Personalisierte Medizin bei der rheumatoiden Arthritis

Nowadays B and T-cell directed biologics in addition to TNF inhibitors are established as effective and safe treatment options for rheumatoid arthritis. As shown by the approval of rituximab for the treatment of systemic vasculitis, these drugs can also be useful for the treatment of other systemic autoimmune diseases; however, to optimize therapeutic strategies, predictive factors for treatment response as well as a good characterized safety profile are essential. So far implementation of real personalized medicine is not feasible in the field of rheumatology, but first biomarkers have already been identified and provide promising results. In this context, it has been shown that a B-cell directed therapy with rituximab is more effective in seropositive patients with rheumatoid arthritis. In addition, characterization of the cytokine milieu as well as of circulating and tissue infiltrating B and T-cell subsets might be useful for prediction of treatment response in the near future.     

Autoantikörperprofile bei der rheumatoiden Arthritis

Antibodies against citrullinated protein/peptides antigens (ACPA) are well recognized serological markers for rheumatoid arthritis. In addition to rheumatoid factor, they provide high diagnostic specificity and are also useful diagnostic tools in the search for early disease manifestation. As shown by several studies, both autoantibodies correlate with disease severity and the radiologic progression of rheumatoid arthritis. However, it is important to note that only the detection of rheumatoid factors is internationally standardized. Whether autoantibody profiling is also of significance for the stratification and monitoring of rheumatoid arthritis is the focus of ongoing investigations.     

Zytokin- und Anti-Zytokintherapie bei der rheumatoiden Arthritis

Zum Thema Zur Behandlung der rheumatoiden Arthritis als chronische inflammatorische Autoimmunerkrankung steht keine kausale Therapie zur Verfügung. Die etablierten Therapieregimes mit Basistherapeutika führen lediglich zur Verlangsamung der Progression, zudem sind sie deutlich nebenwirkungsbelastet. Die zytokinmodulierende Therapie stellt dagegen ein neues Konzept zur Behandlung der rheumatoiden Arthritis zur Verfügung. Der vorliegende Beitrag zeigt die aktuellen Ergebnisse von Forschung und klinischen Studien. Die Erfolge in der Anwendung der Tumornekrosefaktor-α-Blockade erlauben die Hoffnung, dass mit Hilfe von Immunbiologika schon in naher Zukunft eine effektivere Therapie der rheumatoiden Arthritis etabliert werden kann.     

Krankheitsmodifizierende Effekte bei der rheumatoiden Arthritis durch Glukokortikoide

Drugs used for managing rheumatoid arthritis (RA) are designated disease-modifying antirheumatic drugs (DMARDs) if they reduce inflammation and pain, limit joint destruction, and improve long-term disease outcome. Glucocorticoids have long been known to have anti-inflammatory, immunosuppressive, and pain-reducing effects. Moreover, they have been shown in recent clinical trials, and also very recently in a systemic analysis of the results of these studies, to contribute to inhibition of the radiographic progression of RA. For these reasons, glucocorticoids can be considered DMARDs if they are used to treat patients suffering from early RA and, according to the current knowledge, are used in combination with other DMARDs.     

Der Einsatz von Leflunomid bei der rheumatoiden Arthritis

Ohne Zusammenfassungund die Kommission Pharmakotherapie der DGRh     

Bildgebende Verfahren in der Rheumatologie: Scoring-Methoden bei der rheumatoiden Arthritis

This is a critical overview of existing scoring methods including their basis, their measurement systems, their advantages and disadvantages. Conventional radiography is still-since available everywhere, interpretable and cost effective-the best imaging method to evaluate the course of RA. Scoring methods are designed to semiquantitatively measure radiographically visible changes, especially erosive destruction and-in part-cartilage loss. These methods are well validated, reproducible, and yield similar results in clinical trials. Most methods overestimate early changes and have a clear ceiling effect. Within the time frame of clinical trials radiographic evaluation is not very sensitive to change since the progression of destruction in RA is relatively slow. Moreover, small erosions cannot be detected if they are not at the margin of the bone or if they are superimposed by other bones. Within the Larsen method the definition of grade 1 by soft tissue swelling is disadvantageous: soft tissue swelling is difficult to identify on X-rays, it is a measure of disease activity and not of destruction and is quickly reversible. Joint space narrowing, measured with Sharp's method and its modifications, may be caused by misprojection due to soft tissue swelling with flexion or subluxation of the joint rather than cartilage loss. Since the measurement error of a scoring method is very much dependent on the severity of the disease of the patient population and on the quality of the radiographs, the measurement error and thereby the minimal detectable change (MDC) should be stated for every single clinical trial. Conventional radiographs and scoring methods are still indispensable to measure the influence of treatment on radiographic progression in RA. A future task will be to include in scoring methods the rating of reparative changes which cannot be scored so far.     

