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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.

Objectives To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. Methods A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. Results Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. Conclusions In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

ObjectiveΤo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs).MethodsPatients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients.ResultsBetween 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and ConclusionsVaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

Objective To assess: (i) the prevalence, and clinical and imaging characteristics of immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events (ir-AEs) in a prospective manner and (ii) whether serum levels of cytokines associated with the Th1/Th2/Th17 response are differentially expressed in patients with and without musculoskeletal Ir-AEs. Methods All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department, and an MRI of the involved area(s) was performed. Results During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEs. The median time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent ‘periarticular’ involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation. Conclusion In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium.

This review summarizes the current state of knowledge on experimental and clinical biomarkers of autoimmunity and aims to highlight important aspects of the immunologic evaluation of a patient with fibrotic lung disease.

Objective Regulatory B cells (Bregs) are a new subset of B cells with immunoregulatory functions, mainly through IL-10 production. Bregs suppress inflammatory Th1 and Th17 differentiation and induce Tregs suppressing autoimmune diseases. The aim of the study was to review the literature related to Bregs in autoimmune rheumatic diseases (ARDs). Methods A literature review of publications in PUBMED published in English was performed using the relevant combinations of terms. Results All relevant publications are discussed. Overall, recent studies in rheumatic diseases found Bregs to be decreased in ANCA-associated vasculitides (AAV) and in systemic sclerosis (SSc), particularly in SSc-associated lung fibrosis. In AAV Bregs levels are negatively correlated with autoantibody levels whereas in SSc this association is less clear but there is an inverse association with Th1 and Th17 cells. In rheumatoid arthritis (RA), Bregs were decreased, particularly in RA-associated lung fibrosis. In psoriatic arthritis IL-10 + Bregs are decreased and inversely associated with Th1 and Th17 cells. In systemic lupus erythematosus (SLE), the role of Bregs is unclear. In experimental diseases, when Bregs were expanded ex-vivo, they ameliorated established disease. Conclusion Bregs appear to be a new player in the pathogenesis of ARDs, and may offer a new strategy for therapeutic intervention.

Background The SAPHO syndrome is a relatively rare clinical entity characterized by a wide range of dermatological and musculoskeletal manifestations. Biologics have been used in cases refractory to conventional treatment. Methods We present herein a patient with refractory to treatment SAPHO syndrome who exhibited a dramatic and fast response to IL-17 blockade. Additionally, we performed a systematic review of all cases of patients with SAPHO syndrome treated with biologics to date. Results We identified 66 cases treated with biologics (45 with TNF blockers, 7 with IL-1 blockers, 13 with biologics targeting the IL-23/IL-17 axis, and 1 with tocilizumab). Data support a positive effect of anti-TNF treatment in SAPHO with a response rate in bone and joint manifestations of 93.3%. Skin disease also improved in 21/29 cases (72.4%). Data related to IL-1 inhibition in SAPHO are encouraging with most patients exhibiting a significant response in musculoskeletal manifestations (6/7, 85.7%). However, IL-1 inhibition is not effective in skin manifestations. Ustekinumab seems to have some efficacy with 2/4 patients responding in skin and 3/5 in bone/joint manifestations. Data related to IL-17 blockade indicate efficacy in skin disease with 4/7 patients responding (57.1%). Joint/bone manifestations improved in 3/8 patients (37.5%). Conclusions In SAPHO patients not responding to conventional treatment, TNF blockers appear to be the first choice. In patients failing TNF blockers, IL-1 inhibitors and biologics targeting the IL-17/IL-23 axis could be used.

Systemic sclerosis (SSc) is a complicated multisystem disease which is characterized by the highest standardized mortality ratio among all systemic rheumatic diseases with no approved therapies so far. From a pathogenetic point of view it is generally considered that autoimmunity, vasculopathy and fibrosis are the main pathophysiologic processes. In this opinion article/minireview we will discuss current and future options for SSc-related fibrotic manifestations (skin thickening and lung fibrosis). Based on the results of SLS II the best treatment option for skin involvement in SSc is mycophenolate mofetil (MMF). Methotrexate (MTX) is another option which is safe and of low cost but evidence supporting its use is weak. The standard of care for SSc-ILD nowadays is MMF. Patients not responding to MMF could be treated with rituximab (RTX) or cyclophosphamide (CYC) (tocilizumab [TCZ] could be an option as well but only for patients with increased inflammatory markers). Hematopoietic stem cell transplantation (HSCT) could be considered in patients with severe/life-threatening disease who have failed conventional treatment. The most promising therapeutic approach currently been evaluated in phase 3 trials is probably the combination of MMF plus pirfenidone.

