Nonspecific Immunosuppression Research Articles

Myeloid-derived Suppressor Cells and Multiple Sclerosis.

Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that play important roles in maintaining immune homeostasis and regulating immune responses. MDSCs can be divided into two main subsets based on their surface markers and functional properties: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Recently greatest attention has been paid to innate immunity in Multiple Sclerosis (MS), so the aim of our review is to provide an overview of the main characteristics of MDSCs in MS and its preclinical model by discussing the most recent data available. The immunosuppressive functions of MDSCs can be dysregulated in MS, leading to an exacerbation of the autoimmune response and disease progression. Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach for autoimmune diseases, but the cellular mechanisms behind successful therapy remain poorly understood. Therefore, targeting MDSCs could be a promising therapeutic approach for MS. Various strategies for modulating MDSCs have been investigated, including the use of pharmacological agents, biological agents, and adoptive transfer of exogenous MDSCs. However, it remained unclear whether MDSCs display any therapeutic potential in MS and how this therapy could modulate different aspects of the disease. Collectively, all the described studies revealed a pivotal role for MDSCs in the regulation of MS.

γδ T cells in immune-mediated kidney disease.

Immune-mediated kidney diseases, including glomerulonephritis (GN), represent a diverse spectrum of disorders characterized by inflammation within the glomerulus and other renal compartments. Despite recent advances, the immunopathogenesis of these diseases remains incompletely understood. Current therapeutic approaches based on nonspecific immunosuppression often result in suboptimal outcomes and significant side effects, highlighting the need for tailored interventions. The complexity of the immune system extends beyond classical T-cell immunity, with the emergence of unconventional T cells - γδ T cells, NKT cells, and MAIT cells - that exhibit a semi-invariant nature and unique functions that bridge innate and adaptive immunity. γδ T cells exhibit unique homing and activation mechanisms and respond to different ligands, implying a multifaceted role in immune regulation. The understanding of γδ T-cell involvement in kidney disease lags behind conventional T-cell research. However, advances in immune cell analysis technologies offer promising avenues for elucidating their precise functions. This review synthesizes the current knowledge on γδ T cells in renal diseases, explores potential therapeutic strategies, and presents a roadmap for future research directions.

Multi-Biomarkers' Responses in Gills of Oreochromis niloticus Exposed to Glyphosate and Polyethylene Microplastic, Isolated and in Mixture.

Microplastics (MPs) and glyphosate-based herbicides (GBH) are among the most common contaminants in aquatic environments. In Brazilian rivers, both contaminants were found in elevated levels, leading to a high probability of their association, which can alter their individual effects and potentially intensify their toxicity. This study evaluated the isolated and combined effects of polyethylene microplastics (PE-MPs) and GBH on Oreochromis niloticus using multi-biomarkers of toxicity. The fish were subjected to a 96-h exposure period, with concentrations set based either isolated, PE-MPs group (5 mg L-1), GBH group (5 mg L-1), or in a group of associated contaminants (GAC), PE-MP + GBH (5 mg L-1 + 5 mg L-1). Toxicity effects were evaluated using biochemical, cytogenetic, hematological, and histopathological biomarkers. We observed change in erythrocyte parameters leading to macrocytic normochromic anemia in GAC. Leukocyte parameters indicate a nonspecific immunosuppression caused by the exposure of associated contaminants, besides the attempts to repair damage caused by PE-MPs. Histopathological markers indicate damage to tissues exposed to contaminants. Besides, there were morphophysiological adjustments on gills, with proliferation and hypertrophy of mitochondria-rich cells on GBH and GAC, besides epithelium ruptures, which were mostly present in the exposed groups. Therefore, this study indicates that PE-MPs and GBHs present toxic effects in O. niloticus with the used concentrations, intensified by the association of contaminants. Thus, multi-biomarkers were useful key to verify toxicity, providing data to the investigation of high levels of contaminant's mixture toxicity present in aquatic environments.

Comparative effectiveness of dimethyl fumarate versus non-specific immunosuppressants: Real-world evidence from MSBase.

The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.

Autoimmune diseases: targets, biology, and drug discovery.

Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing β cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens.