Genetik der rheumatoiden Arthritis

Genetic influences on susceptibility to and clinical course of rheumatoid arthritis have been known for a long time, but have so far eluded systematic, genome-wide analysis. In recent years, the availability of new typing techniques and international consortia with large patient cohorts has generated a wealth of new information on the genetic basis of this autoimmune disease. Newly described associations between immunologically relevant gene polymorphisms and RA susceptibility have already been replicated with great statistical power, and are currently incorporated into new, pathogenetically relevant functional pathways. The resulting new concepts identify cell populations of great potential relevance for the pathogenesis of the disease, and ultimately might lead to new diagnostic and therapeutic approaches in RA.     

Management der rheumatoiden Arthritis

Rheumatoid arthritis is the most common inflammatory rheumatic disease. Due to the destruction of joints in the course of the disease it leads to significant morbidity in affected patients. The quality of life and even life expectancy can be severely impaired. Early diagnosis and early initiation of treatment is a decisive step towards a more benign course of the disease. New classification criteria have been published in order to help in early diagnosis. Methods of imaging, such as ultrasound and magnetic resonance imaging help in the detection of synovitis, which is the major pathomorphological manifestation of arthritis and should be identified without any doubt. Treatment follows the rule of treat to target with the aim of achieving remission or if this is not realistic, at least the lowest possible level of disease activity. The first and perhaps most important step in therapy is the initiation of methotrexate or if contraindications are present, another disease-modifying antirheumatic drug (DMARD) as soon as the diagnosis is made. Initial addition of glucocorticoids is recommended, which should be reduced in dose and terminated as soon as possible. Furthermore, either the combination of different DMARDs or the start of biologic DMARDs, such as tumor necrosis factor alpha (TNF-alpha) inhibitors or second generation biologic DMARDs is possible as a treatment option. The treatment follows the rule of shared decision-making and is the standard to treat comorbidities, the use an interdisciplinary approach and to treat functional deficits by rehabilitation measures, such as physiotherapy.     

Internistische Therapie der rheumatoiden Arthritis

Rheumatoid arthritis is the most common inflammatory joint disease and is characterized by chronic, symmetric, erosive synovitis of small joints of hands and feet. Prevalence in women is threefold higher than in man. Structural damage of the joints starts between the first and second year of the disease. Early therapeutic interventions can alter the course of rheumatoid arthritis by delaying the progression of radiographic joint destruction, which correlates with the grade of disability. Approval of new biologic antirheumatic drugs in the last few years improved the outcome of rheumatoid arthritis.     

Konventionelle Basistherapie der rheumatoiden Arthritis

Conventional disease-modifying antirheumatic drugs (DMARDs) were formerly introduced into the treatment of rheumatoid arthritis and other rheumatic disorders on an empirical basis. In many cases their mode of action is only partially understood but as a rule of thumb they act on more than one point within the cellular metabolism. Less often they exert biological effects in the extracellular space or on the cell membrane.     

Therapie der zervikalen rheumatoiden Arthritis

The rheumatoid involvement of the cervical spine can be divided into three phases. In the early stage of the disease there is an isolated atlantoaxial subluxation (AAS), followed by vertical instability and subaxial instability. If patients show clear symptoms of cervical myelopathy, which can occur during any stage of the disease, the progression cannot be stopped by conservative treatment, which is of great importance at the beginning of the cervical manifestation. Patient education, physiotherapy and immobilization with a stiff collar can significantly reduce pain. Early and effective DMARD therapy can have a positive effect on the natural history of the disease. In case of progressive instability, cervical myelopathy or severe pain operative treatment is indicated. If there is an isolated AAS, fusion can be restricted to the C1/C2 segment. The Magerl transarticular screw fixation is the preferred technique for stabilization. If there is evidence for vertical instability or severe destruction of the C0/C1 joints, occipital cervical fusion has to be performed. Durin the preoperative planning it is necessary to look for signs of subaxial instability. If this is the case, fusion should include the entire cervical spine. Transoral decompression may be necessary when there is persistent anterior compression of the myelon, typically seen in fixed AAS. Non-ambulatory myelopathic patients are more likely to develop severe surgical complications. Therefore, it is important to avoid the development of severe cervical instability by early surgical intervention. The right timing for surgery is still a matter of controversy. Future prospective randomized trials should address this topic to improve the treatment concept for the rheumatoid patient.     

Molekulare Wirkungsmechanismen von Gold bei der Behandlung der rheumatoiden Arthritis – ein Update

