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Constantina A Bounia,1 Eftichia N Theodoropoulou,1 Stamatic-Nick C Liossis1,2 1Division of Rheumatology, Patras University Hospital, Patras, Greece; 2Department of Internal Medicine, University of Patras Medical School, Patras, GreeceCorrespondence: Stamatic-Nick C LiossisDiv. of Rheumatology, Patras University Hospital, GR 26500, Rion, Patras, GreeceTel +30 2613 603 693Fax +30 2610 993 982Email snliossis@med.upatras.grAbstract: Renal failure or acute/chronic kidney damage may present as a clinical manifestation of rheumatic diseases. In addition treatment with DMARDs or biologic drugs may induce nephrotoxicity. In this case-based review, we present two patients with SpA under anti-TNF-α treatment admitted to our hospital because of renal failure and proteinuria. We review previously published yet isolated cases of TNF-α blocker-induced glomerular disease in patients with SpA. Renal manifestations are occasionally seen in patients with ankylosing spondylitis and psoriatic arthritis with IgA nephropathy being the most common of them. Anti-TNF-α agents although reportedly used for the treatment of glomerular nephropathy as a disease manifestation, they have been considered responsible for provoking renal damage in some cases. A diagnostic approach for patients with SpA treated with anti-TNF-α agents presenting with renal manifestations is proposed herein.Keywords: spondylarthritides, glomerular disease, proteinuria, kidney biopsy, anti-TNF-alpha agents

Introduction: This study aimed to determine whether the introduction of anti-SARS-CoV-2 vaccines and the dominance of the omicron variant had a significant impact on the outcome of COVID-19 in patients with systemic autoimmune rheumatic diseases (SAIRDs)., Methods: Using data entered to the Greek Rheumatology Society COVID-19 registry, we investigated the incidence of hospitalization and death due to COVID-19, during the successive periods of the pandemic according to the prevalent strain (wild-type, Alpha, Delta, Omicron) in vaccinated and unvaccinated patients. Variables independently associated with hospitalization and death were explored using multivariate regression analyses, while Kaplan-Meier curves were used to depict survival data., Results: From August 2020 until June 30, 2022, 456 cases (70.2% females) of COVID-19 with a mean age (± SD) of 51.4 ± 14.0 years were reported. In unvaccinated patients, the proportions of hospitalization and death were 24.5% and 4%, compared to 12.5% and 0.8% in the vaccinated group (p < 0.001 for both comparisons). The rates of hospitalization for the wild-type, Alpha, Delta, and Omicron periods were 24.7%, 31.3%, 25.9%, and 8.1% respectively (p < 0.0001), while the case fatality rates were 2.7%, 4%, 7%, and 0%, respectively (p = 0.001). Using multivariable regression analysis, factors independently associated with hospitalization were infection by a non-Omicron variant, being non-vaccinated, exposure to rituximab, older age, and respiratory and cardiovascular disease. Independent predictors for death were contracting COVID-19 during the Alpha or Delta period, pulmonary disease, and older age, while being vaccinated was protective., Conclusions: In this 2-year analysis, the rates of hospitalization and death among patients with SAIRDs have declined significantly. Vaccination and the dominance of the Omicron variant appear to be the major determinants for this shift. Key points • During the late phase of the pandemic, the proportion of severe COVID-19 cases, defined as requiring hospitalization or resulting in death, in patients with systemic autoimmune rheumatic diseases has declined. • Anti-SARS-CoV-2 vaccination and the dominance of the Omicron strain are the key factors that have independently contributed to this shift., (© 2023. The Author(s).)