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 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.

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.

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.

Background Low disease activity is a validated target of current systemic lupus erythematosus (SLE) therapy. The aim of this study was to assess the ability of belimumab to achieve low disease activity states in real-life settings. Methods Multicentre prospective observational study of consecutive SLE patients receiving belimumab for at least 3 months, due to active disease refractory to at least one conventional immunosuppressant. Disease activity, including the recently defined lupus low disease activity state (LLDAS) and remission (clinical SLEDAI-2K = 0), accrual of organ damage, flares and side effects were documented. Results Ninety-one patients were included [94.5% women, mean (SD) age 45.9 (12.5) years]. Most frequent manifestations were arthritis (76.7%), rash (72.5%), serologic activity (low C3/C4 and/or high anti-dsDNA; 54.9%), hair loss (47.2%) and mucosal ulcers (27.5%). Median (range) duration of treatment was 10.5 (3.0–42.1) months. Belimumab significantly decreased average SLEDAI-2K, physician global assessment (PGA) and daily prednisone dose over time, as early as 3 months after initiation, with over 20% of patients discontinuing corticosteroids. Although reduction in clinical (i.e., excluding serology) SLEDAI-2K was more pronounced in patients who were serologically active (from 8 to 1.5 at 12 months) as compared to serologically inactive (from 6 to 4) at baseline, attainment of LLDAS did not differ between the two groups and was reached by more than 40% of completer patients after 9–12 months. In addition, the number of flares and severe flares was reduced by 62% and 50%, respectively, during the first 12 months of treatment. Twenty patients (22.0%) discontinued treatment due to inadequate response and two due to side effects potentially related to the drug. Conclusions In real-life, belimumab is efficacious in achieving low disease activity in over 40% of unselected patients, in combination with reduction of corticosteroid dosage and number of flares. Both serologically active and inactive patients respond to the drug.

Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, autoimmunity, and widespread dermal and visceral fibrosis. This article summarizes the current knowledge about the potential contribution of platelets in the disease process and the rationale of targeting platelets as an adjunct treatment for SSc. Methods We performed an electronic search (Medline) using the keywords platelets, systemic sclerosis, autoimmunity, fibrosis, Raynaud, and pulmonary arterial hypertension. Results The link that connects vasculopathy, autoimmunity, and fibrosis in SSc remains obscure. Experimental data suggest that platelets are not solely cell fragments regulating hemostasis but they have a pleiotropic role in several biologic processes including immune regulation, vasculopathy, fibrosis, and all key features of SSc. Platelets interplay with the impaired endothelium, can interact with immune cells, and they are storages of bioactive molecules involved in tissue injury and remodeling. The potential role of platelets in the pathogenesis of SSc is further supported by experimental data in animal models of SSc. Platelet-derived serotonin represents a novel target in SSc and serotonin blockade is currently being tested in clinical trials. Conclusion Platelets may be actively involved in the pathogenesis of SSc by activating immune responses and facilitating the fibrotic process. However, definite conclusions cannot be drawn until more data from both basic and clinical research are available.

Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment.A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10).Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups.Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.

Dermatomyositis is an idiopathic inflammatory disorder of the muscles associated with characteristic cutaneous findings. Herein we report a 68-year old woman who presented with dermatomyositis associated with painful vasculitic lesions on both hands, refractory to conventional treatment. Steroids, topical tacrolimus, antimalarials and intravenous cyclophosphamide were tried with no beneficial effect. Rituximab was also administered with no initial effect; soon afterwards, intravenous immunoglobulin was administered with good results. Some cases of cutaneous dermatomyositis may require trials of different therapies to identify the treatment regimen that produces satisfactory disease control.

Background Childhood primary angiitis of the central nervous system (cPACNS) is an increasingly recognized inflammatory brain disease in children. Case presentation We present a case of a 17-year-old boy with recurrent ischemic events over a short time period. Diagnosis of angiography positive cPACNS was made based on neuroimaging findings while secondary causes or mimics of CNS vasculitis were meticulously excluded. The patient exhibited rapid deterioration of his condition with poor initial response to immunosuppressive treatment. Conclusions Recognition of cPACNS remains a challenge because of rarity of disease, unexplained etiopathogenesis, protean clinical presentation, as well as lack of specific laboratory and neuroimaging markers.

