Interstitial Lung Disease.

Systemic sclerosis is a systemic, autoimmune disease that in many patients affects not only the skin, but also internal organs, mainly the lung. It is clear that internal organ (ie, lung) involvement determines the prognosis. Therefore, there is an unmet need to introduce novel and more effective treatments capable of halting disease progression and hence improve prognosis. Experimental data over the past decade has accumulated pointing to the B cell as a player in disease pathogenesis. Consequently, a number of controlled and uncontrolled studies have investigated the results of B cell depletion treatment in patients with SSc. The results are preliminary still encouraging for skin as well as for pulmonary involvement. In this review we will analyse and discuss such trials that have currently added B cell depletion as an alternative and promising treatment for resistant interstitial lung disease in scleroderma.

Man-in-a-barrel syndrome: a rare presentation of giant cell arteritis.

We present herein the case of a patient with brachial plexopathy, the first manifestation of giant cell arteritis (GCA). A 71-year-old woman presented with a subacute-onset weakness of her upper extremities; the patient had an initially good clinical response to steroid treatment. However, a few weeks after steroid discontinuation, she manifested fever and fatigue and increased serum markers consistent with a systemic inflammatory response. A PET-CT scan revealed an increased uptake in the subclavian arteries and a temporal biopsy was typical for GCA. Oral administration of high dosage steroids improved the patient's clinical symptoms and normalised her inflammatory serum markers.

B cell depletion treatment decreases Th17 cells in patients with rheumatoid arthritis.

INTRODUCTION: We aimed to evaluate for any possible effects of treatment with rituximab (RTX) on the peripheral Th17 and Treg subpopulations in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: We analyzed 16 patients with RA initiating RTX treatment, 11 patients with RA initiating abatacept treatment, 11 patients with RA treated with other medications, 8 patients with other autoimmune rheumatic diseases initiating RTX, and 14 healthy volunteers. Th17 cells (CD4+IL23R+IL17A+) and Treg cells (CD4+CD25hiFoxP3+) were evaluated flow-cytometrically. RESULTS: Th17 cells from patients treated with RTX decreased significantly at weeks 8 and 16 (mean ± SEΜ: 3.01% ± 0.54℅ CD4+ cells at week 0 vs. 1.53% ± 0.24℅ at week 8 vs 1.10% ± 0.20℅ at week 16, p = 0.0004). Reductions of Th17 cells were evident in clinical responders (DAS28 score ≤ 3.2), ACPA (+) and RF (-) patients; circulating Tregs remained stable. Th17 and Tregs were not affected by ABA treatment or by changes in disease activity. Tregs, but not Th17 cells, decreased following treatment with RTX in patients with other autoimmune diseases (0.75% ± 0.16% at week 0 vs. 0.43% ± 0.16% at week 8, p = 0.033). CONCLUSION: RTX-induced B cell depletion results in a significant reduction of circulating Th17 cell percentages, whereas it has no effect on Tregs of patients with RA. This reduction of Th17 cells was evident particularly in responders to RTX treatment, ACPA+ and RF (-) patients with RA.

Immune Checkpoint Inhibitor-Associated Scleroderma-Like Syndrome: A Report of a Pembrolizumab-Induced "Eosinophilic Fasciitis-Like" Case and a Review of the Literature.

Immune checkpoint inhibitors are a promising new therapeutic strategy in oncology that aims to eliminate cancer cells by enhancing patients' immune response against tumor antigens. Despite their beneficial effects, immune checkpoint inhibitors are also responsible for a plethora of autoimmune manifestations, known as immune-related adverse events. We present a case of eosinophilic fasciitis-like disorder in an 81-year-old patient treated with the programmed death cell protein 1 inhibitor pembrolizumab for non-small-cell lung cancer. The patient developed characteristic indurated skin lesions in his limbs after 1½ years of treatment with pembrolizumab and a typical "groove sign." Raynaud's syndrome was absent. A full-thickness biopsy confirmed the clinical diagnosis of an "EF-like" condition. Neither peripheral eosinophilia nor eosinophilic infiltrates in the skin biopsy were found. His symptoms improved after a 2.5-month CPI discontinuation and treatment with 16 mg of methylprednisolone slowly tapered to a dose of 4 mg. Eosinophilic fasciitis is a rare immune-related adverse event of CPI treatment; our literature search identified only 12 cases that fulfill the criteria of EF in patients receiving CPIs.

Treatment modalities and drug survival in a systemic sclerosis real-life patient cohort.