To evaluate the effect of the phosphodiesterase 4 inhibitor apremilast in biologic-naïve patients with early peripheral PsA in terms of disease activity, clinical manifestations, patient-perceived outcomes, as well as apremilast's safety profile in routine care settings of Greece. Non-interventional, multicenter, 52-week prospective cohort study, enrolling biologic-naïve patients with early active peripheral PsA who started apremilast after intolerance or inadequate response (within the first 12 months of treatment) to an initial conventional synthetic (cs)DMARD treatment. Non-responder imputation was applied for missing data.In total, 167 consecutive patients (mean age: 52.5 years; median PsA duration: 0.9 years) were analyzed. At baseline, the median (interquartile range) clinical Disease Activity in Psoriatic Arthritis (cDAPSA) score was 22.0 (16.0-29.0), with 86.8% of patients having at least moderate (29.3% high) disease activity; 87.4% had skin psoriasis, 37.7% nail psoriasis, 30.7% enthesitis, and 12.4% dactylitis. At 16, 24, and 52 weeks, 28.7, 42.5, and 48.5% of patients, achieved ≥ 50% improvement in their baseline cDAPSA score, respectively. At week 52, 55.6, 50, and 26.8% of evaluable patients achieved complete resolution of enthesitis, dactylitis and nail psoriasis, respectively. Improvements were also observed in patient's health state assessed by the Psoriatic Arthritis Impact of Disease 12-item questionnaire, and health-related quality of life. The 52-week drug survival rate was 75%, while 13.8% of patients experienced at least one adverse drug reaction.Biologic-naïve patients with early PsA, treated with apremilast experienced significant improvements in disease activity, extra-articular manifestations and patient-centered outcomes, accompanied by a favorable tolerability profile., (© 2023. The Author(s).)

Objective: Τo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs)., Methods: Patients 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., Results: Between 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 <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients., Conclusions: Vaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Systemic lupus erythematosus (SLE) is a chronic autoimmune multisystem disease with a variable presentation and manifestations ranging from mild to severe or even life-threatening. There is an ongoing and unmet need for novel, disease-specific, effective and safe treatment modalities. The aim of this review is to summarize data on SLE treatment that have emerged over the last 3 years. We will put emphasis on studies evaluating potential treatments on severe lupus manifestations such as lupus nephritis. Despite the existence of several therapeutic agents in SLE, the disease keeps causing significant morbidity. It is encouraging that a variety of therapeutic options are currently under investigation, although there are occasional trial failures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liossis and Staveri.)

Competing Interests: The authors declare no conflict of interest.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (© 2019 The Mediterranean Journal of Rheumatology (MJR).)

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.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The activity of the Wnt pathway, a critical mediator of fibrosis, is regulated by Dickkopf-1 (Dkk-1). Dkk-1 is absent from scleroderma skin in contrast to skin from healthy subjects where it is clearly expressed. There are no data on circulating levels and function of Dkk-1 in patients with systemic sclerosis (SSc). Our objectives are to assess: i) circulating and functional levels of Dkk-1 in patients with SSc and ii) whether the striking lack of Dkk-1 skin expression is also evident in a) clinically uninvolved skin from patients with SSc and b) very early disease prior to skin thickening., Methods: Circulating Dkk-1 levels were measured in 50 patients with SSc and 50 controls. Skin biopsies were obtained from SSc patients from a) clinically involved skin b) clinically uninvolved skin, c) oedematous skin prior to skin thickening., Results: Circulating and functional Dkk-1 levels were similar in patients with SSc and controls. Healthy skin displayed a high Dkk-1 immuno-expression in the epidermis and dermal fibroblasts in contrast to clinically involved scleroderma skin where Dkk-1 was totally absent. In all biopsies of clinically uninvolved skin Dkk-1 was only moderately expressed whereas skin from very early disease displayed only a weak Dkk-1 immunoreactivity., Conclusions: The downregulation of Dkk-1 at the oedematous phase of the disease indicates that the Wnt pathway is involved early in the disease process and may play a role in driving fibrosis. The decrease in Dkk-1 expression in clinically uninvolved scleroderma skin indicates that skin in SSc is universally affected.