Background Our group, among others, has shown that B cell depletion therapy may improve skin thickening and interstitial lung disease (ILD) related to systemic sclerosis (SSc). All studies assessing the clinical efficacy of B cell depletion therapy in SSc have recruited patients with established disease fulfilling the old classification criteria. In our previous studies we have found that patients with shorter disease duration had a better clinical response to RTX. Objectives It is unknown whether treatment in very early SSc can affect long term outcomes. We aimed at assessing the effect of rituximab (RTX) in patients with very early SSc. Methods We report 2 cases where RTX was administered within 24 months from the appearance of Raynaud’s. Results A 56 year-year-old female with an 18-month history of Raynaud’s developed interstitial lung disease (ILD) with extensive ground glass lesions, a normal FVC (82%) but decreased DLco (44%). A diagnosis of SSc was made based on the presence of positive anti-centromere antibodies, puffy fingers, telangiectasias, positive capillaroscopy, ILD and Raynaud’s. Six months following RTX treatment, her PFT’s had increased (FVC 94% and DLco 55%) and chest HRCT showed an obvious improvement. One year later the patient no longer reported dyspnea. She remained on RTX for 5 years with no respiratory symptoms, stable PFTs and no evidence of disease progression. The second case is a 27-year old female with a 1-year history of Raynaud’s, puffy fingers, positive anti-Scl70 and capillaroscopy. Within a few months her skin thickened rapidly reaching an MRSS of 12 and developed tendon friction rubs. Six months following RTX treatment skin thickening had almost resolved; she only had mild sclerodactyly. Tendon friction rubs disappeared. The patient received 8 consecutive RTX courses throughout a period of 4 years. During this period the patient remained in a steady clinical condition with no signs of disease progression. Conclusion It is generally accepted that autoimmunity/immune dysregulation and vasculopathy are the primary events in SSc that eventually trigger the fibrotic process. Based on this pathogenetic model, one can hypothesize that a therapeutic intervention very early in the disease course, prior to the appearance of fibrotic manifestations could potentially prevent permanent organ damage. Our data suggest that there may be a window of opportunity in SSc. This is why we propose that large scale, controlled studies assessing the efficacy of RTX (or other immune based therapies such as mycophenolate) in patients with very early disease are highly needed. Disclosure of interests None declared

Background It is still unknown whether treatment in very early systemic sclerosis (SSc) can affect long term outcomes. Objectives To systematically review clinical trials in SSc during the last 14 years aiming at answering the following questions: 1) how many clinical trials in SSc have targeted early disease and whether treatment of patients with early disease leads to better clinical outcomes, 2) how is disease duration defined in SSc clinical trials and whether data on duration since Raynaud’s onset are provided and 3) whether the new 2013 ACR/EULAR SSc criteria have been incorporated in clinical trials throughout the last 5 years. Methods A search in published studies indexed in MEDLINE was performed from Jan-2005 to Dec-2018. The Clinical Trial filter was activated and the terms “systemic sclerosis treatment” used. Studies were included if they evaluated adult patients with systemic sclerosis, concerned systemic treatments, presented data for clinical endpoints assessing fibrosis and were prospective in design. Results Seventy-three studies with a total number of 3078 patients met the inclusion criteria and were subjected to data extraction. The total weighted mean disease duration (adjusted to the number of patients in each study) was 38.55 months which is more than 3 years, the usual threshold for defining early disease. Baseline total weighted mean MRSS was 21.54 indicating that most patients had full blown fibrotic disease. Only 24 studies (32.9%) recruited early ( Conclusion 1) The majority of patients recruited in clinical trials throughout the last 14 years do not have early disease, 2) Only one third of the studies were specifically designed to target early disease, 3) The question of whether early implementation of therapy may lead to better clinical outcomes cannot be definitely answered based on existing data, 4) there is confusion related to disease duration definition across SSc clinical trials but an obvious trend towards improvement was evident throughout the last few years and 5) there is still a very low level of incorporation of the new classification criteria in SSc trials. Disclosure of Interests None declared

