Hungarian Immunology

[The importance of etanercept treatment in rheumatology]

GERGELY Péter, POÓR Gyula

MARCH 20, 2007

Hungarian Immunology - 2007;6(03)

[Rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis and psoriatic arthritis are inflammatory rheumatic conditions of unknown origin. Common characteristic features of these disorders include a relatively high prevalence, poorly understood pathogenesis and an unresolved treatment as well as a significant impact on mortality, morbidity and medical expenditures. The recognition of the central role of TNF-α in immune mediated inflammatory conditions, mainly in rheumatoid arthritis has led to the introduction of TNF-α blocking biological therapy into clinical rheumatology revolutionizing the management of these diseases. Etanercept is a human soluble TNF-α receptor attached to human IgG capable of effectively neutralizing TNF-α and lymphotoxin alpha. Since its introduction in 1998 as the first biological agent approved for RA, several clinical trials as well as everyday practice have proven its efficacy and safety. To date approximately 440 thousand patients, mostly with inflammatory rheumatic diseases have been treated with etanercept. In the present paper the pathophysiological role of TNF-α, the results of clinical trials of etanercept and its cost-effectivenes as well as issues regarding the use of etanercept in Hungary are reviewed.]

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Hungarian Immunology

[The use of infliximab in medical therapy]

GESZTES Ákos

Hungarian Immunology

[First experience with rituximab treatment in rheumatoid artritis: a case report of a multiresistant patient]

SIMKOVICS Enikő, BESENYEI Tímea, SZABÓ Zoltán, SZENTPÉTERY Ágnes, SZODORAY Péter, SZŰCS Gabriella, SZÁNTÓ Sándor, SZEKANECZ Zoltán

[INTRODUCTION - Here we describe the case of the first Hungarian rheumatoid arthritis (RA) patient treated with RTX. CASE REPORT - This multiresistant patient had received numerous immunosuppressive drugs and all three anti-TNF agents had been tried. These biologicals had to be stopped due to inefficacy or side effects. RTX treatment resulted in some subjective clinical improvement, as well as a decrease in rheumatoid factor and anti-CCP production. Clinical activity assessed by DAS28 fell after 18 weeks. B cells disappeared from the circulation, however, the percentage of activated T cells increased. We observed initial B cell recovery after 18 weeks. CONCLUSION - Clinical studies suggest that RTX is more effective right after the failure of the first TNF inhibitor. Efficacy of RTX in this patient suggests that this drug may also be effective in a multiresistant patient, who had tried numerous TNF blockers.]

Hungarian Immunology

[Adalimumab in the treatment of Crohn’s disease]

LAKATOS Péter László

[Crohn’s disease (CD) is a chronic inflammatory disorder which may involve any part of gastrointestinal tract. The pathogenesis is only partially understood; various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved resulting in chronic uncontrolled inflammation, and among pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) seems to play a central role in CD. The last few years have witnessed a significant change in the management of Crohn’s disease. The role of and indications for conventional therapy (aminosalicylates, steroids and immunomodulators) have been reassessed. Over the past decade the increasing knowledge on the pathogenesis of CD led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, first of all TNF-α and its receptors. The aim of this paper is to review the rationale for the use one of the new anti TNF-inhibitors, adalimumab in the treatment of CD.]

Hungarian Immunology

[Rituximab in rheumatoid arthritis]

SZEKANECZ Zoltán

[The therapy of rheumatoid arthritis (RA) is not always easy. Classical disease-modifying drugs are ineffective in about 10-15% of the cases. Furthermore, biologic agents, mainly tumor necrosis factor- α (TNF-α) inhibitors, may also be ineffective. Rituximab (RTX) is a B cell-inhibitory monoclonal antibody, which has been registered for the treatment of RA patients refractory to classical immunosuppressive agents including a TNF antagonist. Here we summarize the history of RTX therapy in RA including the presentation of the three major randomized clinical trials. We discuss the efficacy, safety of RTX, the practical points of RTX therapy, as well as some special considerations. The presented data suggest that RTX is a highly effective and safe biological, which can be used upon the inefficacy of any TNF inhibitor. RTX suppresses RA-associated inflammation, symptoms and decreases radiological progression. It may improve the functional capacity and quality of life of RA patients.]

