EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.

OBJECTIVES: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. METHODS: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. RESULTS: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. CONCLUSIONS: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.

Genetic polymorphisms and decreased protein expression of ABCG2 urate transporters are associated with susceptibility to gout, disease severity and renal-overload hyperuricemia.

Gout is a common crystal induced disease of high personal and social burden, characterised by severe arthritis and comorbidity if untreated. Impaired function of ABCG2 transporter is causative in gout and may be responsible for renal-overload type hyperuricemia. Despite its importance, there is limited information on how clinical parameters correlate with protein expression and that with genetic changes. Urate and clinical parameters of 78 gouty patients and healthy controls were measured among standardised circumstances from a Hungarian population. ABCG2 membrane expression of red blood cells was determined by flow cytometry-based method and SNPs of this protein were analysed by TaqMan-based qPCR. The prevalence of ABCG2 functional polymorphisms in gouty and control patients were 32.1 and 13.7%, respectively. Most common SNP was Q141K while one sample with R236X, R383C and the lately described M71V were found in the gouty population. These polymorphisms showed strong linkage with decreased protein expression while the latter was also associated with higher fractional urate excretion (FUE) and urinary urate excretion (UUE). This study firstly evaluated ABCG2 protein expression in a clinically defined gouty population while also proving its associations between ABCG2 genetic changes and renal-overload hyperuricemia. The paper also highlighted relations between ABCG2 SNPs, gout susceptibility and disease severity characterised by an early onset disease with frequent flares and tophi formation.

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update.

BACKGROUND: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. METHODS: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. RESULTS: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. CONCLUSIONS: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

Sodium-Glucose Co-Transporter 2 Inhibitors May Change the Development of Urinary Tract and Hematological Malignancies as Compared With Dipeptidyl Peptidase-4 Inhibitors: Data of the Post-Hoc Analysis of a Nationwide Study.

BACKGROUND: In diabetes mellitus, during the last years, cancer became of equivalent importance as a cardiovascular disease in terms of mortality. In an earlier study, we have analyzed data of the National Health Insurance Fund (NHIF) of Hungary with regards all patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2is) vs. those treated with dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4is) in a given timeframe. In propensity score-matched groups of SGLT2i- vs. DPP-4i-treated patients, we found a lower incidence of cancer in general. In this post-hoc analysis, we aimed to obtain data on the incidence of site-specific cancer. PATIENTS AND METHODS: All patients starting an SGLT2i or a DPP-4i between 2014 and 2017 in Hungary were included; the two groups (SGLT2i vs. DPP-4i) were matched for 54 clinical and demographical parameters. The follow-up period was 639 vs. 696 days, respectively. Patients with a letter "C" International Classification of Diseases, 10th Revision (ICD-10) code have been chosen, and those with a known malignancy within a year before the onset of the study have been excluded from the analysis. RESULTS: We found a lower risk of urinary tract [HR 0.50 (95% CI: 0.32-0.79) p = 0.0027] and hematological malignancies [HR 0.50 (95% CI: 0.28-0.88) p = 0.0174] in patients treated with SGLT2i vs. those on DPP-4i. Risk of other types of cancer (including lung and larynx, lower gastrointestinal (GI) tract, rectum, pancreas, non-melanoma skin cancers, breast, or prostate) did not differ significantly between the two groups. When plotting absolute risk difference against follow-up time, an early divergence of curves was found in case of prostate, urinary tract, and hematological malignancies, whereas late divergence can be seen in case of cancers of the lung and larynx, the lower GI tract, and the breast. CONCLUSIONS: Urinary tract and hematological malignancies were less frequent in patients treated with SGLT2i vs. DPP-4i. An early vs. late divergence could be observed for different cancer types, which deserves further studies.

Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: a nationwide study.