The objective of the study was to explore the phenotype and intracellular signaling events of B cells in patients with systemic sclerosis (SSc). Peripheral blood B cell surface markers CD19 and CD22 were evaluated by flow cytometry in 23 patients with SSc and seven healthy individuals. Levels of intracellular kinases Lyn, Syk and P-Y 348 Syk along with phosphatase SHP-1 were examined with Western immunoblotting in selected patients. P-Y 822 CD22 was subsequently evaluated flow cytometrically in antigen receptor stimulated B cells. A statistically significant decrease in CD22 B cell surface expression was found in the diffuse subset of patients (median CD22 MFI ± SD was 5.90 ± 2.35 vs 10.20 ± 1.88 for patients vs healthy controls respectively; p = 0.021), while no statistically significant change was found regarding CD19. CD22 underexpression was more pronounced when interstitial lung disease (ILD) was present (median CD22 MFI ± SD was 5.90 ± 2.25 vs 10.20 ± 1.88 for patients with ILD vs healthy controls respectively; p = 0.011). CD22 phosphorylation following B cell receptor (BCR) stimulation was also found to be impaired in patients with diffuse SSc (median change in MFI ± SD was 0.28 ± 0.09 vs 0.38 ± 0.08 for patients vs healthy controls respectively; p = 0.034). Low CD22 expression was arithmetically correlated with kinase Lyn underexpression (Pearson coefficient 0.926; p = ns) in B cells from a small sample of patients. These results suggest that CD22 underexpression and impaired phosphorylation along with implications for Lyn kinase aberrations could contribute to the activated B cell phenotype in SSc.

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.

Dickkopf-1 (Dkk-1) is a Wnt signaling pathway inhibitor that has been shown to play an important role in joint remodeling, in experimental models of arthritis and in humans. Recent data suggest that this molecule is involved in the fibrotic process as well., Objectives: This review summarizes all the available data regarding the role of Dkk-1 in joint remodeling and fibrosis., Methods: An electronic search in literature was performed using the terms Dickkopf-1 (Dkk-1), fibrosis, Systemic Sclerosis (Scleroderma), joint remodeling, Ankylosing Spondylitis. Moreover, references in the retrieved articles were reviewed., Results: Dkk1 expression seems to determine the fate of an arthritic joint, shifting the process of joint remodelling towards either an erosive/destructive phenotype, when Dkk1 is overexpressed or new bone formation when its expression is decreased. In humans, evidence suggests that Dkk-1 may be dysfunctional in patients with ankylosing spondylitis. Moreover, data from animal models indicate that Dkk-1 may be crucially involved in the fibrotic process in several organs such as the liver, lungs and kidneys. In animal models, enhanced expression of Dkk-1 had a clear suppressive effect on fibrosis suggesting that this molecule could be an attractive target in fibrotic diseases. In humans, Dkk-1 is clearly expressed in the skin. However, in patients with systemic sclerosis Dkk-1 is strikingly absent from the skin., Conclusion: Dkk-1 plays a critical role in joint remodeling and fibrosis and could serve as either a biomarker in diseases characterized by pathological joint remodeling or as a potential therapeutic target in fibrotic diseases., (© 2017 The Mediterranean Journal of Rheumatology (MJR).)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Objectives: To directly assess the prevalence of inflammatory rheumatic disease under treatment with biologic disease modifying anti-rheumatic drugs (b-DMARDs) and compare treatment patterns between rheumatoid arthritis (RA) and spondyloarthropathy (SpA), including psoriatic arthritis., Methods: The obligatory country-wide prescription electronic database covering 10.223.000 Greek citizens (95.1% of the population, 99.5% Caucasian), all of whom with fully reinbursed access to b-DMARDs, was used to retrospectively capture all patients under b-DMARDs for RA/SpA between June 2014-May 2015. Age, gender and medications for RA/SpA and co-morbid classical cardiovascular risk factors (hypertension, dyslipidaemia, diabetes) were retrieved and analysed., Results: A total of 9.824 RA (61.2±14.0 years, 79% women) and 9.279 SpA patients (51.4±13.1 years, 41% women) using pharmacy-dispensed prescriptions for b-DMARDs were identified (overall prevalence 0.19%). Tumour necrosis factor inhibitors were used in 73% and 99% of RA and SpA patients, respectively. B-DMARD monotherapy (RA: 18.71%, SpA: 52.11%), b-DMARD switching during 12 months (RA: 7.73%, SpA: 6.26%), and use of methotrexate (RA: 50.25%, SpA: 27.35%) and corticosteroids (RA: 55.8%, SpA: 23.63%) differed between the two patient subgroups. In both subgroups, women received more often than men methotrexate, leflunomide, hydroxychloroquine and corticosteroids, and less often b-DMARD monotherapy. After adjustments for age, gender and concomitant drugs, the probability for anti-hypertensive and lipid-lowering drug prescription was higher in SpA than RA [OR=1.41 (95%CI: 1.29-1.54) and 1.24 (1.14-1.36), respectively, p<0.001], whereas for anti-diabetics it was similar., Conclusions: In the first country-wide study that examines the characteristics of rheumatic disease patients under b-DMARD we show that their exact prevalence is 0.19%, with RA patients being older by 10 years, only slightly more numerous, and less likely to receive treatment for hypertension and dyslipidaemia than their demographically matched SpA counterparts. Longitudinal studies should assess the implications of these novel findings on the differential financial burden of rheumatic diseases, as well as on cardiovascular morbidity and mortality of these patients.