Background Immune check point inhibitors (ICI) were a breakthrough in cancer therapeutics. These agents target certain “brakes” of the immune system aiming at activating T cells to fight cancer. Taking into account their mechanism of action it is no surprise that they have been associated with immune related adverse events Objectives To assess the prevalence, clinical and imaging characteristics of ICI-induced musculoskeletal manifestations in a prospective manner Methods This is a prospective, clinical and MRI study conducted from Jan 2016 to Oct 2018. All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department and subjected to a full clinical assessment and laboratory workup. An MRI of the involved area(s) was performed within one week of the initial clinical evaluation. In 2 patients MRI was not performed due to claustrophobia (n=1) and presence of non compatible metal implant (n=1). Results During the study period a total of 130 patients were treated with ICI. Of those, 10 (7.7%) developed ICI-induced musculoskeletal manifestations. They suffered from lung (n=4), bladder (n=3), renal cancer (n=2) or melanoma (n=1) and received treatment with nivolumab (n=7), pembrolizumab (n=1), durvalumab (n=1) and atezolizumab (n=1). They were mostly male (n=8) with a mean ± SEM age of 66.7 ± 2.6 years. The median (range) time from ICI treatment since development of symptoms was 2.5 (1-22) months. Autoantibodies (RF/ACPA/ANA) were negative in all patients and only 3/10 had a mild/moderate increase of inflammatory markers at disease onset. Three different patterns of musculoskeletal manifestations were found: i) Prominent joint involvement (n=3). Areas involved were the small joints of the hands (n=2) and knee/ankle (n=1). The MRI of the latter patient depicted not only synovitis but also myositis of the muscles surrounding the involved joints, ii) Prominent “periarticular” involvement (n=4). These patients had diffuse swelling of the hands (n=4) feet (n=3) or knees (n=1). Joints retained a good and relatively painless range of motion. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases, iii) Myo-fasciitis (n=3). In all 3 such cases the involved area was the knee. Clinically, these patients presented with pain in the knee and either no objective signs of arthritis (n=2) or swelling with non inflammatory synovial fluid. MRI depicted myo-fasciitis of the surrounding muscles in all cases; a partial tear of the quadriceps tendon was also found in the patient with knee swelling. Overall, symptoms were mild/moderate and responded well to treatment (low dose steroids in 6 and NSAIDs/analgesics in 4) with no need for ICI discontinuation. Conclusion In our cohort ICI-induced musculoskeletal manifestations were not uncommon and developed in 7.7% of patients. Imaging evidence of myo-fasciitis was found in all patients indicating that the muscle/fascia is more frequently involved than the synovium. Our clinical and imaging data point to the direction that ICI-induced musculoskeletal manifestations mostly involve periarticular structures and associate mainly with myo-fasciitis and not synovium based pathology Disclosure of Interests None declared

Background: The pathophysiology of Systemic Sclerosis (SSc) encompasses autoimmunity, microvascular damage and fibrosis of the skin and internal organs. Accordingly, the two mainstays of treatment comprise antiproliferative and vasoactive regimens. So far there are limited data regarding the actual use of these agents in daily clinical practice. Objectives: To describe current treatment modalities based on standard practice decisions according to published recommendations and/or guidelines for SSc, as well as to determine to which extent different disease modifying agents, namely antiproliferative and vasoactive drugs, are administered to these patients. Methods: Consecutive patients from 7 academic rheumatology departments across Greece who fulfilled the 1980 american College of Rheumatology criteria for classification of SSc and were examined between January 2016 and December 2018 at least once, were included in the study. Patients’ medical records were analyzed and antiproliferative and vasoactive agents administered anytime during the disease course were recorded. Results: A total of 457 patients (87% women, 51% diffuse SSc, 62% with pulmonary fibrosis, 55% with digital ulcers, mean±SD age at diagnosis 49.2±13.1 years, disease duration 10.4±8 years) were studied. Methotrexate was the most frequent antiproliferative agent ever administered (53% of patients, 55% of them with diffuse SSc) followed by cyclophosphamide (26%, 78% of them diffuse), mycophenolate (11%, 63% of them diffuse), azathioprine (10%, 64% of them diffuse), rituximab (9%, 84% of them diffuse) and tocilizumab (3%, 68% of them diffuse). Among vasoactive agents, endothelin receptor antagonists (ERA) were most frequently ever administered in 39% of patients (64% with diffuse SSc) followed by iloprost in 7% (55% diffuse) and 5 phosphodiesterase (5PDE) inhibitors in 5.5% of patients (62% diffuse). Among all antiproliferative/vasoactive agents used, the greatest retention rate at last follow-up visit since initiation had ERA (82%) and 5PDE inhibitors (86%). Of note, 20% of SSc patients (90% women, 70% limited SSc, age at diagnosis 50.4±13.2 years, disease duration 8.4±6.4 years) had never been treated with either antiproliferative or vasoactive agents, whereas 41% had ever received only antiproliferative and 8% only vasoactive therapy. Moreover, 1/5 of patients with pulmonary fibrosis had never received antiproliferative treatment, whereas 1/3 of patients with digital ulcers had never received vasoactive drugs (Table). Conclusion: About 20% of contemporary SSc patients, including patients with pulmonary fibrosis and digital ulcers, have never received antiproliferative or vasoactive therapy, possibly reflecting the spectrum of benign disease and/or a subgroup of under-treated patients. References: Disclosure of interests: None declared

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.