INTRODUCTION: Mortality and disability in diabetes mellitus are determined mostly by cardiovascular complications and cancer. The impact of dipeptidyl peptidase-4 inhibitor (DPP-4i) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) monotherapy or combination on long-term complications of type 2 diabetes mellitus was studied. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes treated with DPP-4i or SGLT2i during a 3-year period were identified in the database of the National Institute of Health Insurance Fund in Hungary. All-cause mortality, acute myocardial infarction, stroke, hospitalization for heart failure (HHF), lower limb amputation (LLA) and cancer were assessed. Outcomes of add-on SGLT2i to DPP-4i treatment in comparison with switching DPP-4i therapy to SGLT2i were also evaluated. After propensity score matching, survival analysis was performed with a Cox proportional hazards model. RESULTS: After propensity score matching, both SGLT2i and DPP-4i groups included 18 583 patients. All-cause mortality (HR, 0.80; 95% CI 0.68 to 0.94; p=0.0057), HHF (HR, 0.81; 95% CI 0.71 to 0.92; p=0.0018), and risk of cancer (HR, 0.75; 95% CI 0.66 to 0.86; p<0.0001) were lower in the SGLT2i population compared with DPP-4i. Risk of LLA was higher in the SGLT2i group (HR, 1.35; 95% CI 1.03 to 1.77; p=0.0315). SGLT2i in combination with DPP-4i results in lower all-cause mortality (HR, 0.46; 95% CI 0.31 to 0.67; p=0.0001), with a lower trend in stroke, LLA, HHF and cancer, but without any statistical difference. CONCLUSIONS: SGLT2i treatment leads to a lower risk of overall mortality, HHF and cancer when compared with DPP-4i treatment. Adding SGLT2i to DPP-4i instead of switching from DPP-4i to SGLT2i further lowers the risk of all-cause mortality.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.

OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.

Glucocorticoid receptor polymorphisms in rheumatoid arthritis: results from a single centre.

OBJECTIVES: Until now, glucocorticoids (GCs) with their anti-inflammatory and immune suppressive effects are one of the most effective agents in therapy of several autoimmune disorders including rheumatoid arthritis (RA). Glucocorticoid receptor (GR) polymorphisms may result in variable sensitivity to glucocorticoids playing an important role in the development and control of symptoms in RA. We aimed to test whether the functional polymorphisms of the GR encoding gene (NR3C1) are associated with susceptibility to RA and with various clinical signs and symptoms. METHODS: 146 patients were enrolled at the National Institute of Reumatology. Clinical diagnosis was based on the criteria of the American College of Rheumatism (ACR) 2010. Complex clinical, routine laboratory and immunlaboratory evaluations were performed. For genotyping of the GR polymorphisms N363S (rs6195), BclI (rs41423247) and 9ß (rs6198) peripheral blood DNA was used, extracted with commercially available reagents. Genotyping was performed with routine molecular biological methods. Genetic data were compared to those obtained in a healthy control group (n=160) using Chi square or Fisher tests. Associations between GR genotypes and clinical and immunological parameters were determined with ANOVA. RESULTS: The main finding of the present study is the lower frequency of the BclI in RA patients. Furthermore, regarding the laboratory and immunoserological parameters, the level of anti-DNA antibody was significantly higher in homozygous BclI carriers compared to heterozygous carriers, irrespective of the anti-TNF-alpha therapy. CONCLUSIONS: Our results reveal that although GR polymorphisms are not key players in development or clinical course of RA, they might affect glucocorticoid action and, together with other endogenous and exogenous factors, interfere with the pathomechanism of RA. Our results reveal some possible factors (including BclI polymorphism), and therefore contribute to elucidate the implication of the combination of GR functional variants.

Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression.

The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability. Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.

[Recent advances in the treatment of antineutrophil cytoplasm antibody associated vasculitides]. / Antineutrofil citoplazmatikus antitest asszociált vasculitisek korszeru kezelése.

The authors review the nomenclature of vasculitides and the classification of antineutrophil cytoplasm antibody associated vasculitides and present the method of measuring disease activity (Five-factor Score, Birmingham Vasculitis Activity Score) and its role in defining therapeutical needs. They discuss the treatment algorithm of antineutrophil cytoplasm antibody associated vasculitides, present the sometimes equipotential medications used during the induction therapy followed by a maintenance regimen, and outline their usage and possible side-effects that may require medical attention. They point out the importance of plasmapheresis as an adjunctive treatment in some cases, as well as indications and possible outcome of kidney transplantation in therapy-resistant cases. Finally, they review several ongoing clinical studies, as their outcome will probably influence therapeutical opportunities of antineutrophil cytoplasm antibody associated vasculitides in the next few years.

