Inflammatory arthritis in the era of the biologics

Over the last decade there have been some profound changes in the way we treat inflammatory arthritis. In the late 1980's and early 1990's, a significant philosophy change that had been underway for at least a decade was formalized with the concept of “inverting the pyramid”, which was to treat patients early and aggressively to prevent joint damage. In the late 1990's the biologic agents became available and these played into this concept of early aggressive therapy with their ability to affect inflammation rapidly and prevent joint damage. Currently the use of the biologic agents is undergoing some “fine tuning” as we add their power to older disease modifying agents such as methotrexate. New biologic agents are on the horizon that will hopefully add to the ability to diminish the impact of inflammatory arthritis. Cost and unknown long-term side effects add caution to the use of these agents. Rheumatologists finally have therapies that we do not need statisticians to tell us that they work; our patients demonstrate their efficacy to us daily.     

Inflammatory diseases of the bones and joints

The inflammatory diseases of the bones and joints encompass infections and the consequences of immunologically mediated local and systemic disease. Infections involve bones (osteomyelitis) and joints (septic arthritis) separately as well as together and result in necrosis with inflammatory features determined by the duration of the infection. In many cases, the infecting organism, whether bacterial, fungal or mycobacterial, is present within the infected site, but occasionally is no longer identifiable locally despite the persistence of infection-related phenomena. Granulomatous infections in bones and joints require distinction from Sarcoidosis. The diagnosis of the immunologically mediated inflammatory diseases, such as RA, depends as much on the clinical features as on the histologic ones, with a few findings that might point to one or the other in ambiguous cases. Any discussion of inflammatory arthropathies should at least mention Osteoarthritis, if for no other reason than to compare it with the traditionally regarded inflammatory diseases. However, there has been increasing interest on the potential role that synovial inflammation may play in the pathogenesis of this vary common arthritis. Ultimately, the diagnosis of the inflammatory diseases of the bones and joints requires the synthesis of information from many sources: clinical, serological, microbiological, radiographic, and pathological.     

Biologic therapies and systemic bone loss in rheumatoid arthritis

Chronic inflammation affects bone metabolism leading to disequilibrium in the rates of bone resorption and repair and subsequently to local and generalized bone loss. Osteoporosis represents an important co-morbidity of rheumatoid arthritis (RA) patients, which exhibit increased fracture risk. Osteoclasts play a pivotal role in the development and progression of bone loss, while resident synovial cells such as T cells, monocytes and synovial fibroblasts have been identified as sources of osteoclast differentiation signals in RA. This process is mainly mediated through the receptor activator of nuclear-kappa B ligand (RANKL) signalling system, which is upregulated by numerous proinflammatory cytokines involved in the pathogenesis of RA. Improved knowledge of the association between cells and cytokines of the immune system and their relationship to bone remodeling has revealed several promising targets for the treatment of inflammatory bone loss in RA. In this respect, initiation of biologic therapies targeting inflammatory cytokines and/or lymphocyte activation has modified RA therapy not only by blocking local and systemic inflammatory cascades but also by providing beneficial effects against bone and joint degradation. In this article we briefly present the modern view of the mechanisms that govern inflammatory bone loss, highlighting the role of cytokine-induced molecular pathways, and discuss in detail the effects of different biologic treatment strategies on bone mass in RA patients.     

Immunotherapeutic Biologic Agents in Autoimmune and Autoinflammatory Diseases

In recent decades, innovative strategies to treat patients with inflammatory, immunologically based diseases have advanced in concert with our increased understanding of molecular immunology. Recognition of the spectrum and pathophysiology of autoimmune and autoinflammatory disorders has allowed for the development of cutting-edge therapies for such patients. In this review, key immunotherapeutic approaches for treating inflammatory autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as genetic autoinflammatory diseases, such as cryopyrin associated periodic syndromes, are addressed. Indications, risks and additional considerations in the use of these agents are reviewed.     

Intestinal microsporidiosis: a hidden risk in rheumatic disease patients undergoing anti-tumor necrosis factor therapy combined with disease-modifying anti-rheumatic drugs?

OBJECTIVE:

Immunosuppressed patients are at risk of microsporidiosis, and this parasitosis has an increased rate of dissemination in this population. Our objective was to evaluate the presence of microsporidiosis and other intestinal parasites in rheumatic disease patients undergoing anti-tumor necrosis factor/disease-modifying anti-rheumatic drug treatment.

METHODS:

Ninety-eight patients (47 with rheumatoid arthritis, 31 with ankylosing spondylitis and 11 with psoriatic arthritis) and 92 healthy control patients were enrolled in the study. Three stool samples and cultures were collected from each subject.