BACKGROUND: European data indicate that systemic sclerosis (SSc)-related death rates are increasing, thus raising concerns about SSc's optimal management. Herein, we describe current treatment modalities and drug survival in a real-life SSc cohort. METHODS: Details on immunosuppressive/antiproliferative (methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, tocilizumab) and vasoactive agent [(endothelin receptor antagonists (ERAs), sildenafil, iloprost, and calcium channel blockers (CCB)] administration during the disease course (11.8 ± 8.4 years, mean + SD) of 497 consecutive patients examined between 2016 and 2018 were retrospectively recorded. Drug survival was assessed by Kaplan-Meier analysis. RESULTS: Methotrexate was the most frequently administered immunosuppressive/antiproliferative agent (53% of patients), followed by cyclophosphamide (26%), mycophenolate (12%), and azathioprine (11%). Regarding vasoactive agents, CCB had been ever administered in 68%, ERAs in 38%, iloprost in 7%, and sildenafil in 7% of patients; 23% of patients with pulmonary fibrosis had never received immunosuppressive/antiproliferative agents, 33% of those with digital ulcers had never received ERAs, iloprost, or sildenafil, whereas 19% of all patients had never received either immunosuppressive/antiproliferative or other than CCB vasoactive agents. Survival rates of methotrexate, cyclophosphamide, and mycophenolate differed significantly, being 84/75%, 59/43%, and 74/63% at 12/24 months, respectively, with inefficacy being the most frequent discontinuation cause. Conversely, CCB, ERAs, and sildenafil had high and comparable retention rates of 97/91%, 88/86%, and 80/80%, respectively. CONCLUSIONS: Existing therapeutic limitations indicate that more evidence-based treatment is warranted for successful management of SSc. Vasculopathy seems to be managed more rigorously, but the low retention rates of immunosuppressive/antiproliferative drugs suggest that effective and targeted disease-modifying agents are warranted.

B cell depletion treatment decreases CD4+IL4+ and CD4+CD40L+ T cells in patients with systemic sclerosis.

Recent data suggests that rituximab may favorably affect skin fibrosis and lung function in patients with systemic sclerosis. Based on experimental data suggesting a key role of B and T cells in scleroderma we aimed to explore the effect(s) of rituximab treatment on T cell subpopulations. Fifteen patients with scleroderma who received rituximab treatment and six who received standard treatment alone were recruited. Peripheral CD4+IL4+, CD4+INFγ+, CD4+IL17+ and CD4+CD40L+ T cells were assessed using flow cytometry. Using ELISA, serum levels of IL4 were assessed. Skin CD4+IL4+ T cells were assessed with confocal microscopy from skin biopsies. Following rituximab treatment skin CD4+IL4+ T cells obviously decreased as seen with confocal microscopy. Moreover, peripheral CD4+IL4+ T cells decreased significantly compared to those from patients who received standard treatment alone: median (IQR): 14.9 (22.63-12.88) vs 7.87 (12.81-4.9)%, p = 0.005 and 9.43 (19.53-7.50)% vs 14.86 (21.96-6.75)%, p = NS at baseline and 6 months later respectively, whereas there was no difference in serum IL4 levels. Peripheral CD4+CD40L+ T cells also decreased significantly following rituximab treatment compared to those from patients who received standard treatment alone: median (IQR): 17.78 (25.64-14.44)% vs 8.15 (22.85-3.08)%, p = 0.04 and 22.13 (58.77-8.20)% vs 72.11 (73.05-20.45)%, p = NS at baseline and 6 months later respectively. Furthermore, peripheral CD4+INFγ+ and CD4+IL17+ T cells revealed no differences following rituximab treatment. Our study demonstrates a link between rituximab treatment and CD4+IL4+ T cell decrease both in the skin and peripheral blood of patients with SSc.

From Basic Immunology to Clinical Practice: Bio-Originators versus Bio-Similars.

Biologic agents are macromolecules, and as such, they have a high level of structural heterogeneity. Treatment with such agents has been extremely expensive limiting thus their availability to increasing numbers of patients; therefore, many manufacturers chose to develop biologics that are highly similar to the originators, the biosimilars. The immunological properties of both products should therefore be characterized and compared. The biosimilar developers must have a complete qualitative documentation, appropriate preclinical pharmacodynamic and pharmacokinetic studies, and finally comparative studies with the originator to define the relative similarity in terms of biologic activity, quality characteristics, efficacy and safety. Immunogenicity assessment of the biosimilars continues through clinical trials and pharmacovigilance programs.

A 40-Year-Old Woman with Asymmetric Arthritis and Skin Lesions.