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

AbstractLupus nephritis (LN), an immune complex‐mediated glomerulonephritis, is one of the most severe complications of systemic lupus erythematosus. Current therapeutic regimens for LN mainly involve nonspecific immunosuppressants and biologics targeting immune cells, but these treatments are not always effective and some patients are nonresponsive and susceptible to recurrence. Podocytes are essential for maintaining the glomerular filtration barrier. Injury to and loss of podocytes lead to proteinuria, a hallmark of renal involvement and LN. Podocytes are, therefore, emerging as prospective therapeutic targets for LN. There are numerous mechanisms underlying podocyte malfunction in LN, with autophagy, mitochondrial dysregulation, and programmed cell death being the main processes behind podocyte loss. This review summarizes recent advances in understanding podocyte dysfunction in LN pathogenesis and discusses potential therapeutic interventions targeting podocytes in LN.

Chlorophyll a and novel synthetic derivatives alleviate atopic dermatitis by suppressing Th2 cell differentiation via IL-4 receptor modulation

Atopic dermatitis (AD) treatment has largely relied on non-specific broad immunosuppressants despite their long-term toxicities until the approval of dupilumab, which blocks IL-4 signaling to target Th2 cell responses. Here, we report the discovery of compound 4aa, a novel compound derived from the structure of chlorophyll a, and the efficacy of chlorophyll a to alleviate AD symptoms by oral administration in human AD patients. 4aa downregulated GATA3 and IL-4 in differentiating Th2 cells by potently blocking IL-4 receptor dimerization. In the murine model, oral administration of 4aa reduced the clinical severity of symptoms and scratching behavior by 76% and 72%, respectively. Notably, the elevated serum levels of Th2 cytokines reduced to levels similar to those in the normal group after oral administration of 4aa. Additionally, the toxicological studies showed favorable safety profiles and good tolerance. In conclusion, 4aa may be applied for novel therapeutic developments for patients with AD.

Circular RNA MAP2K2-modified immunosuppressive dendritic cells for preventing alloimmune rejection in organ transplantation.

Long-term patient and graft survival has been achieved in organ transplantation but at the expense of toxic side effects that are associated with long-term use of nonspecific immunosuppressive drugs. Discovering new regulators of dendritic cells is the key for development of an ideal treatment to prevent immune rejection. We hypothesized that knockdown of circMAP2K2 induces immunosuppressive DCs and that treatment with circMAP2K2 silenced-DCs can prevent alloimmune rejection. DCs were cultured and transfected with siRNA for circMAP2K2. circMAP2K2 levels were measured by qRT-PCR. DC's maturation and immune function were assessed by flow cytometry and mixed lymphocyte reactions. The function of circMAP2K2 was illustrated by a series of RIP and IP. The therapeutics of engineered DCs was tested in a mouse heart transplantation model. We found that circMAP2K2 was highly expressed in mature DCs. Knockdown of circMAP2K2 reduced expression of MHCII, CD40 and CD80, attenuated the ability of DCs to activate allogeneic naïve T cells, and enhanced CD4+CD25+FOXP3+ regulatory T cells (Treg). circMAP2K2-induced immunosuppressive DCs by interacting with SENP3. Treatment with circMAP2K2-knockdown DCs attenuated alloimmune rejection and prolonged allograft survival in a murine heart transplantation model. The immune suppression induced in vivo was donor-antigen specific. In conclusion, knockdown of circMAP2K2 can induce immunosuppressive DCs which are able to inhibit overactive immune response, highlighting a new promising therapeutic approach for immune disorder diseases.