RESULTS:

The frequency of microsporidia was significantly higher in rheumatic disease patients than in control subjects (36 vs. 4%, respectively; p<0.0001), as well as in those with rheumatic diseases (32 vs. 4%, respectively; p<0.0001), ankylosing spondylitis (45 vs. 4%, respectively; p<0.0001) and psoriatic arthritis (40 vs. 4%, respectively; p<0.0001), despite a similar social-economic class distribution in both the patient and control groups (p = 0.1153). Of note, concomitant fecal leukocytes were observed in the majority of the microsporidia-positive patients (79.5%). Approximately 80% of the patients had gastrointestinal symptoms, such as diarrhea (26%), abdominal pain (31%) and weight loss (5%), although the frequencies of these symptoms were comparable in patients with and without this infection (p>0.05). Rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis disease activity parameters were comparable in both groups (p>0.05). The duration of anti-tumor necrosis factor/disease-modifying anti-rheumatic drugs and glucocorticoid use were also similar in both groups.

CONCLUSION:

We have documented that microsporidiosis with intestinal mucosa disruption is frequent in patients undergoing concomitant anti-tumor necrosis factor/disease-modifying anti-rheumatic drug therapy. Impaired host defenses due to the combination of the underlying disease and the immunosuppressive therapy is the most likely explanation for this finding, and this increased susceptibility reinforces the need for the investigation of microsporidia and implementation of treatment strategies in this population.     

双侧人工全膝关节同时置换47例临床报道

目的:探讨双侧人工全膝关节同时置换治疗严重双侧膝关节病的手术操作技巧.方法:采用双侧人工全膝关节置换术治疗严重双膝关节病患者47例94膝,其中类风湿性关节炎28例,骨性关节炎16例,强直性脊柱炎3例.结果:所有病例随访2～24 个月,平均10个月.手术前膝关节KSS评分平均38分,出院前膝关节KSS评分平均78分,随访平均评分88分.感染病例为零.结论:应用双侧人工全膝关节同时置换治疗功能严重受损的双侧膝关节效果显著.     

B-Cell Depletion and Repopulation in Autoimmune Diseases

Although T-lymphocytes have long been regarded as the prime effector of autoimmune diseases, numerous studies have since highlighted a key role for B-lymphocytes. For example, disturbances in the distribution of circulating B-cell subsets were reported in primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE). Consequently, this was the rationale to treat such patients for B-cell depletion with anti-CD20 monoclonal antibody (rituximab). The aim of this review is to describe and analyze the B-cell subset distribution at baseline and after rituximab therapy in patients with SLE, rheumatoid arthritis, and pSS. Finally, we will compare factors that may interfere with anti-CD20-mediated B-cell depletion in these autoimmune diseases.     

Risk of Pregnancy Complications and Low Birth Weight Offsprings in Korean Women With Rheumatic Diseases: A Nationwide Population-Based Study

BackgroundTo determine the risk of pregnancy complications and adverse offspring outcomes in Korean women with rheumatic diseases (RDs).MethodsWomen aged 20–44 years with pregnancies ending in delivery were identified from the National Health Insurance Service-National Health Information Database (2009–2016). Women with RD including systemic lupus erythematosus (SLE), seropositive rheumatoid arthritis (SPRA), and ankylosing spondylitis (AS) (n = 4,284) were age-matched with controls (n = 26,023). Outcome variables included threatened abortion (TA), preterm birth (PB), preeclampsia/eclampsia (PE/E), intrauterine growth retardation (IGR), urinary tract infection, low birth weight (LBW) offsprings, and offspring death within 1 year of birth.ResultsWomen with RDs had increased risks for cesarean section delivery (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.4–1.6), TA (OR, 1.4; 95% CI, 1.2–1.5), PB (OR, 2.4; 95% CI, 1.9–3.2), PE/E (OR, 4.4; 95% CI, 3.3–5.9), and IGR (OR, 2.4; 95% CI, 2.0–3.1) than the controls. The risk of pregnancy complications was increased in SLE and SPRA pregnancies but not in AS pregnancies. Offsprings of women with RDs had an increased risk of LBW (OR, 4.0; 95% CI, 3.2–4.9). The offspring mortality rate within 1 year of birth was higher in women with RDs (6.2/10,000 persons) than in the controls (4.9/10,000 persons).ConclusionWomen with RDs are at a risk of developing pregnancy complications, and the risk of LBW offsprings and offspring death within 1 year of birth is increased in these women. Therefore, this population requires special attention during their childbearing years.     

Autoimmune diseases and reproductive aging

As the population ages, more individuals with autoimmune diseases are experiencing reproductive senescence. Understanding the impact of menopause and age-related androgen decline on disease onset and course, as well as the potential for hormonal interventions, is critically important. In men, lupus erythematosis (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) are associated with lower androgen levels. However, the impact of age-related declines in testosterone, as well as of testosterone replacement, on disease course remains underexplored. In women, the course of all three diseases with onset after the age of menopause differs from that with onset before menopause. Early age at menopause is associated with increased disease risk, and after menopause, disease course changes in SLE and RA. Less is known about MS. This article summarizes what is known about the relationship between reproductive aging and autoimmune diseases in men and women, and highlights areas for further investigation.     

