Immunogenicity of biologic therapies: causes and consequences

Introduction: Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional therapies, and subsequently revolutionized the management of numerous chronic diseases. Repetitive administration of these protein-based therapeutics to immunocompetent patients elicit immune responses in the form of Anti Drug Antibodies (ADAs), which in turn impact their pharmacological properties and may trigger adverse events.

Areas covered: Structural characteristics determining the immunogenicity of biologics are reviewed along with strategies to minimize it. Next, the different types of treatment-emerging ADAs, their potential clinical implications, and assays to detect them are addressed. Emphasis is put on the review of data on the immunogenicity of different types of biologics across numerous indications. Finally, practical considerations are discussed on how to manage patients with issues around the immunogenicity of their biologic treatment.

Expert commentary: Immunogenicity is a clinically relevant criterion when selecting a biologic. Besides intrinsic properties of the agent (namely its structure), its respective mode of action, dosing regimen, comedication, and the indication treated must be considered. ADA detection assays need to be standardized to improve comparability of available data and to allow clinical decision-making.     

Use of synthetic and biologic DMARDs during pregnancy

Introduction: Since most of the autoimmune diseases (AID) affect mostly women in their fertile years, and fertility is in general preserved, the use of disease-modifying antirheumatic drugs (DMARDs) during conception, pregnancy, and lactation has been a matter of concern in the treatment of women affected by AID.

Areas covered: We performed a comprehensive review of the latest and most relevant research papers published in the field and discussed different aspects related to the use of synthetic and biologic DMARDs and immunosuppressants in the preconceptional period, during pregnancy and lactation in AID patients, both in males and females.

Expert commentary: Active AID impose an increased risk for adverse maternal and fetal outcomes, such as preeclampsia, miscarriage, intrauterine growth restriction, prematurity, low birth weight, and stillbirth. Family planning with proper contraception and shared decision-making on the ideal time to conceive with treatment adjustment must be a rule. One of the main challenges when counseling and/or adjusting treatment of patients that are planning a pregnancy is to provide a medication that is at the same time efficacious and safe at the conceptional period and to developing the fetus.     

Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases

ABSTRACT

Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics.

Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab.

Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.     

The effect of antidrug antibodies on the sustainable efficacy of biologic therapies in rheumatoid arthritis: practical consequences

Biologic therapies, predominantly TNF-α inhibitors, have revolutionized the treatment of rheumatoid arthritis (RA). However, their clinical utility can be limited by the development of antidrug antibodies (ADAs). Immunogenicity is a complex phenomenon related to various drug, disease, and patient characteristics, and may be more common with the monoclonal antibodies than with etanercept, a soluble TNF receptor-Fc immunoglobulin fusion protein. Neutralizing antibodies – those that hinder bioactivity by preventing drug molecules from binding to TNF – are correlated with reduced serum drug concentrations, loss of therapeutic response, adverse events, and treatment discontinuation. Cost-effective use of these agents will depend on further research into drug and ADA assays, and how they should guide dose reduction or switching strategies.     

Unmet needs in the management of cardiovascular risk in inflammatory joint diseases

ABSTRACT

Introduction: Increased cardiovascular (CV) morbidity and mortality is observed in inflammatory joint diseases (IJDs) such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the management of CV disease in these conditions is far from being well established.

Areas covered: This review summarizes the main epidemiologic, pathophysiological, and clinical risk factors of CV disease associated with IJDs. Less common aspects on early diagnosis and risk stratification of the CV disease in these conditions are also discussed. In Europe, the most commonly used risk algorithm in patients with IJDs is the modified SCORE index based on the revised recommendations proposed by the EULAR task force in 2017.

Expert opinion: Early identification of IJD patients at high risk of CV disease is essential. It should include the use of complementary noninvasive imaging techniques. A multidisciplinary approach aimed to improve heart-healthy habits, including strict control of classic CV risk factors is crucial. Adequate management of the underlying IJD is also of main importance since the reduction of disease activity decreases the risk of CV events. Non-steroidal anti-inflammatory drugs may have a lesser harmful effect in IJD than in the general population, due to their anti-inflammatory effects along with other potential beneficial effects.     

Relationship between histological findings and clinical findings in rheumatoid arthritis

The aim of the present study was to compare histological findings and clinical symptoms of patients with advanced stages of rheumatoid arthritis (RA). Synovial tissue specimens were obtained during reconstructive knee surgery from 93 RA patients (18 men; 75 women). The histological assessments of specimens were evaluated using two histological scoring systems reported by Rooney and Koizumi. Clinical symptoms (duration of morning stiffness, joint score, grip strength), laboratory data (erythrocyte sedimentation ratio, C-reactive protein (CRP), rheumatoid factor), X-ray findings (Larsen score) and drug usage were assessed before surgery. Significant statistical correlations between both histological scoring systems were observed; however, there was no significant correlation between the clinical findings and the histological scoring systems. A statistically significant correlation was found between the levels of CRP and Koizumi's scoring system. In addition, Koizumi score correlated significantly to X-ray findings. Rooney's scoring system had an inverse correlation to methotrexate history. Histological findings do not correlate to simultaneous clinical symptoms in advanced RA patients. However, our data indicate that observed histological changes reflect X-ray damage.     