A 40-year old woman with recent asymmetric arthritis and fever was evaluated in our clinic. NSAIDs were recommended, but a few days later she was admitted to our hospital because of worsening arthritis along with the appearance of new skin lesions in both feet. Although she was treated with antibiotics and high dosages of steroids, her arthritis did not improve. The skin lesions progressed from bullous initially to ulcerative pyoderma gangrenosum, so we suggested endoscopic examination of the colon which revealed Crohn's disease. The patient received I.V. treatment with infliximab resulting in a remarkable response. Some patients with Crohn's disease may present with extraintestinal manifestations well before the bowel disease is manifested and diagnosed.

Th1/17 cells, a subset of Th17 cells, are expanded in patients with active systemic lupus erythematosus.

Skewed cytokine production characterizes T cells in Systemic Lupus Erythematosus (SLE). Among Th17 cells that are expanded in lupus, a subset (Th1/17) retains the ability to produce IFNγ. We aimed to analyze Th17 and Th1/17 cells in patients with SLE. Patients with active disease displayed increased percentages of circulating Τh17 and Th1/17 cells. Stimulated T cells from patients with lupus secreted significantly more IL-17 compared to healthy donors. Also, T cells from patients with active SLE released significantly lower levels of IFN-γ compared to controls. However, following stimulation, levels of IFN-γ also rose significantly. Our data suggest that lupus Th1/17 cells are not only expanded but also functional. In summary, in this study it was shown that patients with active SLE display increased Th17 and functional Th1/17 cells. This impaired T-cell axis might represent a possible future therapeutic target.

B Cell-Based Treatments in SLE: Past Experience and Current Directions.

PURPOSE OF REVIEW: B cells have been targeted recently by novel therapeutic approaches in patients with SLE. In this review, we discuss recent data that have emerged on this issue placing special emphasis in studies published during the last 5 years. RECENT FINDINGS: Despite the negative results stemming from double-blind placebo-controlled studies, B cell depletion with rituximab is indeed employed worldwide, particularly in standard treatment refractory lupus, with promising results. In addition, positive experience with the approved agent belimumab is steadily increasing. Both regimens have an acceptable safety profile. Identification of B cells as a therapeutic target in SLE has been so far rewarding, since one such treatment, belimumab, has been the only regulatory authority-approved medication in SLE for over half a century. Focusing specifically on autoreactive instead of non-specifically altering/depleting lupus, B cells may lead to more rational treatment modes.

New onset of lupus nephritis in two patients with SLE shortly after initiation of treatment with belimumab.

PURPOSE: Belimumab is currently approved for the treatment of patients with active SLE despite standard treatment. However, it has not been formally tested for patients with lupus nephritis because such patients had been excluded from the clinical trials. In this report, we present two patients with SLE who developed lupus nephritis de novo shortly after belimumab treatment initiation; both patients improved rapidly upon belimumab discontinuation. RESULTS: The first patient (a 30-year-old female, with a 15-year disease duration, receiving prednisolone, hydroxychloroquine, and azathioprine, with no previous history of nephritis that was repeatedly anti-dsDNA negative) had exacerbation of a facial butterfly-like rash developed after 3 months of belimumab treatment initiation. Concomitantly, her urinalysis became abnormal for the first time during her long follow-up (15-20 red blood cells per hpf, and a 24-h urine protein of 1600mg), and a renal biopsy documented the diagnosis of a Class III (WHO classification). Her anti-dsDNA titers became highly positive for the first time. Belimumab was discontinued and her proteinuria and abnormal urinalysis reverted to normal rapidly, and before MMF administration was approved by local regulatory authorities. Our second patient (a 38-year-old female with a 19-year disease duration) was being treated with prednisone and azathioprine. Two months following belimumab treatment initiation, she became edematous and had an active urine sediment (50-60 rbc per hpf, dysmorphic, and a 24-h urine protein levelabove 6000mg) for the first time during her disease course. Her renal biopsy was compatible with a Class V membranous nephritis. Belimumab was discontinued and MMF (2g/d) was substituted for azathioprine with her urinary protein declining to 2.7g/d just 10 days afterwards. CONCLUSIONS: In this report, apart from our two patients, we discuss the relevant literature consisting of a handful of studies and case reports. The studies analyze patients with renal involvement treated with belimumab and are inconclusive. There are only a few case reports in which belimumab along with other agents had a potential benefit, although not straightforward. There is only one case report with striking similarities to the two patients with SLE we report herein. It could be claimed that belimumab was unable to prevent the appearance of lupus nephritis during a potentially serious disease exacerbation. Certainly, a causative association between belimumab treatment and the de novo appearance of lupus nephritis cannot be claimed because of our report. However, a potential association between belimumab treatment and the development of such a serious manifestation cannot be entirely excluded. In support of the latter hypothesis is the quick resolution/significant reduction of proteinuria shortly after belimumab discontinuation and before other treatment measures had any reasonable effect. Studies evaluating the potential usefulness of belimumab in patients with lupus nephritis are currently ongoing; until then, one should keep in mind unanswered questions as far as renal safety is concerned.