Clinical and radiological dissociation of anti-TNF plus methotrexate treatment in early rheumatoid arthritis in routine care: results from the ABRAB study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoinflammatory joint disease which leads to the destruction of joints and disability of the patients. Anti-tumour necrosis factor (anti-TNF) drugs can halt radiological progression better than conventional DMARDs even in clinical non-responders. METHODS: The efficacy of anti-TNF plus methotrexate (MTX) treatment versus MTX monotherapy on clinical and radiological outcomes were compared in early rheumatoid arthritis (RA) patients in clinical practice by retrospective analysis of an observational cohort.49 early RA patients (group A) on first-line MTX monotherapy and 35 early RA patients (group B) on anti-TNF plus MTX treatment were selected from an observational cohort and evaluated retrospectively focusing on their first twelve months of treatment. Data on disease activity (DAS28) and functional status (HAQ-DI) were collected three monthly. One-yearly radiological progression was calculated according to the van der Heijde modified Sharp method (vdHS). Clinical non-responder patients in both groups were selectively investigated from a radiological point of view. RESULTS: Disease activity was decreased and functional status was improved significantly in both groups. One-yearly radiological progression was significantly lower in group B than in group A. The percentage of patients showing radiological non-progression or rapid radiological progression demonstrated a significant advantage for group B patients. In addition non-responder patients in group B showed similar radiological results as responders, while a similar phenomenon was not observed in patients in group A. CONCLUSIONS: Clinical efficacy within our study was similar for tight-controlled MTX monotherapy as well as for combination treatment with anti-TNF and MTX. However MTX monotherapy was accompanied by more rapid radiological progression and less radiological non-progression. Anti-TNF plus MTX decreased radiological progression even in clinical non-responders supporting the advantage of anti-TNF plus MTX combination in dissociating clinical and radiological effects.

Complement receptor type 1 (CR1, CD35) is a potent inhibitor of B-cell functions in rheumatoid arthritis patients.

The involvement of B cells, complement activation and subsequent immune complex deposition has all been implicated in the pathogenesis of rheumatoid arthritis (RA). Although the reduced expression of complement receptor 1 (CR1, CD35) and 2 (CR2, CD21) on the B cells of RA patients has been known for a long time, their exact role in B-cell tolerance and autoimmunity is not yet fully understood. To get a deeper insight into the possible mechanisms, we studied the expression and function of CR1 and CR2 on various subsets of B cells of healthy donors and RA patients at various stages of the disease by FACS analysis, (3)H-thymidine incorporation and ELISA. We found that CD19(+)CD27(-) naive B cells up-regulate the expression of the inhibitory CR1 during differentiation to CD19(+)CD27(+) memory B cells both in healthy donors and in RA patients, whereas the expression of the activatory CR2 is down-regulated. This clearly demonstrates that the expression of these two antagonistic complement receptors is regulated differentially during the development of human B cells, a phenomenon which may influence the maintenance of peripheral B-cell tolerance. Our functional studies show that after clustering CR1 both by its natural ligand and To5 mAb, the inhibitory function of CD35 is maintained in RA patients, despite its significantly reduced expression compared with healthy individuals. Besides blocking B-cell receptor-induced proliferation, CR1 inhibits the differentiation of B cells to plasmablasts and their immunoglobulin production. Since the reduced expression of CR1 in RA patients does not affect its inhibitory function, this receptor might serve as a new target for therapeutical interventions.

Psychosocial, educational, and somatic factors in chronic nonspecific low back pain.