Treatment of rheumatoid arthritis during pregnancy: present and future

Introduction: For the management of rheumatoid arthritis patients who plan to become pregnant, both disease activity and therapeutic regimens have to be taken into consideration. In the case of stable inactive disease, pregnancy can be planned and therapy can be adjusted with drugs compatible with pregnancy.

Areas covered: Drugs to be discontinued before pregnancy are methotrexate, leflunomide, tocilizumab, rituximab, abatacept and tofacitinib. Pregnancy compatible disease modifying drugs are antimalarial drugs and sulfasalazine. TNF-inhibitors can be continued during the first half of pregnancy, yet if indicated during the third trimester TNF-inhibitors with a low rate of transplacental passage should be used. Glucocorticoids may be considered at the lowest effective dose throughout pregnancy. Non-selective COX-inhibitors can be continued until gestational week 32.

Expert commentary: Together, a tailored treatment throughout pregnancy is possible with reasonable safety. Controlling disease activity during pregnancy is important for both, maternal and fetal health.     

Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic

Background/aim To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.Materials and methods A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).Results A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients. Conclusion Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.     

Rheumatoid factor is a marker of disease severity in Korean rheumatoid arthritis

Serum rheumatoid factor (RF) is important in the diagnosis and prognosis of rheumatoid arthritis (RA). The purpose of this study is to compare the clinical characteristics and treatment patterns of RA according to the presence of RF in Korean patients. A retrospective analysis was performed on the records of 109 patients who were followed for at least 2 years, among 230 RA patients who visited at the rheumatology clinic in Ajou University Hospital and who fulfilled the 1987 revised American College of Rheumatology criteria for RA. Sixty-four patients were RF positive (58.7%) and 91 patients were female (83.5%). There was no significant difference in demographic characteristics, joint involvements, or percentage of morning stiffness between seropositive and seronegative groups. Antinuclear antibody was detected more frequently in the seropositive group (p < 0.05). At initial diagnosis, the seropositive group had higher white blood cell and platelet counts than the seronegative group (p < 0.01). However, the difference was disappeared at the last follow-up. Inflammatory markers such as ESR and CRP were also higher at diagnosis in the seropositive group (p < 0.01). These inflammatory markers were still greater than the seronegative group at the last follow-up (p < 0.01). There was no significant difference in the use of disease modifying antirheumatic drug (DMARD) and steroid dosage between groups. However, DMARD combination therapy was more commonly used in the seropositive group (p < 0.05), especially triple DMARD combination. These results suggest that disease activity is more severe in the seropositive than the seronegative group, and more aggressive treatments are needed in the seropositive group.     

Prediction of response to methotrexate in rheumatoid arthritis

Introduction: Methotrexate (MTX) is the first-line disease-modifying drug of choice in controlling active inflammation of the synovium that characterises rheumatoid arthritis, a chronic autoimmune inflammatory condition. However, many patients do not respond to treatment with MTX or cannot tolerate the medication. Pre-treatment characteristics that predict response to MTX are, therefore, of particular interest and potential clinical utility.

Areas covered: This narrative review seeks to cover various genotypic and phenotypic characteristics that have been investigated as predictors of treatment response to MTX in RA. Ovid Medline searches (1946 to January 2018) were carried out for ‘methotrexate’ and ‘rheumatoid arthritis’, in combination with relevant terms. All papers identified were English language, with abstracts. Relevant references were also reviewed.

Expert commentary: Despite the introduction of biologic medication and targeted therapies, MTX is likely to remain the mainstay of RA treatment, largely due to its much cheaper cost. Development of a multifactorial predictive algorithm for response to MTX may be of clinical utility, as well as routine MTX drug level testing to improve medication adherence and persistence.     