Symposium 3

Systemic sclerosis (SSc) remains a refractory condition with poor functional and survival outcomes. This is attributable primarily to the extremely diverse clinical course and distribution of organ involvement. The pathogenesis of SSc includes microangiopathy and chronic inflammation, leading to accumulation of extracellular matrix and resultant irreversible fibrosis resulting in distortion of the normal tissue architecture. This pathogenic process is analogous to that observed in rheumatoid arthritis, in which persistent synovitis leads to articular cartilage and bone destruction, resulting in functional impairment due to joint deformity. Therefore, successful experiences in developing treatment strategies in patients with rheumatoid arthritis can also be applied to SSc. These include early diagnosis and intervention, treat-to-target strategy aiming at achievement of clinical remission or low-disease activity, prediction of disease progression and prognosis, and disease modification by pharmacologic treatment. Immunosuppressants targeting lymphocytes, including mycophenolate mofetil and cyclophosphamide, have been the mainstream of the treatment of SSc, based on treatment evidence showing prevention of decline in forced vital capacity, promotion of improving modified Rodnan skin thickness score, and improved patient-reported outcomes. However, survival benefit has not been shown in long-term follow-up of patients treated with non-specific immunosuppressants. Recently, drugs targeting a variety of molecules involved in the pathologic process of SSc, such as tocilizumab and nintedanib, have been shown to prevent progression of certain organ involvement in clinical trials, resulting in expanding treatment options. Implementation of those potential disease-modifying therapies in management of SSc requires adequate assessment of disease activity and treatment goal setting. In addition, clinical characteristics that predict the progression of organ manifestations, such as skin sclerosis and interstitial lung disease, need to be identified as prognosis factors. Like other rheumatic diseases, early interventions have been shown to be more effective than delayed intervention. This lecture features current standings and challenges of treat-to-target strategy in SSc patients.

Cell Communication‐Mediated Selective Drug Delivery for Epitope‐Specific Deletion of Alloreactive T Cells in Organ Transplant

AbstractAllogeneic grafts are vulnerable to the attack launched by host alloreactive T cells, which accounts primarily for allograft failure in the clinic. Conventional pharmacological intervention mainly involves broad‐acting, nonspecific immunosuppressants that provide limited protection over the graft and may cause deleterious side effects due to insufficient allospecificity. Here, core–shell structured nanoparticles co‐loaded with allogeneic antigen (Ag) and immunosuppressive agent Tacrolimus (Ag@FK506‐NPs) are constructed. Dendritic cells (DCs) pulsed with Ag@FK506‐NPs present alloantigenic epitopes on the cell surface as a bait to capture specific T cells, especially CD8+ T cells, for intercellular FK506 transfer and alloreactive T‐cell deletion. Meanwhile, DCs are maintained in an immature tolerogenic state that induces the functional inactivation of recruited T cells. Compared with free FK506, the adoptive transfer of low immunosuppressant dose (25 000‐fold lower) of Ag@FK506‐NPs pulsed DCs is enough to yield a superior antirejection effect in a major histocompatibility complex‐mismatched murine skin transplant model. Of note, due to the cell–cell communication conferred selective T‐cell suppression, the recipient mouse is able to respond to the subsequent stimulation of an irrelevant Ag, indicating that off‐target toxicity is bypassed. Overall, this work may address some of the limitations of current allograft therapeutics.

Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS.

Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

New Therapeutic Agents in Myasthenia Gravis

Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder characterized by fatigable muscle weakness. Mainstay therapies for MG include anticholinesterase inhibitor, thymectomy, corticosteroids, and non-specific immunotherapy, such as azathioprine, tacrolimus, mycophenolate mofetil, intravenous immunoglobulin, and plasma exchange. These therapeutic methods have significantly improved MG treatment in recent decades. However, there are still some patients with MG refractory to conventional treatments. In addition, long-term use of corticosteroids and non-specific immunosuppressants can lead to serious complications, including metabolic derangement, infections, malignancies, and systemic organ dysfunction. Recently, new therapeutic agents have been developed based on advancements in our understanding of the immunopathogenesis of MG. These agents are more specific and have a more rapid effect compared with conventional treatments. This article reviews novel therapeutic agents and their scientific basis.