Interstitial lung diseases (ILD) represent a group of heterogeneous parenchymal lung disorders with complex pathophysiology, characterized by different clinical and radiological patterns, ultimately leading to pulmonary fibrosis. A considerable proportion of these disease entities present with no effective treatment, as current therapeutic regimens only slow down disease progression, thus leaving patients, at best case, with considerable functional disability. Biologic therapies have emerged and are being investigated in patients with different forms of ILD. Unfortunately, their safety profile has raised many concerns, as evidence shows that they might cause or exacerbate ILD status in a subgroup of patients. This review article aims to summarize the current state of knowledge on their role in patients with ILD and highlight future perspectives.

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.

Background Comorbidities are common in chronic systemic connective tissue diseases and are associated with adverse outcomes, increased morbidity and mortality. Although the prevalence of comorbidities has been well-studied in isolated diseases, comparative studies between different autoimmune diseases are limited. In this study, we compared the prevalence of common comorbidities between patients with systemic sclerosis (SSc) and patients with rheumatoid arthritis (RA). Methods Between 2016 and 2017, 408 consecutive patients with SSc, aged 59 ± 13 years (87% women), were matched 1:1 for age and gender with 408 patients with RA; mean disease duration was 10 ± 8 and 9 ± 8 years, respectively. Rates of cardiovascular risk factors, coronary artery disease, stroke, chronic obstructive pulmonary disease (COPD), osteoporosis, neoplasms and depression were compared between the two cohorts. Results The prevalence of dyslipidemia (18.4% vs 30.1%, p = 0.001) and diabetes mellitus (5.6% vs 11.8%, p = 0.007) and body mass index (p = 0.001) were lower in SSc compared to RA, while there was no difference in arterial hypertension or smoking. While there was a trend for lower prevalence of ischemic stroke in SSc than in RA (1.1% vs 3.2%, p = 0.085), coronary artery disease was comparable (2.7% vs 3.7%). No differences were found between patients with SSc and patients with RA in the prevalence of COPD (5.2% vs 3.7%), osteoporosis (24% vs 22%) or neoplasms overall (1.1% vs 1.7%); however lung cancer was the most prevalent cancer in SSc (7/17, 41%), whereas hematologic malignancies (7/19, 36%) and breast cancer (7/19, 36%) predominated in RA. Depression was more prevalent in SSc (22% vs 12%, p = 0.001), especially in diffuse SSc. Conclusions Despite the prevalence of dyslipidemia and diabetes mellitus in SSc being almost half that in RA, the cardiovascular comorbidity burden appears to be similar in both. The overall prevalence of neoplasms is no higher in SSc than in RA, but SSc has a more negative impact on quality of life, as clearly, more SSc patients develop depression compared to patients with RA.

Evidence suggests that serotonin is an inhibitor of bone formation. We aimed to assess: 1) serum serotonin levels in patients with ankylosing spondylitis (AS), a prototype bone-forming disease, compared with patients with rheumatoid arthritis (RA) and healthy subjects; 2) the effect(s) of TNFα blockers on serum serotonin levels in patients with AS and RA; and 3) the effect(s) of serum of AS patients on serotonin signaling. Serum serotonin levels were measured in 47 patients with AS, 28 patients with RA, and 40 healthy subjects by radioimmunoassay; t test was used to assess differences between groups. The effect of serum on serotonin signaling was assessed using the human osteoblastic cell line Saos2, evaluating levels of phospho-CREB by Western immunoblots. Serotonin serum levels were significantly lower in patients with AS compared with healthy subjects (mean ± SEM ng/mL 122.9 ± 11.6 versus 177.4 ± 24.58, p = 0.038) and patients with RA (mean ± SEM ng/mL 244.8 ± 37.5, p = 0.0004). Patients with AS receiving TNFα blockers had significantly lower serotonin levels compared with patients with AS not on such treatment (mean ± SEM ng/mL 95.8 ± 14.9 versus 149.2 ± 16.0, p = 0.019). Serotonin serum levels were inversely correlated with pCREB induction in osteoblast-like Saos-2 cells. Serotonin levels are low in patients with AS and decrease even further during anti-TNFα treatment. Differences in serotonin levels are shown to have a functional impact on osteoblast-like Saos-2 cells. Therefore, serotonin may be involved in new bone formation in AS.