Hungarian Immunology

[Adalimumab treatment in inflammatory joint diseases]

SZÁNTÓ Sándor

[The development of anti-TNF-α agents represents a great advance in the treatment of inflammatory joint diseases. Adalimumab is the first fully human, recombinant IgG1 monoclonal antibody that blocks the interaction of TNF with the p55 and p75 cell surface TNF receptors, thereby neutralising the activity of this cytokine. In well designed, placebocontrolled trials adalimumab significantly reduced symptoms, improved quality of life, and reduced radiologically evident joint damage in patients with rheumatoid athritis, ankylosing spondylitis and psoriatic arhritis. The drug was generally well tolerated, and the follow up studies confirmed, that the incidence of serious adverse events was similar to that generally seen in patients not receiving anti-TNF agents. This review summarises the recent available data related to the efficacy and safety of adalimumab in inflammatory joint diseases.]

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[A paradox of articular protective phenomenon: more serious-damaged rudimentary hand in rheumatoid arthitis]

SZÁNTÓ Dezső, SZŰCS Gabriella, DITRÓI Edit

[INTRODUCTION - The joints have been secured from rheumatoid arthritis by diminution of biomechanical effeciency. This effect was analyzed and named articular protective phenomenon three decades ago. CASE REPORT - A case of bilateral rheumatoid arthritis associated with unilateral developmental abnormality hand and bronchial asthma in a 35 year old female patient is presented. Her left 2nd, 3rd, 4th and 5th metacarpal bones moreover her fingers had not evolved. The patient has been treated by antiasthmatic steroid drugs for five years. Rheumatoid disorders of the affected left hand were more severe, than the abnormality of the normal upper limb. Eight years later the most severe bony lesions (ankylosis and mutilation) appeared on this side, only. CONCLUSION - The patient's hand was not saved by inborn bone defect in rheumatoid arthritis. The absence of articular protective phenomenon can be explained by the undisturbed innervation of limb, the motility of hypotrophic carpus besides to steroid-induced suppression.]

Hungarian Immunology

[Biological therapy of arthritis and systemic autoimmune diseases - 2007]

SZEKANECZ Zoltán, TAMÁSI László

[Biological therapy acts at a specific point of inflammation. Today, rheumatoid arthritis is the prototype disease in this context due to the relatively high number of accessible patients and wellstandardized follow-up tools. However, apart from this disease, biological therapy has been introduced to the treatment of other diseases including various forms of arthritis, such as ankylosing spondylitis and psoriatic arthritis, as well as systemic autoimmune disorders, such as lupus, scleroderma, inflammatory myopathies and Sjogren’s syndrome. Anti-tumor necrosis factor-α (TNF-α) agents play a central role in biological therapy as these agents have been successfully tried in most of these diseases. However, when seeking for specific targets for biologicals, specific pathogenic factors of the given disease should be determined. For example, while anti-TNF agents seem to be most effective in various types of arthritis, anti-B cell therapy may be the first choice in other autoimmune conditions, such as lupus, Sjogren’s syndrome or dermatomyositis. It is important to consider the specific characteristics of the administered agents as there may be differences regarding side-effects.]

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[The pathogenic and clinical significance of the RANK-RANKL-osteoprotegerin system in rheumatoid arthritis]

SZENTPÉTERY Ágnes, VÁNCSA Andrea, SZABÓ Zoltán, SZEKANECZ Zoltán

[Rheumatoid arthritis (RA) is characterised by increased local and generalised bone resorption, which manifests in the develoment of marginal erosions and generalised osteoporosis, respectively. An increasing number of data suggest that lymphocytes, proinflammatory cytokines and other mediators involved in inflammation contribute to arthritic bone resorption. Therefore, the term ‘osteoimmunology’ has also become widely used. In RA, Receptor Activator of Nuclear Factor kappa B (RANK) and its ligand (RANKL) play a crucial role in bone resorption. These proteins, which belong to the tumor necrosis factor a (TNF-a) receptor and TNF ligand superfamilies, respectively, activate osteoclasts while interacting with T cells, synovial fibroblasts and other cytokines (e.g. IL-1, IL-17), which results in bone resorption. Osteoprotegerin (OPG) is a decoy receptor that also belongs to the TNF receptor family and inhibits RANK-RANKL interactions. There is increased RANKL production and decreased OPG production in RA. The interaction of RANKL with IL-17 is particularly important. Regarding therapy, sulfasalazine, methotrexate and biological agents, especially TNF inhibitors suppress RANKL-mediated bone resorption and thus the development of joint erosions. RANKL-RANK interaction can be directly inhibited by recombinant OPG or anti-RANKL antibody (denosumab). Among these agents, denosumab gave promising results in experiments performed in animal models of arthritis. These were followed by a phase II human RA trial, which proved that denosumab decreased MRI erosion scores in RA.]