Potential Use of Janus Kinase Inhibitors in the Treatment of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with unclear pathogenesis. One characteristic of SLE is pro-inflammatory and anti-inflammatory cytokine imbalance. Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase essential for many cytokine signaling pathways. Dysregulation of the JAK/signal transduction and transcriptional activator (STAT) pathway is an important process in SLE pathogenesis. Targeting JAK/STAT proteins can simultaneously block the functions of multiple cytokines. Current SLE treatment with non-specific corticosteroids and immunosuppressants can cause many adverse reactions. Therefore, treatments designed to control specific molecular targets for SLE are desirable. JAK inhibitors (JAKis) are a potential treatment for rheumatic diseases; however, the use of targeted signaling pathways to treat SLE remains a challenge, and its efficacy has not been determined. JAKis have shown positive results in reducing the use of glucocorticoids and/or non-specific immunosuppressants for SLE. JAKis are currently undergoing several clinical trials and expected to be the next stage in the treatment of SLE. Therefore, inhibition of the JAK/STAT pathway through JAKis may improve traditional treatment strategies for SLE.

Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.

Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects. To understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions. Pathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions. Our data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.

JAK inhibitors in dermatology

The four Janus Kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) factors mediate the intracellular signaling pathway of cytokine receptors, which are described in the pathogenesis of many autoimmune, allergic, and inflammatory dermatoses. The development of targeted small-molecule therapies like JAK inhibitors has enabled a paradigm shift in the treatment of various cutaneous disorders. JAK inhibitors are effective in the treatment of atopic dermatitis, vitiligo, alopecia areata, psoriasis, lupus erythematosus, dermatomyositis, mastocytosis, etc. Various blood parameters include complete blood count, liver, and renal function, the viral marker to be checked and tuberculosis to be ruled out before starting the therapy. There is a risk of acquiring serious infections such as upper respiratory tract infections, urinary tract infections, reactivation of latent tuberculosis, opportunistic infections, hepatitis B virus reactivation, and alteration of various blood parameters; so regular monitoring is required. The use of JAK inhibitors will open a new horizon by reducing the burden of systemic steroids and other non-specific immunosuppressants in the treatment of immune-mediated inflammatory dermatoses.

Progress and unmet needs in understanding fundamental mechanisms of autoimmunity

The rising incidence of autoimmune diseases is straining the healthcare system's capacity to care for patients with autoimmunity. To further compound this growing crisis, this rise occurs at a time when virulent infectious diseases exacerbate pre-existing conditions. Despite some novel targeted therapies introduced over the preceding decades, current treatment strategies must often fall back on non-specific immunosuppression, inflicting its own toll on patient morbidity. To improve patient care, we must re-double our efforts to understand and target the fundamental mechanisms of autoimmune disease initiation and progression. Technologic innovations have recently accelerated our ability to discover key components of the processes leading to loss of tolerance and propagation of self-tissue damage in autoimmune conditions. The special issue "Cellular and Molecular Mechanisms of Autoimmunity" highlights many of these findings through primary research and review articles which detail advances in genetics, molecular processes, cellular functions, and host-pathogen interactions. Discussion of topics ranging from non-coding RNA and the complement cascade to T-cell aging and the microbiome uncovers exciting avenues for basic and clinical investigation. Importantly, the issue seeks to focus attention on both established and emerging mechanisms of autoimmunity to ultimately help improve the specificity, safety, and efficacy of treatments for this group of challenging immune disorders.

Manufacturing and validation of Good Manufacturing Practice–compliant regulatory dendritic cells for infusion into organ transplant recipients