Objectives: 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., Methods: 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)., Results: 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 (p < 0.01, 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., Conclusions: 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway., Methods: Fourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration., Results: In baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.030). In contrast, TGFβ expression in the upper dermis was significantly attenuated following treatment. Moreover, this decreased expression of TGFβ in the skin was significantly more pronounced in the subgroup of patients with Dkk-1 upregulation. In this subgroup TGFβ was downregulated by 50.88 % in contrast to only 15.98 % in patients who did not have Dkk-1 upregulation (p = 0.022)., Conclusions: This is the first study demonstrating a link between B cell depletion and skin Dkk-1 upregulation in patients with SSc. RTX-mediated B cell depletion may mechanistically function via the recently established TGFβ-Dkk-1 axis in improving skin fibrosis.

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., (© 2015 American Society for Bone and Mineral Research.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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., (© 2013 Elsevier Inc. All rights reserved.)

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.

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 PDGFRβ expression on spindle-like cells and collagen deposition in SSc biopsies (r = 0.97 and r = 0.96 for PDGFRα and PDGFRβ, respectively; P < 0.0001 for both), indicating a strong link between PDGFR expression and fibrosis. Expression of PDGFRα and PDGFRβ 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 PDGFRβ, 37.14 ± 4.94 vs. 24.01 ± 3.27, P = 0.012). Similarly, expression of phosphorylated PDGFRα and PDGFRβ in the papillary dermis significantly decreased following RTX administration (P = 0.006 and P = 0.013 for phospho-PDGFRα and phospho-PDGFRβ, 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.