Analysis of the effect of psychosocial factors and co-morbidities on the health status of patients with chronic nonspecific low back pain and patients with surgical intervention because of disk herniation was performed. One hundred and two nonselected consecutive inpatients with chronic nonspecific low back pain were included in the study. Their average age was 56.7 (SD = 10.9) years. The control group consisted of 199 subjects matched according to age and sex, chosen from the database of the national representative health survey Hungarostudy 2006, which involved 4,527 subjects. We measured quality of life including mental health with the SF-36 questionnaire validated for use in Hungary, the short 9-item version of the Beck Depression Inventory, the WHO-Five Well-Being Index, and the Hospital Anxiety-Depression Scale. We characterized the socio-demographic status with variables on age, sex, marital status, and education. Data on symptoms and signs of low back pain, other musculoskeletal diseases, and their treatments including spinal surgery were recorded. Co-morbidity and body mass index were considered as independent indicators of health. Depression as measured by Beck Depression Inventory and severity of depression did not vary significantly according to marital status, education, hypertension, diabetes, and gastrointestinal disease. Only half of the patients (52 %) were in the normal range of the scale; 22 % suffered from mild, 16 % from moderate, and 12 % from severe depression. Average values for anxiety and depression as measured by Hospital Anxiety-Depression Scale and Beck Depression Inventory were both significantly higher in the patient than in the control group (Hospital Anxiety Scale: p = 0.0001; Beck Depression Inventory: p = 0.0001). According to the WHO Well-Being Index-5 scale, the difference between patients and the control group was significant (p = 0.0001). Furthermore, correlation was found between the incidence of depression and surgery. Depression was demonstrated in 47.4 % of those patients who had no surgery, in 50 % of patients who had one round of surgery, and in 62.5 % of those who had undergone surgery more than once; the contingence coefficient was 0.211. According to different measurements, the psychological state of patients with chronic nonspecific low back pain was significantly altered as compared to the matched Hungarian population. Higher anxiety and depression markers occurred in 48 % of the patients. There was no correlation between the depression of patients with low back pain and variables such as marital status, education, and co-morbidities. Our study is the first to demonstrate that depression runs parallel with the number of surgical procedures. Therefore, if there is a relative indication for surgery, depression and severity of depression should be assessed and considered when deciding on the intervention.

Marked diversity of IL23R gene haplotype variants in rheumatoid arthritis comparing with Crohn's disease and ankylosing spondylitis.

Haplotype tagging SNPs of interleukin-23 receptor gene rs1004819, rs7517847, rs7530511, rs2201841, rs1343151 and rs10889677 were determined in 396 patients with rheumatoid arthritis, 190 patients with Crohn's disease, 206 patients with ankylosing spondylitis and 182 controls. Using regression analysis models the rs1004819, rs2201841, and rs10889677 SNPs were found to confer risk for Crohn's disease and ankylosing spondylitis, while rs1343151 had a protective effect in both of these diseases, and the rs2201841 and rs10889677 SNPs showed susceptibility nature for rheumatoid arthritis. Using these SNPs we could study the susceptibility haplotype profiles in these diseases with special attention to the rheumatoid arthritis, first in the literature. Seven different haplotypes could be differentiated. We found that the SNPs exert their susceptibility character in specific haplotype blocks: thus, for rheumatoid arthritis the rs1343151 SNP was risk factor only in a specific haplotype surrounding; this can explain the controversial results published so far about this variant. More importantly, we observed, that while a specific haplotype can confer risk for rheumatoid arthritis, the same haplotype tended to protect against the development of the other two diseases. The data presented here serve evidence for the need of haplotype analysis instead of just single standing SNP analysis when susceptibility to or protection against a certain disease are interpreted.

[Systemic autoimmune disorders and pregnancy]. / Szisztémás autoimmun betegségek és terhesség.

The coincidence of systemic autoimmune diseases and pregnancy may modify the outcome of the disease and the pregnancy due to the background immunologic and hormonal processes. The great majority of patients with autoimmune diseases are young females in their reproductive years, willing to have babies. Consequently, we have to prepare for this special situation. Our concept on childbearing in autoimmune women has changed within the last 30 years. Earlier, systemic lupus erythematosus flared in about 50% of patients during pregnancy, but the flare rate has significantly decreased recently. This improvement can be attributed to increased attention to low diseases activity at the time of conception, which might reduce to the half of the risk for flare. Tight control of patients and appropriate use of corticosteroids also contribute to the better results. The adequate use of anti-thrombotic agents resulted in a significant amelioration of pregnancy outcome in antiphospholipid syndrome. The earlier use of methotrexate and the introduction of tumor necrosis factor-alpha inhibitors in the treatment of rheumatoid arthritis have changed the natural characteristics of the disease. The increase in remission rate indirectly has beneficial effect on the number of planned and carried out pregnancies. Authors review the connection between systemic autoimmune disorders and pregnancy as well as the possibilities of medical treatment of such diseases during pregnancy.

[Paget's disease: clinical update]. / A Paget-kór aktuális kérdései.