Background aimsRegulatory (or “tolerogenic”) dendritic cells (DCregs) are a highly promising, innovative cell therapy for the induction or restoration of antigen-specific tolerance in immune-mediated inflammatory disorders. These conditions include organ allograft rejection, graft-versus-host disease following bone marrow transplantation and various autoimmune disorders. DCregs generated for adoptive transfer have potential to reduce patients’ dependence on non-specific immunosuppressive drugs that can induce serious side effects and enhance the risk of infection and certain types of cancer. Here, our aim was to provide a detailed account of our experience manufacturing and validating comparatively large numbers of Good Manufacturing Practice–grade DCregs for systemic (intravenous) infusion into 28 organ (liver) transplant recipients and to discuss factors that influence the satisfaction of release criteria and attainment of target cell numbers. ResultsDCregs were generated in granulocyte-macrophage colony stimulating factor and interleukin (IL)-4 from elutriated monocyte fractions isolated from non-mobilized leukapheresis products of consenting healthy adult prospective liver transplant donors. Vitamin D3 was added on day 0 and 4 and IL-10 on day 4 during the 7-day culture period. Release and post-release criteria included cell viability, purity, phenotype, sterility and functional assessment. The overall conversion rate of monocytes to DCregs was 28 ± 8.2%, with 94 ± 5.1% product viability. The mean cell surface T-cell co-inhibitory to co-stimulatory molecule (programmed death ligand-1:CD86) mean fluorescence intensity ratio was 3.9 ± 2.2, and the mean ratio of anti-inflammatory:pro-inflammatory cytokine product (IL-10:IL-12p70) secreted upon CD40 ligation was 60 ± 63 (median = 40). The mean total number of DCregs generated from a single leukapheresis product (n = 25 donors) and from two leukapheresis products (n = 3 donors) was 489 ± 223 × 106 (n = 28). The mean total number of DCregs infused was 5.9 ± 2.8 × 106 per kg body weight. DCreg numbers within a target cell range of 2.5–10 × 106/kg were achieved for 25 of 27 (92.6%) of products generated. ConclusionsHigh-purity DCregs meeting a range of quality criteria were readily generated from circulating blood monocytes under Good Manufacturing Practice conditions to meet target cell numbers for infusion into prospective organ transplant recipients.

Adalimumab plus Conventional Therapy versus Conventional Therapy in Refractory Non-Infectious Scleritis.

Long-term systemic glucocorticoids and non-specific immunosuppressants remain the mainstay of treatment for refractory scleritis, and result in serious side-effects and repeated inflammation flares. To assess the efficacy and safety of additional adalimumab, patients diagnosed with refractory non-infectious scleritis were enrolled. They were assigned to the conventional-therapy (CT, using systemic glucocorticoids and other immunosuppressants) group or the adalimumab-plus-conventional-therapy (ACT) group according to the treatments they received. The primary outcome was time to achieve sustained remission, assessed by a reduction in modified McCluskey's scleritis scores. Other outcomes included changes in McCluskey's scores, scleritis flares, best-corrected visual acuity, and spared glucocorticoid dosage. Patients in the ACT group achieved faster remission than those in the CT group, as the median periods before remission were 4 months vs. 2.5 months (p = 0.016). Scleritis flares occurred in 11/11 eyes in the CT group and 5/12 eyes in the ACT group (p = 0.005). Successful glucocorticoid sparing was realized in both groups, but the ACT group made it faster. No severe adverse events were observed. Data suggest that adalimumab plus conventional therapy could shorten the time to remission, reduce disease flares, and accelerate glucocorticoid withdrawal compared with conventional therapy alone.

Renal manifestations in connective tissue diseases

Connective tissue diseases (CTD) comprise agroup of inflammatory systemic diseases that can affect various organs. Kidney involvement is frequently associated with significant irreversible damage and often before patients become symptomatic. Screening tests of blood and urine as well as clinical vigilance are therefore essential for all CTDs with possible renal involvement. Akidney biopsy is the gold standard for the diagnosis, prognosis and treatment decisions. Acommon and severe organ involvement in systemic lupus erythematosus (SLE) is glomerulonephritis (GN), also collectively referred to as lupus nephritis (LN). If left untreated LN often leads to end-stage renal failure. The treatment depends on the clinical parameters and histopathology of the renal involvement. Mycophenolate mofetil and cyclophosphamide are potent but nonspecific immunosuppressants which have been available for many years. Recently, new substances specific for LN have also been approved for the first time. Kidney involvement in Sjogren's syndrome has been far less studied. In studies the frequency of renal involvement is still unclear and ranges from 5% to 33%. Tubulointerstitial nephritis (IN) is the typical form of renal involvement which clearly differs from GN in its clinical presentation. Recommendations for treatment are based exclusively on retrospective studies. Arenal crisis in systemic scleroderma (SSc) is a rare but feared complication with ahigh mortality. An antiphospholipid syndrome (APS) nephropathy (APSN) can occur during CTD. These entities are vasculopathies and often thrombotic microangiopathies, which clearly differ from GN and IN in terms of pathophysiology, clinical features and treatment. This article provides an overview of the diversity of the most important renal manifestations of CTDs.