Objectives: Calcinosis is frequently encountered in patients with systemic sclerosis (SSc) and may be associated with significant morbidity. No treatment has shown so far an unequivocal beneficial effect., Methods: We performed an extensive internet search (MEDLINE) using the keywords calcinosis, calcification, scleroderma, systemic sclerosis, and treatment., Results: Our patient had extensive Calcinosis, Raynaud, Esophagitis, Sclerodactyly, telangiectasia (CREST)-related calcinosis, frequently ulcerating and painful. Following 2 rituximab courses (consisting of 4 weekly infusions, 375 mg/m(2) each), calcinosis significantly improved and pain disappeared. Pharmacologic agents used in the treatment of SSc-associated calcinosis include diltiazem, minocycline, warfarin, biphosphonates, and intravenous immunoglobulin. Other therapeutic approaches include surgical excision, laser vaporization, and extracorporeal shock wave lithotripsy., Conclusions: Evidence for all existing therapies is weak and therefore larger scale controlled studies are needed. Rituximab appears as a promising treatment especially in view of recent evidence that this therapy may be also effective in the underlying disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To assess the safety and efficacy of long-term treatment with rituximab (RTX) in patients with systemic sclerosis (SSc)., Methods: Eight patients with SSc-associated interstitial lung disease (ILD) received 4 cycles of RTX and had a follow-up of 2 years. Lung involvement was assessed by pulmonary function tests and chest HRCT. Skin involvement was assessed both clinically and histologically., Results: We found a linear improvement of lung function and skin thickening over the 2 years of RTX treatment. There was a significant increase of FVC at 2 years compared to baseline (mean ± SEM: 77.13±7.13 vs. 68.13±6.96, respectively, p<0.0001). Similarly, DLco increased significantly at 2 years compared to baseline (mean ± SEM: 63.13±7.65 vs. 52.25±7.32, respectively, p<0.001). Skin thickening, assessed with the MRSS, improved significantly at 2 years compared to baseline (mean ± SEM: 4.87±0.83 vs. 13.5±2.42, respectively, p<0.0001). A reduction in myofibroblast score was seen histologically following RTX treatment., Conclusions: Our results indicate that long-term treatment with RTX may favourably affect lung function and skin fibrosis in patients with SSc. Larger scale, multicentre, randomised, controlled studies are needed to further explore the efficacy of RTX in SSc.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Systemic sclerosis (SSc) is a systemic rheumatic disease with poor prognosis since therapeutic options are limited. Recent evidence from animal models suggests that B-cells may be actively involved in the fibrotic process. B-cells from tight skin mice, an animal model of scleroderma, display a "hyperresponsive" phenotype; treatment with rituximab (RTX) significantly attenuates skin fibrosis in this animal model. In humans, B-cell infiltration is a prominent finding in most lung biopsies obtained from patients with SSc-associated interstitial lung disease. Several open label studies have assessed the clinical efficacy of RTX in SSc. In most patients skin fibrosis improved; lung function either improved or remained stable. Definite conclusions regarding the clinical efficacy of RTX in SSc cannot be drawn but further exploration with a multicenter, randomized study is warranted.

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.

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., (© 2010 Elsevier Inc. All rights reserved.)

Objectives: To review current developments, regarding the pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus (SLE)., Methods: We searched Medline for articles written in the English language using the following terms: monocyte(s) or macrophage(s) and lupus. Although our search spanned the years 1971 to 2008, the majority of the short-listed articles belonged to the period 2000 to 2008. Published literature on phenotypic and functional properties of monocytes/macrophages (Mo/Mphi) in SLE was reviewed. References from identified articles were also selected. Currently available experimental data and their relevance to the pathogenesis of SLE are critically discussed., Results: It has traditionally been held that impaired phagocytosis by monocytes and macrophages in SLE allows for the accumulation of apoptotic debris leading to a sequel of autoimmune phenomena. Recent paradigms derived from animal models of systemic autoimmunity, however, has broadened our understanding regarding the possible pathophysiologic roles of Mo/Mphi in SLE. Data derived from studies in patients with SLE show multiple aberrations in activation status and secretory functions of circulating and tissue-infiltrating Mo/Mphi. Such aberrations may be associated with dysregulation of T-cell function and autoantibody production in SLE. Moreover, emerging evidence suggests that phagocytic capacity and antigen-presenting properties of Mo/Mphi are enhanced in some patients with SLE., Conclusions: While defective phagocytosis represents a distinctive feature of monocyte function in some patients with SLE, aberrant activation of the Mo/Mphi system may be a more appropriate concept to encompass the broad spectrum of Mo/Mphi disorders in SLE. Aberrant function of lupus Mo/Mphi appears to play a dynamic role in the initiation and perpetuation of the systemic autoimmune response and organ damage. Delineation of the altered biology of lupus Mo/Mphi could provide possible future therapeutic targets for patients with SLE., (Copyright 2010 Elsevier Inc. All rights reserved.)