Molecular abnormalities of the B cell in systemic lupus erythematosus are candidates for functional inhibition treatments.

INTRODUCTION: The B cell is a key player in the pathogenesis of systemic lupus erythematosus (SLE). Loss of B cell tolerance resulting in autoantibody production and immune complex formation and deposition are central features of the disease. B cell overactivity is a hallmark of SLE and molecular abnormalities in B cell signaling cascade have been described. AREAS COVERED: In this review, we will focus on the aberrant phenotype of B cell signaling in patients with lupus. We will also discuss data stemming from the use of small molecules that have recently been recognized to target important steps of the B cell signal transduction pathways with therapeutic implications for SLE. EXPERT OPINION: Attempts to target the B cell in SLE have been made through depletion, blocking of survival factors and co-receptor inhibition. However, the still unmet need for effective therapy of refractory disease makes the necessity for new drugs impelling.

Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity.

PTPN22 is a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems. Polymorphisms in PTPN22 are associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and type 1 diabetes. This review discusses the role of PTPN22 in T and B cells, and its function in innate immune cells, such as monocytes, dendritic cells and NK cells. We focus particularly on the complexity that underlies the function of PTPN22 in the biological processes of the immune system; such complexity has led various research groups to produce rather conflicting data.

B cells tell scleroderma fibroblasts to produce collagen.

In fibrosis fibroblasts are activated and overproduce collagen in a process with unknown drivers and equally unknown brakes that recently implicated a novel and surprising player, the B cell. B cells may be crucially involved in fibrosis in several ways: B cells may produce autoantibodies that can directly stimulate fibroblasts; B cells can produce profibrotic cytokines such as IL-6 or transforming growth factor beta; and, finally, B cells could directly stimulate fibroblasts by a contact-dependent mechanism. Recent experimental evidence suggests that B cells can enhance collagen production by fibroblasts, by a contact-dependent mechanism, and therefore are profibrotic ex vivo. These data strengthen the rationale of pursuing B-cell targeting therapies in systemic sclerosis.

B-cell depletion therapy in patients with diffuse systemic sclerosis associates with a significant decrease in PDGFR expression and activation in spindle-like cells in the skin.

INTRODUCTION: Recently, several studies assessing the clinical efficacy of rituximab (RTX) in systemic sclerosis (SSc) have reported encouraging results. We aimed at exploring whether RTX exerts its beneficial effects on fibrosis through attenuation of platelet-derived growth factor receptor (PDGFR) pathway activation. METHODS: We immunohistochemically assessed skin biopsies obtained from eight patients with SSc prior to and 6 months following RTX treatment, three control SSc patients (at the same time points) and three healthy subjects. We assessed the expression of platelet-derived growth factor, PDGFR and phosphorylated (activated) PDGFR. RESULTS: We found a strong correlation of PDGFRα and PDGFRß expression on spindle-like cells and collagen deposition in SSc biopsies (r = 0.97 and r = 0.96 for PDGFRα and PDGFRß, respectively; P < 0.0001 for both), indicating a strong link between PDGFR expression and fibrosis. Expression of PDGFRα and PDGFRß in the papillary dermis significantly decreased following RTX administration (mean ± standard error of the mean at baseline vs. 6 months, respectively: PDGFRα, 42.05 ± 5.03 vs. 26.85 ± 3.00, P = 0.004; and PDGFRß, 37.14 ± 4.94 vs. 24.01 ± 3.27, P = 0.012). Similarly, expression of phosphorylated PDGFRα and PDGFRß in the papillary dermis significantly decreased following RTX administration (P = 0.006 and P = 0.013 for phospho-PDGFRα and phospho-PDGFRß, respectively). No changes in platelet-derived growth factor tissue expression or serum levels were found following RTX treatment. CONCLUSION: RTX may favorably affect skin fibrosis through attenuation of PDGFR expression and activation, a finding that supports a disease-modifying role of RTX in SSc. Large-scale, multicenter studies are needed to further explore the efficacy of RTX in SSc.