Objective Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton—the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation. Methods Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model. Results Patients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects ( p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment ( p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment ( p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment. Conclusions Ihh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications.

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. 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.

Rheumatoid arthritis (RA) is associated with HLA-DRB1 shared epitope (HLA-DRB1SE) and anti-citrullinated protein autoantibodies (ACPAs). ACPAs precedes the onset of clinical and subclinical RA. There are strong data for three infectious agents as autoimmunity triggers in RA, namely Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans causes of periodontal disease (PD), and Epstein-Barr virus (EBV). P. gingivalis expresses arginine gingipains, that cleave proteins at the arginine residues, and peptidyl arginine deiminase (PPAD), which citrullinates arginine residues of proteins, thus forming neoantigens that lead to ACPA production. Peripheral blood plasmablasts from ACPA+RA patients produce ACPAs the majority of which react against P. gingivalis. A. actinocycetemcomitans produces leukotoxin A, a toxin that forms pores in the neutrophil membranes and leads to citrullination and release of citrullinated autoantigens in the gums. EBV can infect B cells and epithelial cells and resides as latent infection in resting B cells. Abs against citrullinated peptides derived from EBV nuclear antigen appear years before RA and cross-react with human citrullinated fibrin. Citrullinated proteins are potential arthritogenic autoantigens in RA. The conversion of arginine to citrulline increases the peptide binding affinity to HLA-DRB1SE. Also, citrullinated fibrinogen induces arthritis in HLA-DRB1*0401 transgenic mice, and transfer of their splenic T cells causes arthritis to recipient mice.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, autoantibodies, and extensive fibrosis. Intestinal involvement is frequent in SSc and represents a significant cause of morbidity. The pathogenesis of intestinal involvement includes vascular damage, nerve dysfunction, smooth muscle atrophy, and fibrosis, causing hypomotility, which leads to small intestinal bacterial overgrowth (SIBO), malabsorption, malnutrition, diarrhea, pseudo-obstruction, constipation, pneumatosis intestinalis, and fecal incontinence. Manifestations are often troublesome and reduce quality of life and life expectancy. Assessment of intestinal involvement includes screening for small intestine hypomotility, malnutrition, SIBO, and anorectal dysfunction. Current management of intestinal manifestations is largely inadequate. Patients with diarrhea are managed with low-fat diet, medium-chain triglycerides, avoidance of lactulose and fructose, and control of bacterial overgrowth with antibiotics for SIBO. In diarrhea/malabsorption, bile acid sequestrant and pancreatic enzyme supplementation may help, and nutritional support is needed. General measures are applied for constipation, and intestine rest plus antibiotics for pseudo-obstruction. Fecal incontinence is managed with measures for associated SIBO, or constipation, and with behavioral therapies. Pneumatosis intestinalis is usually an incidental finding that does not require any specific treatment. Immunomoduation should be considered early in intestinal involvement. Multidisciplinary approach of intestinal manifestations in SSc by gastroenterologists and rheumatologists is required for optimum management.

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.

Background Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical roles in embryonic development. Evidence suggests that this molecule regulates several aspects of both bone biology and fibrosis. Objectives To provide an overview of our current knowledge of the role of Dkk-1 in joint remodeling and fibrosis. Methods We performed an electronic search (Medline) using the following key words: Dickkopf-1 (or Dkk-1), new bone formation, joint remodeling, ankylosing spondylitis, systemic sclerosis (or scleroderma), and fibrosis, supplemented by a manual search of references from retrieved articles. Results Dkk-1 is a master regulator of joint remodeling in animal models of arthritis shifting the balance toward new bone formation when its expression is decreased and toward erosion/joint destruction when its expression is increased. In humans, evidence suggests that Dkk-1 may be dysfunctional in patients with ankylosing spondylitis, a prototype bone forming disease. Moreover, data from animal models indicate that Dkk-1 has a protective role against fibrosis in several organs. Recent data suggest that inhibiting the canonical Wnt pathway by overexpression of Dkk-1 could be a way to target TGF-β signaling in fibrotic diseases. Finally, B-cell depletion therapy in systemic sclerosis may exert its effects through TGF-β dependent upregulation of Dkk-1. Conclusions Dkk-1 appears to play a crucial role in both joint remodeling/ectopic ossification and fibrosis, and may be a prospective therapeutic modality for fibrotic diseases or diseases characterized by pathologic joint remodeling.

