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Dakkak, Y.J. 2020

The forefoot in early rheumatoid arthritis: Anatomy, imaging and clinical aspects

Doctoral Thesis

open access

Rheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this... Show moreRheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this thesis we studied involvement of the forefoot. Throughout this thesis we found that synovitis in the rheumatoid foot affects more than just the joints. In an anatomic study we revealed that the tendon-sheaths in the forefoot also possess a synovial layer. Inflammation of this, detected by MRI that is referred to as tenosynovitis, was an important aspect of RA involvement in the forefoot. In addition, intermetatarsal bursae also detected by MRI are also often inflamed due to disease-involvement. These extra-articular involvements of the synovium that are found in RA importantly contribute to joint swelling and walking disability, and are therefore clinically relevant. Therefore we believe that it is essential for the clinician to pay attention to the forefeet of patients with RA to have a complete idea of disease activity Show less

Dávila Fajardo, C.L. 2020

Genetic variants contribute to differences in response and toxicity to drugs used in autoimmune diseases: Rheumatoid arthritis and systemic lupus erythematosus

Doctoral Thesis

open access

The primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis... Show moreThe primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis is divided in two parts: pharmacogenetics related with drugs used in RA and pharmacogenetics of rituximab used in SLE and other autoimmune diseases. Part 1: Pharmacogenetics of drugs used in RA MTX is the most common DMARD used in RA. However, its use is hampered by frequent adverse drug events among which gastrointestinal toxicity is most frequent. Hepatotoxicity is a relatively rare but serious adverse event related to the use of MTX and is largely unpredictable. In chapter 2 an overview is presented of the previously performed studies concerning pharmacogenetic predictive biomarkers for MTX-induced hepatotoxicity. Treatment with anti-TNF agents results in a reduction of disease activity in most RA patients. However, a substantial part of patients does not respond to this therapy for unknown reasons. It would be highly beneficial to be able to predict whether or not an individual patient responds to treatment. Chapters 4 and 5 describe the investigations on the role of different candidate SNPs related to the efficacy of the treatment with different anti-TNFs in RA. In addition, in chapter 3 a replication study is presented based on 4 polymorphisms that were found associated with anti-TNF response in RA in a previously published genomewide association study. Part 2: Pharmacogenetics of rituximab used in SLE and other autoimmune diseases In chapters 6–8 the role of different genetic variants related to the pharmacodynamics of the drug or of the diseases are evaluated to study the contribution to differences in the response to rituximab in patients with SLE and other systemic autoimmune diseases. In chapter 6, the possible involvement of the -174 IL-6 polymorphism in the clinical response to rituximab in different systemic autoimmune diseases is assessed. In chapter 7, the aim is to investigate the possible involvement of the FCGR3A-158F/V polymorphism in the clinical response to rituximab in Spanish patients with different systemic autoimmune diseases. In chapter 8, the role of G/T polymorphism at the IL2–IL21 region in the rituximab response in a cohort of SLE patient and different autoimmune disorders is analyzed. Chapter 9 provides a summary of this thesis, chapter 10 the Dutch summary (Nederlandse samenvatting), and chapter 11 the general discussion and future perspective of this thesis. Show less

Boeters, D.M. 2020

Early identification and resolution of rheumatoid arthritis

Doctoral Thesis

open access

overzicht van verschillende voorspellers voor het ontwikkelen van RA binnen patiënten met artralgie

rol van nieuwe autoantistoffen en MRI in vroege diagnostiek RA

onderzoek naar behalen van DMARD...

overzicht van verschillende voorspellers voor het ontwikkelen van RA binnen patiënten met artralgie

rol van nieuwe autoantistoffen en MRI in vroege diagnostiek RA

onderzoek naar behalen van DMARD-vrije remissie: voorkomen van immunologische remissie en identificatie van subgroep van RA-patiënten met verhoogde kans op remissie

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Hafkenscheid, L. 2020

Anti Citrullinated Protein Antibodies-IgG variable domain glycosylation in rheumatoid arthritis