FcγRⅡb基因多态性与常见风湿病发病相关性研究进展

FcγRⅡb属FcγR中的抑制性受体,编码基因位于染色体1 q23.多项研究认为其基因多态性与系统性红斑狼疮(systemic lupus erythematosus,SLE),类风湿关节炎(rheumatoid arthritis,RA),强直性脊柱炎(ankylosing spondylitis,AS)等风湿免疫病相关.而在不同种族的人群中研究结果不同,但仍可以认为,FcγRⅡb基因多态性在某些人群的常见风湿免疫病发病过程中起重要作用.

Abstract：

IgG Fc receptor Ⅱ b ( FcγR Ⅱ b ) is an inhibitory Fc receptor expressed on B cells and myeloid cells, and its coding gene is located on Chromsome 1 q23. These receptors are very important for the regulation of body' s responses to infection. The reduced expression of function of these receptors may predispose to autoimmunity. The FcγR Ⅱ b gene polymorphisms affect the affinity with which FcRs interact with immunoglobulin molecules. Correlation of the FcγR Ⅱ b polymorphisma with susceptibility of common rheumatic diseases, such as Systemic Lupus Erythematosus ( SLE ) , Rheumatoid Arthritis ( RA ) ,Ankylosing Spondylitis (AS) , has been reported in various populations, but the results were inconsistent.     

Vaccinations and Autoimmune Diseases

Vaccine administration is a very effective tool to prevent infectious diseases, but its powerful stimulus on the immune system has generated the fear of exacerbating previously diagnosed autoimmune diseases. Such a fear is also a consequence of the generally anecdotal observation of post-vaccine autoimmune reactions in few previously healthy susceptible individuals. However, patients with autoimmune diseases have an approximately double risk than the general population of developing infections. Thus, the matter has been analyzed from a double point of view, the possible induction of autoimmunity by vaccinations in healthy people and the vaccination safety and immunogenicity in patients with autoimmune diseases.     

Histidine-Rich Glycoprotein Modulation of Immune/Autoimmune, Vascular, and Coagulation Systems

Histidine-rich glycoprotein (HRG) is plasma glycoprotein that has a multidomain structure, interacts with many ligands, and exhibit many modulatory functions in diverse biological systems. HRG ligands include Zn2+, tropomyosin, heparin and heparan sulphate, plasminogen, plasmin, fibrinogen, thrombospondin, IgG, FcgR, and complement. In many cases, the histidine-rich region of the molecule enhances ligand binding after interaction with Zn2+ or exposure to low pH, conditions associated with sites of tissue injury or tumor growth. The multidomain nature of HRG and diverse ligand binding properties indicates that it can act as an extracellular adaptor protein, bridging together different ligands mainly on cell surfaces. Apart from cell surface molecules, HRG can differentially target IgG, preventing generation of insoluble immune complexes. HRG binds to most cells primarily via heparan sulphate proteoglycans. HRG can enhance clearance of apoptotic and necrotic phagocytes as well as immune complexes. The anti-angiogenic properties of HRG are well established in vitro and in vivo. HRG can modulate other physiological processes such as cell adhesion and migration, fibrinolysis and coagulation, complement activation. This review presents an update on the molecular, structural, biological, and clinical properties of HRG and associated autoimmunity conditions.     

Homocysteine modification of HLA antigens and its immunological consequences

Homocysteine-treated cells can be specifically lysed by cytotoxic T lymphocytes (CTL) identifiable in patients with ankylosing spondylitis and reactive arthritis. Sensitization of target cells involves disulfide bonding and the interaction between homocysteine and HLA antigens occurs in a pre-Golgi compartment in the cells. Salmonella-infected B cells are also lysed by homocysteine-specific CTL, suggesting that intracellular invading microorganisms may provide homocysteine which would gain access to the newly synthesized intracellular HLA molecules and modify them inside the cells. Two different mechanisms for homocysteine modification of HLA antigens are proposed: homocysteine could bind directly to the unpaired cysteine residues in HLA antigens, or it could bind indirectly to HLA antigens through cysteine-containing peptides bound to them. Thus, HLA antigens containing unpaired cysteine residues (e.g. HLA B27) could be modified by homocysteine directly or indirectly, while HLA antigens without unpaired cysteine residues (e.g. HLA A68) could only be modified indirectly. The results are discussed in relation to the potential involvement of homocysteine-specific CTL in ankylosing spondylitis and reactive arthritis, both of which are related to bacterial infections, associated with HLA B27, and considered to be autoimmune diseases.     