To dissect the mechanisms of anti-TNFα-induced autoimmunity we examined the phenotype and function of B cells from anti-TNFα-treated patients. Levels of Lyn, Syk, SHP-1, tyrosine 348 phospho-Syk (Y348-Syk) and tyrosine phosphorylated (P-Y) proteins were evaluated and B-cell-surface CD20, CD21 and CD5 were also assessed in 29 patients treated with TNF-α blockers. Following treatment, Lyn, but not Syk or SHP-1, significantly increased particularly in patients with spondyloarthropathies. Increased Lyn levels following treatment correlated with increased Lyn activity as evidenced by a 2.9-fold increase of Y348-Syk (a Lyn target). Peripheral B-cells from 56.3% of the patients displayed a tendency towards increased P-Y levels without any BCR-initiated activation during treatment. CD20, but not CD21, significantly increased in patients with rheumatoid arthritis. Circulating CD5+ B-cells were also significantly expanded during treatment. Our findings suggest that B cells in anti-TNFα-treated patients display functional and phenotypical aberrations that may enhance our understanding of TNF-α blocker-induced autoimmunity.

Increased Age-Related B-cells in Patients with Aplastic Anemia Introduction: Aplastic anemia is a rare disease characterized by immune dysregulation. T cells in aplastic anemia are characterized by various intrinsic defects leading to increased IFN-g levels and Fas-mediated apoptosis of hematopoietic stem cells. We and others, have previously shown that the transcription factor T-bet is over-expressed in T cells from patients with aplastic anemia. Recently it was shown that a subpopulation of B cells also express T-bet; these cells are characterized as age-related B cells (ABCs) and express high levels of CD11c and CD19, they are CD21 negative and express T-bet. These T-bet+ ABCs are found increased in patients with autoimmune diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis). Stimulation of B cells with antigens, Toll-like receptors and IFN-g leads to the formation of ABCs, which in turn "talk" to the T cells and stimulate them. Stimulation of T cells leads to IFN-g production, and this IFN-g may lead to further induction of T-bet expressing B cells (ABCs). Specific aim: In this study we wanted to examine the expression of ABCs in patients with aplastic anemia. We isolated peripheral blood mononuclear cells (PBMCs) from patients with aplastic anemia (n=10) and eight healthy, age- matched controls. Written informed consent was obtained from all study subjects. Cells were stained with the surface markers CD11c, CD19 and CD21, and subsequently analyzed using flow cytometry. An anti-Tbet antibody was also used after cell permeabilization. The CD11c-high, CD19 positive, CD21 negative, T-bet positive population represent the ABCs. Results: Patients with aplastic anemia at presentation showed increased numbers of circulating ABCs compared to healthy controls (29,08±1,62% vs 4,06 ±0,4 % respectively, p Conclusion: Although the number of patients analyzed is limited, our preliminary results suggest that aplastic anemia patients show expanded ABCs compared to age-matched control subjects, and these numbers are related to disease status. Further analysis of a larger pool of subjects is underway along with the examination of the specific transcription factor Bcl-6, that is implicated in T-bet expression in ABCs. These results will reveal the role of ABCs in the immune pathogenesis of aplastic anemia. Figure 1. Figure 1. Disclosures Kattamis: CELGENE: Consultancy, Honoraria; Vifor Pharma: Consultancy; Novartis: Consultancy, Honoraria; ApoPharma: Honoraria.

Objectives Rituximab (RTX) has been successfully used in the treatment of several rheumatic diseases with an acceptable safety profile. We present herein a patient with systemic sclerosis (SSc) who exhibited significant improvement of his lung function and skin fibrosis following RTX administration, and review the literature regarding the role of B-cells in SSc and the potential efficacy of RTX in its treatment. Methods We performed an internet search using the keywords systemic sclerosis, scleroderma, rituximab, B-cells, fibrosis, interstitial lung disease (ILD), and therapy. Results Our patient, a 40-year old man with severe SSc-associated ILD, received 4 courses of RTX. The patient's lung function improved; forced vital capacity and diffusing capacity of carbon monoxide reached values of 35% and 33%, respectively, compared with 30% and 14% of pretreatment values. Skin thickening assessed clinically and histologically improved as well. Several lines of evidence suggest that B-cells may have a pathogenic role in SSc. B-cells from tight skin mice—an animal model of SSc—exhibit chronic hyperactivity; likewise, B-cells from patients with SSc overexpress CD19 and are chronically activated. Furthermore, studies have revealed that B-cell genes were specifically transcribed in SSc skin and that B-cell infiltration was a prominent feature of SSc-associated ILD. The potential clinical efficacy of RTX in SSc has been explored in a limited number of patients with encouraging results. Preliminary data suggest that RTX may favorably affect skin as well as lung disease in SSc. Conclusions Several basic research data underscore the potential pathogenic role of B-cells in SSc and clinical evidence suggests that RTX might be a therapeutic option in SSc. Large-scale multicenter studies are needed to evaluate the potential clinical efficacy of RTX in SSc.