Vor 90 Jahren wurde Gold erstmals von Robert Koch in der Annahme einer mykobakteriellen Verursachung der rheumatoiden Arthritis in Analogie zur Tuberkulose intraven?s als Zyan-Gold-Verbindung eingesetzt. Schnell wurde klar, dass diese ursprüngliche Rationale nicht für die positiven Wirkungen von Gold verantwortlich ist, und seit dieser Zeit bemühen sich die Wissenschaftler um die Aufkl?rung des Wirkungsmechanismus von Gold in der Therapie rheumatischer Erkrankungen. Nahezu in jedem Bereich des Immunsystems wurden inhibierende Wirkungen des Goldes nachgewiesen, wobei unklar ist, ob es einen gemeinsamen Nenner dieser Wirkungen gibt oder aber ob Goldverbindungen parallele Wirkungsmechanismen beinhalten, die unabh?ngig voneinander aktiv sind. Jedoch erscheint auch anhand jüngster Studien die Reaktivit?t von Goldverbindungen mit Thiol-Gruppen ein entscheidender Faktor zu sein. Bei der Analyse der Wirkungen von Gold auf die unterschiedlichen Phasen der Immunreaktion spielt vermutlich Gold gleich am Anfang, n?mlich bei der Aufnahme von Antigenen in antigenpr?sentierende Zellen eine wesentliche Rolle. So wird Gold insbesondere von Makrophagen aufgenommen und lagert sich dort in den Lysosomen der Makrophagen ab. Hier entstehen die sog. Aureosomen, wobei Gold I nach Losl?sung von seinem Tr?germolekül die Antigenprozessierung hemmt. Hier spielen insbesondere Peptidantigene eine wichtige Rolle, die schwefelhaltige Aminos?uren beinhalten, wie Cystein und Methionin, so dass die T-Zell-Erkennung solcher Peptide gehemmt wird. Auch auf der molekularen Ebene konnte zwischenzeitlich gezeigt werden, dass Gold die NF-Kappa B-Bindungsaktivit?t unterdrückt sowie die Aktivierung der I-Kappa B-Kinase behindert. Vermutlich durch diesen Mechanismus kommt es anschlie?end zu einer verminderten Produktion pro-inflammatorischer Enzyme, insbesondere von TNF-α, Interleukin-1 und Interleukin-6. Auf der nachfolgenden T-Zell-Ebene führt Gold vermutlich über eine Hochregulation der mRNA für Interleukin-4 zu einer Verschiebung der T-Zell-Subpopulationen in Richtung Th2. Zudem wird die Aktivierung der B-Zellen vermutlich ebenfalls über einen T-Zell-vermittelten Mechanismus behindert. Auf der Effektorebene kann Gold einen weiteren Einfluss auf proteolytische Enzyme durch Interaktion mit Disulfidbrücken ausüben. Weiterhin zeigen die destruktiven synovialen Fibroblasten bei in vitro-Studien toxische Deformierungen und Lysezeichen, so dass m?glicherweise auch in dieser Phase Gold wirksam ist. Zusammenfassend ist Gold weiterhin eines der faszinierendsten antirheumatischen Pharmaka mit einem au?erordentlich vielf?ltigen Wirkungsspektrum. Durch weitere Analyse molekularer Mechanismen, insbesondere im Bereich der Signaltransduktion, dürften in absehbarer Zeit neue fundamentale Erkenntnisse über seine Wirkung entwickelt werden, die sicher auch Rückschlüsse auf die Wirksamkeit anderer Antirheumatika erlauben und zum Pathogeneseverst?ndnis der rheumatoiden Arthritis beitragen werden.     

B-Zell-Depletion in der Therapie der rheumatoiden Arthritis

New strategies including the blockade of TNFalpha showed excellent therapeutic effects even in so far refractory rheumatic diseases. Moreover, these approaches provided us with important informations about the pathogenic role of the mediators involved and distinct autoimmune cellular subsets. Here, we discuss recent data of a temporary B cell depletion using a monoclonal anti-CD20 antibody in the therapeutic arsenal of rheumatoid arthritis.     

Radiologische Diagnostik der zervikalen rheumatoiden Arthritis

Rheumatoid arthritis leads to characteristic findings at the synovial joints, the intervertebral discs and the processes of the cervical spine. Isolated findings are not specific for rheumatoid arthritis. In fact, due to common underlying pathophysiologic changes they also develop in other inflammatory diseases affecting the cervical spine. Therefore, each radiological examination is to be understood and used as a piece in the diagnostic puzzle. Only in conjunction with clinical information does it add to a conclusive diagnosis. Nevertheless certain patterns of findings help in narrowing the list of differential diagnosis. Besides their role in initial diagnosis, radiological examinations are crucial tools in the peri- and post-operative work-up and in the detection of typical complications of rheumatoid arthritis with cervical manifestations, i. e. various instabilities and their consequences, as those have an impact on the therapeutic approach and prognosis.     

Kombinationstherapie der rheumatoiden Arthritis mit Gold

Zusammenfassung Intramuskul?res Gold geh?rte über Jahrzehnte hinweg zu den Standard-Basistherapeutika der rheumatoiden Arthritis. Studien zur Kombination mit anderen Basistherapeutika weisen lediglich auf einen marginalen Zugewinn an Wirksamkeit, der in Einzelf?llen durchaus genutzt werden kann. Prospektive Studien selektiv bei Frühf?llen mit hoher Prozessaktivit?t fehlen jedoch v?llig, obgleich gerade bei ihnen eine gesteigerte therapeutische Wirksamkeit erwartet werden kann. Es wird spekuliert, dass die Kombination des langsam wirkenden Goldes mit rasch wirkenden Substanzen wie Leflunomid oder TNFα-Blockern zu einer Optimierung des Therapieergebnisses führt. Derartige Kombinationen sollten in Zukunft gezielt untersucht werden.