Peptide-Based Molecular Analyses of HLA class II-Associated Susceptibility to Autoimmune Diseases

Recent advances in knowledge of crystal structures of MHC class II molecules has advanced understanding of the molecular basis for interactions between peptides and HLA class II molecules. Polymorphism of HLA class II molecules influences structures of peptides bound to HLA class II molecules. To better understand mechanisms related to particular HLA class II alleles and autoimmune diseases, it is important to identify self-peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative autoreactive T cells. Autoimmune diseases occur in Caucasians, Blacks and Asians, albeit with a different incidence. In some autoimmune diseases, disease-susceptible HLA class II alleles are closely related but different, and clinical manifestations of diseases differ among ethnic groups. These phenomena strongly suggest that difference in autoimmune self-peptide(s) in the context of disease-susceptible HLA class II molecules may explain the different clinical manifestations of diseases. Therefore, a comparison among disease-susceptible HLA class II alleles, autoimmune self-peptides and clinical manifestations of autoimmune diseases in different ethnic groups would be instructive. We directed efforts to determining: (1) HLA-class II alleles specific to Asian populations and which are associated with susceptibility to autoimmune diseases, (2) binding-peptide motifs for these HLA class II molecules, and (3) self-peptides presented by susceptible HLA class II molecules to stimulate autoreactive T cells related to the development of autoimmune diseases in Asians. In this review, our related recent investigations are described and the uniqueness of HLA class II-associated autoimmune diseases in Asians is given emphasis.     

Matrix Metalloproteinase-9 and Autoimmune Diseases

Matrix metalloproteinases (also named matrixin or MMPs) are a major group of enzymes that regulate cell-matrix composition by using zinc for their proteolytic activities. They are essential for various normal biological processes such as embryonic development, morphogenesis, reproduction tissue resorption, and remodeling. Metalloproteinases also play a role in pathological processes including inflammation, arthritis, cardiovascular diseases, pulmonary diseases and cancer. Herein we review the involvement of MMP-9 in a variety of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis, multiple sclerosis, polymyositis and atherosclerosis. MMP-9 plays either a primary or secondary role in each one of those autoimmune diseases by its up or down-regulation. It is not expressed constantly but rather is induced or suppressed by many regulating molecules. This feature of MMP-9 along with its involvement in disease pathogenesis turns it into a target for therapy of autoimmune diseases.     

Mechanisms and Efficacy of Immunobiologic Therapies for Inflammatory Bowel Diseases

Current advances in understanding of the pathogenesis of inflammatory bowel disease have encouraged the development of many new therapies targeted at specific and non-specific mediators of the inflammatory bowel disease inflammatory pathway. Crohn's disease and ulcerative colitis, two common inflammatory bowel diseases likely result from interaction of multiple genetic and environmental risk and protective factors, deregulation of mucosal immunity in gut and breakdown of delicate balance of proinflammatory and anti-inflammatory cytokines. Immunobiologic agents targeted against TNF, leukocyte adhesion, Th1 polarization, T cell activation, nuclear factor-kappaB (NF-κB), and others are being assessed and will open exciting perspectives on development of therapies for inflammatory bowel disease.     

The management of first-line biologic therapy failures in rheumatoid arthritis: Current practice and future perspectives

The introduction of biologic disease–modifying anti-rheumatic drugs (bDMARDs) has dramatically changed the management of rheumatoid arthritis (RA). However, in a real-life setting about 30–40% of bDMARD treated patients experience drug discontinuation because of either inefficacy or adverse events. According to international recommendations, to date the best strategy for managing first-line bDMARD failures has not been defined yet and available data (especially on TNF inhibitors [TNFis]) seem to drive toward a personalized approach for the individual patient. Some TNFi partial responders may benefit from optimization of concomitant methotrexate therapy or from switching to a different concomitant sDMARD such as leflunomide. Conversely, apart from infliximab, TNFi dose escalation seems to be poor efficacious and poor cost-effective compared with alternative strategies. Albeit counterintuitive, the use of a second TNFi after the failure of the first-one (cycling strategy) is supported by clear evidences and has become widespread in the 2000s as the result of the limited alternative options till the introduction of bDMARDs with a mechanism of action other than TNF blockade. Nowadays, the use of abatacept, rituximab, tocilizumab, or JAK inhibitors as second-line agent (swapping strategy) is strongly supported by RCTs and real-life experiences. In the absence of head-to-head trials directly comparing these two strategies, meta-analyses of separated RCTs failed to find significant differences in favor of one or another choice. However, results from most observational studies, including well designed prospective pragmatic randomised analyses, demonstrated the superiority of swapping over cycling approach, whereas only few studies reported a comparable effectiveness. In this review, we aimed to critically analyze all the potential therapeutic options for the treatment of first-line bDMARD failures in order to provide a comprehensive overview of available strategies to be applied in clinical practice.