Doctoral Thesis

open access

Rheumatoid arthritis (RA) is an auto-inflammatory disease, affecting ~1% of the world population. RA is hallmarked by the presence of autoantibodies, one of the well-known autoantibodies in RA are... Show moreRheumatoid arthritis (RA) is an auto-inflammatory disease, affecting ~1% of the world population. RA is hallmarked by the presence of autoantibodies, one of the well-known autoantibodies in RA are the anti-citrullinated protein antibodies (ACPA). ACPA is highly specific for RA and about 70-80% of the RA patients are positive for ACPA. Previously, we discovered that ACPA-IgG are extensively glycosylated in the variable (V) region. In this thesis, we determined that over 90% of the ACPA-IgG carries glycans in the v-domain were as only 17% of the conventional IgG carries additional glycans. Additionally, the glycans were highly sialylated. Intriguingly, we also showed that the glycans are introduced via somatic hyper mutations in the germinal center reaction. Furthermore, we discovered that ACPA-IgG v-domain glycosylation is a predictive marker for the development of ACPA positive RA. Lastly, we found that the binding strength is not influenced by the glycans but it influences the amount of available binding sites. Nevertheless, the ACPA-BCR still overcome negative selection which might suggest that the glycans can trigger an alternative way for positive selection in the germinal center. This will be subject for further studies regarding the role of ACPA-IgG v-domain glycosylation. Show less

Kempers, A.C. 2020

The Anti-Citrullinated Protein Antibody immune response and its effector functions in Rheumatoid Arthritis

Doctoral Thesis

some documents under embargo

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic and persistent inflammation of the joints. Around 50-80% of the RA patients harbour either one or multiple types... Show moreRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic and persistent inflammation of the joints. Around 50-80% of the RA patients harbour either one or multiple types of autoantibodies, under which also Anti-Citrullinated Protein Antibodies (ACPA). ACPA are highly specific for RA and are strongly associated with the severity of arthritis. The studies described in this thesis aim to explore the structure and biological function of ACPA and the B cells producing these ACPA.The studies highlight the importance of the synovial environment for the survival of ACPA B cells. Moreover, we demonstrate that the variable region of ACPA-IgG differs from that of ACPA-IgM by the introduction of glycans, and that glycans in the constant part of antibodies can be modulated by influences from the micro-environment. This may affect the biological functions of the antibodies. Furthermore, we show that ACPA can bind to so-called Fc gamma receptor I on immune cells which could be a potential effector mechanisms of ACPA. These findings demonstrate that the structure and environment of ACPA play an important role in the ACPA immune response and provide multiple arguments for the active contribution of ACPA in the chronic inflammation of RA. Show less

Delft, M.A.M. van 2020

The characterization of anti-carbamylated protein antibodies in rheumatic diseases : isotype usage, avidity and molecular composition

Doctoral Thesis

open access

The scope of this thesis is to describe the immunological characteristics and molecular composition of anti-CarP antibodies in rheumatoid arthritis, as well as the presence of anti-CarP antibodies... Show moreThe scope of this thesis is to describe the immunological characteristics and molecular composition of anti-CarP antibodies in rheumatoid arthritis, as well as the presence of anti-CarP antibodies in relation to bone erosions on diseases other than RA. This thesis is subdivided in three parts.Part 1: Characterisation of the anti-CarP antibody response in rheumatoid arthritisBoth ACPA and anti-CarP antibodies are present in RA.We describe the examination of the anti-CarP antibody response in RA by means of isotype and IgG-subclass usage in baseline serum samples of RA-patients as well as by means of the avidity of anti-CarP antibodies. Moreover, the anti-CarP IgG V-domain glycosylation was studied.Part 2: Possibilities for a mucosal origin of autoantibodies in rheumatoid arthritisSeveral lines of evidence obtained in the recent years indicate a role for mucosal surfaces in the development of auto-immune responses associated with RA. Therefore, we studied the molecular composition of RA associated IgA autoantibodies.Part 3: anti-CarP antibodies in other rheumatic diseases that can be characterized by bone erosionsBecause anti-CarP antibodies and ACPAs are also present in other clinical conditions than RA, we investigated their presence and association with bone erosions in Systemic Lupus Erythematosus and hand osteorthritis. Show less

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