Paget's disease is a chronic disorder of bone remodeling, characterized by an abnormal increase of osteoclast and, hence, osteoblast activity. The imbalance of bone turnover results in the formation of unhealthy and fragile bone. It also leads to impairment of adjacent joints and to a risk of various complications. Current research focuses on the elucidation of the etiologic role viral infection and predisposing genetic factors. Paget's disease is commonly discovered by chance; its suspicion is raised either by high level of alkaline phosphatase or by the X-ray of the pathological bone. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Their use is recommended when bone-derived serum alkaline phosphatase is high and/or when disease localizations are highly suspected for the development of complications.

[Diabetes and bone metabolism]. / Diabetes és csontanyagcsere.

In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic ß-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures.

Experiences with tumour necrosis factor-{alpha} inhibitors in patients with juvenile idiopathic arthritis: Hungarian data from the National Institute of Rheumatology and Physiotherapy Registry.

OBJECTIVE: To report the efficacy and safety of TNF-α inhibitors (etanercept and adalimumab) in a cohort of patients with JIA treated in a single paediatric rheumatological centre. METHODS: Patients with JIA under the age of 18 years, treated with TNF-α blockers at the Paediatric Rheumatologic Centre of the National Institute of Rheumatology and Physiotherapy (Budapest, Hungary) from 2002, were enrolled in an open, observational study. At baseline, patient and disease characteristics were registered. Disease activity was evaluated (before the start of the treatment and after every 3 months) according to the JIA core set of the ACR paediatric definition of improvement (ACR Pedi). Adverse events (AEs) were documented. RESULTS: In all, 72 patients were evaluated. Mean (S.D.) age at onset was 5.5 (3.8) years, mean disease duration was 7.4 (3.9) years. All disease activity parameters improved significantly in the first 3 months of treatment. After 3 and 12 months of treatment, 88 and 76% of patients, respectively, achieved the criteria of the ACR Pedi 30. AEs were uncommon. After 12 months, >85% of patients continued the therapy. CONCLUSION: Anti-TNF-α agents (etanercept and adalimumab) are effective, safe and well tolerated in JIA patients. Extension of this study for a longer follow-up period and to the patients with JIA after the age of 18 years (with validated and comparable disease activity parameters) is needed to evaluate the long-term effectiveness and safety of the TNF-α inhibitors.

Genetic and immunological processes in the pathomechanism of gluten-sensitive enteropathy and associated metabolic bone disorders.

Celiac disease, or gluten sensitive enteropathy is a relatively common disease of the jejunum, leading to malabsorption. It is an immune mediated disease, induced by gluten on the grounds of a specific genetic makeup. After gluten exposition immune processes are induced mainly by T-cells, causing typical intestinal and extra intestinal manifestations. The diagnosis of celiac disease is based on jejunal biopsy histology and the presence of antibodies against endomysium and tissue transglutaminase. Genetically, celiac disease is associated with HLA DQ2/DQ8. Strict gluten-free diet improves the clinical, histological and serological picture and remission may be achieved. In the etiopathogenesis of celiac disease several genetic and immunological mechanisms have been recognized in the recent years. Concerning accompanying diseases/extraintestinal manifestations, several disorders have been shown, including rheumatological diseases. In celiac disease, bone metabolic changes are more frequent compared to the prevalence of inflammatory join disorders. In this review, we aim to give an overview on various aspects of the genetic and immunological processes in the pathomechanism of gluten-sensitive enteropathy and associated metabolic bone disorders.

Overlapping juvenile idiopathic arthritis and systemic lupus erythematosus: a case report.

Hereby, we report the case of a 12-year-old girl developing oligoarthritis and progressing into a polyarticular form. Rheumatoid factor was positive, and juvenile idiopathic arthritis (JIA) was diagnosed. After a poor response to DMARDs, an anti-TNF agent (infliximab) was initiated, but to be discontinued due to an allergic reaction. The same complication was observed with the fully human derivative, adalimumab. At the age of 22, the patient presented septicemia with severe anemia and subsequent development of leukopenia, myocarditis with heart failure, and ANA, aSm, aSS-A, aCL positives, and nephrotic syndrome. These new clinical manifestations fulfilled the classification criteria for the diagnosis of systemic lupus erythematosus. Due to the poor therapeutic responses for both diseases, alternative medical options have to be considered, such as targeted therapy with anti-CD20 or interleukin-6 receptor antagonist monoclonal antibodies. This patient may also be a candidate for autologous hemopoietic stem cell transplantation.