B-cell targeted therapies in human autoimmune diseases: an updated perspective

Summary: The advent of therapies that specifically target the B-lymphocyte lineage in human disease has rejuvenated interest in the mechanistic biology by which B cells mediate autoimmunity. B cells have a multitude of effector functions including production of self-reactive antibodies, ability to present antigen to T lymphocytes in the context of costimulation, involvement in generation and maintenance of neo-organogenesis at sites of disease, and opposing function through production of both immunostimulatory and immunomodulatory cytokines. In this review, we first discuss the role of B cells in driving autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and Sjögren’s syndrome, and discuss how studies in these diseases have revealed differentially important roles for the multiple B-cell effector functions. These data reveal the complex and interrelated roles of B cells working in concert with other components of the innate and adaptive immune system to drive pathogenesis. We then focus on data from mouse and human in which B cells in the setting of disease have been targeted with drugs directed against CD20, CD22, and the BAFF (B-cell activating factor belonging to the tumor necrosis factor family)/APRIL (a proliferation inducing ligand) pathways. Pre-clinical studies in animal models in addition to and clinical trials targeting B cells have added further to the understanding of the differential roles B cells play in disease both through demonstration of clinical efficacy in the context of B-cell depletion or modulation, and also by failure of B-cell targeting in some diseases and disease patient subgroups. Moving forward, it will be imperative to apply these lessons to new interventional trials to ensure better targeting of the B-cell lineage and concomitantly better selection of patients most likely to benefit from these therapies.     

Use of immunomodulators and biologic therapies in children with inflammatory bowel disease

The immunomodulators (6-mercaptopurine, azathioprine and methotrexate) and biologics (infliximab, adalimumab, certolizumab and natalizumab) are medications essential in the management of pediatric inflammatory bowel disease. If properly utilized, these medications can control active disease, reduce corticosteroid exposure, induce remission, and promote normal growth and development. However, these medications also have significant toxicity and increase the risk of infections and lymphoma. This article provides information about the safety and efficacy of these medications in the treatment of children with Crohn’s disease and ulcerative colitis.     

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.     

Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics

Summary: Advances in cDNA and monoclonal antibody technology in the 1980s fuelled the discovery and characterization of the properties of cytokines. It became apparent that because cytokines were expressed in tissues derived from autoimmune diseases, they were likely to be of fundamental importance in disease pathogenesis and developing a new class of biological therapeutics. In this review, we describe the history of bench to bedside translation of work that led to the identification of tumor necrosis factor (TNF) as a key regulator of the loss of homeostatic immune-inflammatory responses in rheumatoid arthritis (RA) and a good therapeutic target. First in human clinical trials in collaboration with a biotechnology company, the safety and efficacy of TNF blockade with a chimeric monoclonal antibody was substantiated in patients refractory to standard anti-rheumatoid drugs. Abnormal immune-inflammatory responses after therapy showed improvement and remain a focus of ongoing research in many laboratories. Longer term multi-center studies that followed with several anti-TNF biologicals have demonstrated the augmented efficacy, including inducing clinical remission, of low dose methotrexate and anti-TNF therapy co-therapy, but serious infections and lymphomas in a low frequency have been observed. In the course of the past decades, three 'blockbuster' anti-TNF biologicals are in the clinic. Over a million patients with RA and other immune-mediated diseases have been successfully treated, and a better perspective on the risk of harm and its management has become part of good clinical practice. This success has encouraged a burgeoning industry of biologicals for chronic diseases.     

The role of imaging in early diagnosis and prevention of joint damage in inflammatory arthritis

Introduction: Inflammatory arthritis is characterized by chronic inflammation in the synovium, associated with degradation of cartilage and erosion of juxta-articular bone. The bone loss and joint destruction mediated by aberrant immunological responses resulting in proin?ammatory cytokine release and various immune cell activation are known as osteoimmunology.

Areas covered: A structured literature search including Medline and PubMed, Cochrane meta-analyses and abstracts of international congresses was performed to review joint damage in inflammatory arthritis in terms of pathogenesis, novel imaging assessment, and prevention.

Expert commentary: Deeper understanding of the integration of the skeletal and immune as well as inflammatory system is paving the way to prevent bone loss and bone destruction in inflammatory arthritis. With the availability of various imaging modalities such as ultrasound, magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT), we are now able to detect early joint damage, early diagnosis of inflammatory arthritis, monitor the progression or even ascertain whether the inflammatory process is effectively suppressed to allow repair of joint damage by novel therapeutic agents.     

Anti‐tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis

We investigated changes in circulating T helper type 17 (Th17) cells following anti‐tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)‐17 enzyme‐linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL‐17‐producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4⁺IL‐17⁺ cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti‐TNF treatment increases circulating Th17 cells in three different diseases.     