Tumour necrosis factor alpha (TNF-α) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that TNF-α may be implicated in the pathogenesis of various autoimmune and non-infectious inflammatory conditions. Over the past decade pharmaceutical agents directed against TNF-α (infliximab, adalimumab and etanercept) have been widely and successfully employed for the management of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and inflammatory bowel disease, whereas two novel anti-TNF-α agents, golimumab and certolimumab pegol, recently entered the market for the treatment of RA, AS, Crohn's disease and psoriasis. Encouraged by the positive results obtained from the use of TNF-α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of TNF-α in the pathogenesis of numerous disorders, anti-TNF-α agents have been considered for the management of diseases other than the ones they were initially approved for. Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of TNF-α blockers had been less than favourable, in other cases of non-infectious inflammatory conditions the response to TNF-α inhibition had been fairly beneficial. More specifically, according to well-documented clinical trials, anti-TNF-α agents exhibited favourable results in Behçet's disease, non-infectious ocular inflammation, pyoderma gangrenosum and hidradenitis suppurativa. In this review we discuss the successful outcomes as well as the prospects for the future from the off-label use of TNF-α antagonists.

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system, and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal, and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review novel information that deals with 1) genes associated with disease expression, 2) immune cell molecular abnormalities that lead to autoimmune pathology, 3) the role of hormones and sex chromosomes in the development of disease, 4) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we emphasize molecular defects intimately associated with the disease process of SLE that represent ideal therapeutic targets and disease biomarkers.

Objective Dkk-1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk-1 in ankylosing spondylitis (AS), a prototypical bone-forming disease. Methods Serum Dkk-1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme-linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk-1 to its receptor (low-density lipoprotein receptor–related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti–Dkk-1 monoclonal antibody, by Western immunoblotting. Results Serum Dkk-1 levels were significantly increased in patients with AS (mean ± SEM 2,730 ± 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti–tumor necrosis factor α (anti-TNFα) treatment had significantly higher serum Dkk-1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti-TNFα administration exhibited a significant increase in serum Dkk-1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk-1 blockade significantly enhanced Wnt signaling in control serum–treated, but not AS serum–treated, Jurkat T cells. Conclusion Our findings indicate that in patients with AS, circulating bone formation–promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk-1–mediated inhibition.

Objective. To assess the efficacy of rituximab (RTX) in SSc. Methods. Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m2)] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically. Results. There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean ± s.d.: 68.13 ± 19.69 vs 75.63 ± 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DLCO) increased significantly in the RTX group compared with baseline (mean ± s.d.: 52.25 ± 20.71 vs 62 ± 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DLCO in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean ± s.d.: 13.5 ± 6.84 vs 8.37 ± 6.45 at baseline vs 1-year, respectively, P < 0.001). Conclusion. Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.

Peripheral B cell depletion strategies have been employed recently in the treatment of systemic autoimmune diseases and the initial clinical results have been encouraging. Although the major target of rituximab-based treatments was to reduce the levels of circulating autoantibodies, additional mechanisms of action may operate. Recent studies have addressed the question of potential effects of transient B cell depletion on other, non-B cell populations. The data, albeit uncontrolled, suggest that anti-CD20 monoclonal antibody treatment is associated with significant effects in the T cell pool, whereas individual clinical responses do not always correlate with changes in autoantibody titers. More specifically, it has been reported that rituximab administration may decrease the activated phenotype of peripheral and tissue-resident T cells by abolishing antigen presentation by B cells, and may enhance the numbers and function of regulatory T cells. In this review we analyze and discuss available data emerging from B cell depletion studies in patients with systemic lupus erythematosus, rheumatoid arthritis and other autoimmune conditions. Further controlled studies are needed to confirm the role of B cell depletion in modifying T cell function in vivo.