Hungarian Immunology

[Immunology of Felty’s syndrome]

BÁLINT Géza, BÁLINT Péter

[Felty’s syndrome can be regarded as “super-rheumatoid” disease. Immungenetically the syndrome is much more homogenous, than rheumatoid arthritis. HLA-DRB1*0401 antigen is present in 83% of the patients. Felty’s syndrome develops usually after a longer course of rheumatoid arthritis, in 1% of rheumatoid patients. Rheumatoid arthritis patients with long lasting unexplained neutropenia can be diagnosed having Felty’s syndrome, even without detectable splenomegaly. On the contrary, rheumatoid arthritis with splenomegaly, but without present or previous neutropenia with unexplained origin cannot be regarded as having Felty’s syndrome. Inspite of the fact, that the arthritis of Felty’s syndrome can be inactive, because of the neutropenia and increased risk of recurrent infections, the patients should be kept under tight supervision, and should be properly treated, if required. Immunologically Felty’s syndrome is characterized by rheumatoid factor positivity in 95-100%, ANA positivity in 50-100%, antihistone positivity in 63-83%. Antibodies against dsDNA rarely, but against ssDNA frequently occur. No anti Sm and interestingly no anti Ro and anti La antibodies can be detected inspite of the high incidence of associated Sjögren’s syndrome. Immunoglobulin levels are higher and complement levels are lower, than in rheumatoid arthritis. Circulating immuncomplex level is usually high. Non-specific antineutrophil anticitoplasmatic antibodies can be found in high percentage. The neutropenia of Felty’s syndrome can be either caused by increased IgG neutrophilic binding activity or by inhibition of the granulocytes colony growing in the bone marrow, by peripheral blood mononuclear cells. Expansion of large granular lymphocytes can be seen in 30-40% of patients with Felty’s syndrome. Large granular lymphocyte syndrome is not rarely associated with rheumatoid arthritis. The neutrophil account is normal or elevated in this syndrome, but splenomegaly occurs. These cases are called as pseudo Felty’s syndrome. The patients with Felty's syndrome suffering from recurrent infections required treatment even if the arthritis is inactive. Methotrexate treatment should be started first, if this treatment fails, other disease modifying drugs or colony stimulating factor can be given. There is no experience with other biological treatments. In treatment of resistant cases splenectomy is indicated. Non-steroid anti-inflammatory drugs should be better avoided.]

Hungarian Immunology

[First experience with rituximab treatment in rheumatoid artritis: a case report of a multiresistant patient]

SIMKOVICS Enikő, BESENYEI Tímea, SZABÓ Zoltán, SZENTPÉTERY Ágnes, SZODORAY Péter, SZŰCS Gabriella, SZÁNTÓ Sándor, SZEKANECZ Zoltán

[INTRODUCTION - Here we describe the case of the first Hungarian rheumatoid arthritis (RA) patient treated with RTX. CASE REPORT - This multiresistant patient had received numerous immunosuppressive drugs and all three anti-TNF agents had been tried. These biologicals had to be stopped due to inefficacy or side effects. RTX treatment resulted in some subjective clinical improvement, as well as a decrease in rheumatoid factor and anti-CCP production. Clinical activity assessed by DAS28 fell after 18 weeks. B cells disappeared from the circulation, however, the percentage of activated T cells increased. We observed initial B cell recovery after 18 weeks. CONCLUSION - Clinical studies suggest that RTX is more effective right after the failure of the first TNF inhibitor. Efficacy of RTX in this patient suggests that this drug may also be effective in a multiresistant patient, who had tried numerous TNF blockers.]