Reactivation of latent tuberculosis with TNF inhibitors: critical role of the beta 2 chain of the IL-12 receptor

Tumor necrosis factor (TNF) inhibitors have improved a lot the treatment of numerous diseases, with the well-known example of rheumatoid arthritis (RA). In the early 2000s, postmarketing data quickly revealed an alarming number of severe tuberculosis (TB) under such treatment. These findings were consistent with previous results in mice where TNF is essential for lymph node formation and granuloma organization. The effects of TNF inhibition on RA synovium structure are very similar to those on granuloma, with changes in cellular interactions, cytokine, and chemokine production. In addition to the role of TNF in granuloma, the interleukin (IL)-12/interferon (IFN)-γ pathway is required for an efficient host defense against TB. Primary and secondary immunodeficiencies affecting this pathway lead to severe bacillus Calmette-Guérin (BCG) reaction or full TB. Any chronic inflammation as in RA induces a systemic Th1 defect that predisposes to TB through specific downregulation of the IL-12Rß2 chain. When TNF inhibitors are initiated, this transiently increases this risk of TB, through effects on cellular interactions in a latent TB granuloma. At a later stage, when a better control disease activity is obtained, the risk of TB is reduced but not abrogated. Given the clear benefit from TNF inhibition, latent TB infection screening at baseline is essential for an optimal safety.     

Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11

Summary: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joint synovium. The normal synovium consists of a lining layer of fibroblast-like synoviocytes (FLS) and macrophages, one to three cells deep that overlies the loose connective tissue of the synovial sublining. During the course of RA, the synovium is the site of inflammation where immune cells are massively infiltrated, and the lining layer becomes hyperplastic and transforms into a pannus tissue that destroys articular cartilage and bone. FLS play an important role in this RA pathogenesis. In this review, we explain that cadherin-11, an adhesion molecule, is selectively expressed on FLS and required for synovial lining formation. In addition, cadherin-11 on FLS contributes to synovial inflammation and mediates cartilage degradation in a mouse model of inflammatory arthritis. Therefore, we suggest that FLS are critical regulators of synovial inflammation and arthritis pathology via mechanisms that are mediated by cadherin-11.     

Tocilizumab: molecular intervention therapy in children with systemic juvenile idiopathic arthritis

Systemic juvenile idiopathic arthritis (JIA) is a subtype of chronic childhood arthritis of unknown etiology, manifested by long-lasting systemic inflammation and complicated by joint destruction, functional disability and growth impairment. Macrophage activation syndrome is the most devastating complication, which is associated with serious morbidity. IL-6 has been hypothesized to be a pathogenic factor of this disease. The anti-IL-6 receptor monoclonal antibody, tocilizumab, was developed, and we investigated the safety and efficacy of tocilizumab in children with this disorder. The Phase II trial revealed that high-grade fever abruptly subsided and that inflammatory markers were also normalized. The dose of tocilizumab for systemic JIA was revealed to be 8 mg/kg at 2-week intervals. The Phase III trial, a placebo-controlled, double-blind study, indicated that patients in the tocilizumab group had sustained clinical measures of effectiveness and wellbeing, whereas most of those in the placebo group needed rescue treatment. The most common adverse events were symptoms of mild infections and transient increases of alanine aminotransferase. Serious adverse events were anaphylactoid reaction and gastrointestinal hemorrhage. Clinical and laboratory improvement in fever, sickness behavior, C-reactive protein gene expression and chronic inflammatory anemia in children with systemic JIA treated with tocilizumab indicated the possible roles played by IL-6 in this inflammatory disease. Thus, tocilizumab is generally safe and well tolerated. It might be a suitable treatment in the control of this disorder, which has so far been difficult to manage.     

Expression and functions of very late antigen 1 in inflammatory joint diseases

In the human immune system, very late antigen 1 (VLA-1), a putative collagen receptor, is expressed on the surface of T lymphocytes that have undergone mitogenic or antigenic stimulation. A new VLA-1-specific monoclonal antibody, 1B3.1, was used to probe the expression and function of VLA-1 on T lymphocytes in patients with arthritis. Synovial mononuclear cells from the joints of patients with rheumatoid arthritis or other joint diseases contained 32.9±13.8% 1B3.1-positive cells (42.8±10.4% in patients with rheumatoid arthritis and 28 ± 12.6% in non rheumatoid patients). In the peripheral blood, patients with active rheumatoid arthritis expressed VLA-1 on 11.7±6.0% of their mononuclear cells, compared to 1.9±1.5% in controls (P<0.001). Using dual fluorescence analysis, virtually all the 1B3.1-positive synovial cells were CD3+ T lymphocytes and included both CD4+ and CD8+ T cells. When 1B3.1-expressing synovial mononuclear cells orin vitro activated T lymphocytes were triggered with anti-CD3 antibodies, marked augmentation of their proliferation occurred if they were simultaneously cross-linked with mab 1B3.1. Collagen type IV, a putative ligand of VLA-1, also augmented T-cell proliferation to anti-CD3. The data suggest that the VLA-1 molecule could play an important role in the pathophysiology of arthritis by modulating T-cell activation in these diseases.