[Hyperuricemia. When and how to treat?]. / Hyperurikämie. Wann und wie behandeln?

The prevalence of (asymptomatic) hyperuricemia and gout has substantially increased in recent decades. This development is due to fundamental lifestyle changes, dramatically rising prevalence of obesity and metabolic syndrome, as well as the increasing age of patients. Therefore, medical treatment of hyperuricemia has regained interest in recent years, in particular since after decades of therapeutic stagnation, new treatments of hyperuricemia have been approved or are currently being investigated in clinical trials. European and American guidelines/recommendations for treatment of hyperuricemia and gout have been updated and revised. Furthermore, the role of asymptomatic hyperuricemia as an (independent) cardiovascular risk factor is again under debate. This article provides assistance in integrating our present knowledge in a therapeutic context and summarizes currently recommended treatment strategies.

[Metabolic bone disease osteomalacia]. / Metabolische Knochenkrankheit Osteomalazie.

Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases.

[Innovative individualized rehabilitation concepts in oncology]. / Innovative individualisierte Rehabilitationskonzepte in der Onkologie.

Die onkologische Rehabilitation zielt auf die Verbesserung der körperlichen, psychischen und sozialen Fähigkeiten und Unterstützung bei der Bewältigung der Krankheit ("Coping") ab. Ein wichtiges Ziel ist dabei neben der psycho-onkologischen Therapie die Steigerung der körperlichen Aktivität zur Prävention und Therapie chronischer Krankheiten, insbesondere auch der mit steigender Überlebensrate an Bedeutung zunehmenden Folge- und Begleiterkrankungen. Immer mehr Beobachtungsstudien weisen außerdem darauf, dass körperliche Aktivität auch die Prognose der Krebserkrankung günstig beeinflussen kann. Die beste Evidenz besteht dabei bislang für das (Hormonrezeptor-positive) postmenopausale Mamma-Karzinom. Eine nachhaltige Lebensstilmodifikation ist bislang oft nur schwer erreichbar. Langfristig angelegte, interdisziplinäre Rehabilitationskonzepte, deren Ziel eine intensive und nachhaltige Steigerung der körperlichen Aktivität ist, scheinen bei Brustkrebspatientinnen ein erfolgversprechender Ansatz zu sein und werden durch das hier vorgestellte Studienkonzept exemplarisch erläutert.

[Rheumatic and hemato-/oncological disorders]. / Rheuma und hämato-onkologische Erkrankungen.

The association of rheumatic diseases with common and some of the less common hematological features such as different forms of anemia, leukopenia and thrombopenia are described in this article. In addition, the occurrence of malignancy in rheumatoid arthritis, systemic lupus erythematosus, myositis and scleroderma and possible causes are discussed. On the other hand, this review also focuses on various rheumatological manifestations of hematological diseases such as leukemia and lymphoma. The aim of the article is to give an overview of the various associations between rheumatological and hemato-/oncological diseases that have to be considered in clinical practice.

[Long-term analysis of clinical disease activity and chronic organ damage in patients with systemic lupus erythematosus]. / Krankheitsaktivität und chronische Organschäden bei Patienten mit systemischem Lupus erythematosus (SLE) im Langzeitverlauf.

BACKGROUND: Systemic lupus erythematosus is a chronic inflammatory and systemic disease with multiple symptoms which is often characterized by a course of exacerbations. Over the last few decades the prognosis of SLE considerably improved with >90% patients living more than 10 years with their disease. AIM OF THE STUDY AND METHODS: The aim of this retrospective-descriptive analysis of 65 patients with the diagnosis of SLE (based on the ARA criteria) was to investigate the symptoms and the laboratory values at the time of diagnosis (TD) and over a period of 10 years (10Y) in the outpatient university clinic of the Department of Nephrology and Rheumatology at Goettingen. In addition to symptoms and laboratory values, disease activity, exacerbations, chronic organ failure, and medical therapy were to be investigated. RESULTS: The long-term analysis revealed a decline in the prevalence of ANAs (TD: 95.6%; >10Y: 78.6%), ds-DNA antibodies (TD: 78.0%; >10Y: 46.7%) and pathological levels of the complement component C3 (TD: 72.7%; >10Y: 42.9%) over time. The symptoms most prevalent at the time of first diagnosis such as the typical butterfly rash (TD: 50.0,%; >10Y: 36.8%), discoid skin lesions (TD: 38.8%; >10Y: 23.5%) were noted less often after a 10 year-disease course. On the contrary the frequency of arthralgias (TD: 61.2%; >10Y: 57.9%), myalgias (TD: 26.1%; >10Y: 26.3%) and fatigue (TD: 63.0%; >10Y: 64.7%) remained stable over time. The prevalence of arterial hypertension (TD: 17.2%; >10Y: 54.5%), proteinuria (TD: 33.3%; >10Y: 66.7%) and erythrocyturia (TD: 27.8%; >10Y: 44.4%) remarkably increased during the disease course. Besides renal damage, coronary artery disease (TD: 6.0%; >10Y: 23.0%) and neurological disease (e.g., cerebrovascular insults) (TD: 10.9%; >10Y: 26.3%) were noted more often after 10 years. Of patients, 56.9% developed one or several exacerbations of the disease. In all cases, clinical symptoms correlated with an increase in the level of ds-DNA-antibodies and a decrease of C3-complement component. Other medications included immunosuppressants, antihypertensive drugs and NSAIDs. High-dose steroids were preferred as the first diagnosis (TD: 44.4%; >10Y: 11.1%), while low-dose steroids were more often prescribed after a 10-years diseases course (TD: 6.7%; >10Y: 27.8%). CONCLUSIONS: There is a shift towards secondary organ damage with a decline of the inflammatory activity in patients with SLE after 10 years of disease. These consecutive diseases are due to the primary damage of SLE as well as to medical treatment (e.g., with steroids).

Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry.

OBJECTIVE: A Th1/Th2 cytokine imbalance with a predominance of Th1 cytokines has been suggested to be of pathogenetic importance in rheumatoid arthritis (RA). To evaluate the role of Th1/Th2 cytokines in RA, we used intracellular cytokine flow cytometry to determine cytokine profiles of CD4+ and CD8+ T cells in 34 peripheral blood (PB) and 10 synovial fluid (SF) samples from patients with RA. Results were compared with 10 PB samples from healthy controls (HC) and 5 SF samples from patients with non-RA synovitis. METHODS: After stimulating cells with PMA and ionomycin or alternatively with anti-CD3/CD28 in the presence of brefeldin A, intracellular levels of Th1 [interleukin 2 (IL-2), interferon-gamma (IFN-gamma)] and Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were determined for CD3+CD8- (i.e., CD4+ Th1 and Th2 cells) and CD3+CD8+ (i.e., CD8+ Tc1 and Tc2 cells) T cells. RESULTS: The percentages of CD4+ and CD8+ Th1 and Th2 cytokines producing T cells (PB) were similar in patients with RA and healthy controls (HC), with a clear predominance of Th1 cytokines expressing, T cells. With regard to T cell subsets, IFN-gamma-producing T cells were significantly more frequently detected in the CD8+ subset [CD8+: median 45.1% (RA; p < 0.001), 38.2% (HC; p = 0.009) vs CD4+: 10.8%(RA), 17.0% (HC)]. Conversely, IL-2 was found in a higher percentage of CD4+ T cells [CD4+: median 33.4% (RA), 17.9% (HC) vs CD8+: 23.6% (RA), 12.3% (HC)]. Patients not in disease remission tended to have more IFN-gamma-producing CD8+ and IL-2-producing CD4+ T cells than patients in remission [CD8+: median 45.9% (IFN-gamma) vs 23.0% (IFN-gamma); CD4+: median 34.1% (IL-2) vs 18.2% (IL-2)1. In all PB samples, the proportion of T cells producing the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 did not exceed 2%. Cytokine profiles did not differ between patients receiving immunosuppressive treatment and patients treated only with nonsteroidal antiinflammatory drugs. In comparison to PB, RA SF analysis revealed a significant increase in the percentage of IFN-gamma-producing CD4+ (p < 0.001) and CD8+ T cells (p < 0.001). In addition, the percentage of IL-10-producing CD4+ (p < 0.001) as well as CD8+ T cells (p = 0.001) was significantly elevated in SF. However, production of the other Th2 cytokines (IL-4, IL-5, IL-13) was similar in SF and PB. CONCLUSION: These data indicate similar cytokine profiles of T cells in PB of RA patients and healthy controls, with a strong predominance of Th1 cytokines producing T cells in the CD4+ and CD8+ T cell subset of both groups. PB cytokine profiles did not significantly differ in patients with active and non-active disease or between patients receiving and those not receiving immunosuppressive medication. In SF, the proportion of Th1 and Tcl cells was significantly elevated compared to PB, emphasizing the local importance of these cells for inflammation. CD8+ T cells (Tc1 cells) mainly contributed to the production of IFN-gamma, indicating an underestimated role of this cell subset for local cytokine production. The upregulation of IL-10-producing Th2 and Tc2 cells in SF may reflect an insufficient effort to down-regulate chronic inflammation in the joint. Modifying this cytokine imbalance in the joints may be a promising therapeutic approach in RA.

Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis.

OBJECTIVES: The interaction between the activation induced surface glycoprotein CD40L (ligand) (CD154) on CD4+ T cells and its receptor CD40, which is expressed on various cell types, plays a crucial part in numerous cell mediated and humoral immune reactions that may be of pathogenetic importance in rheumatoid arthritis (RA). To further evaluate the pathogenetic role of CD40L in RA, expression of CD40L and various other T cell activation antigens as well as costimulatory molecules was investigated on CD4+ T cells in RA by flow cytometry. METHODS: Two colour flow cytometry was used to determine the percentage of CD4+ T cells expressing CD40L, CD69, CD25, HLA-DR, CD39, CD27 and CD28 in peripheral blood (PB) of 62 RA patients in comparison to 20 healthy controls (HC). Disease activity was assessed by clinical, laboratory and radiological examination. Status of clinical remission of RA was evaluated according to the ACR preliminary criteria for complete clinical remission of RA. RESULTS: CD40L was expressed on > 10% of CD4+ T cells in 29% of RA patients thus defining a CD40L(high+) patient group. Disease activity as estimated by C reactive protein, rheumatoid factor and status of clinical remission of disease (p = 0.049) was higher in this subgroup than in the RA CD40L(low+) group. Expression of CD69, CD25, and HLA-DR was significantly increased in both RA patient groups in comparison with HC. However, the percentage of CD39+ CD4+ T cells was increased only in the RA CD40L(high+) subgroup (versus HC p = 0.019, versus RA CD40L(low+) p = 0.044). Furthermore, expression of CD40L and CD39 on CD4+ T cells correlated positively as estimated by Spearman rank correlation (p<0.001). The percentage of CD4+ T cells lacking the costimulatory molecules CD27 (p = 0.002) and CD28 (p = 0.026) was increased in RA CD40L(low+) patients in comparison with HC. CONCLUSIONS: These data suggest that increased expression of CD40L on CD4+ T cells in RA indicates prolonged and increased activation of CD4+ T lymphocytes and is associated with active disease and possibly an unfavourable prognosis. Whether this phenotypically defined RA CD40L(high+) subgroup will preferentially respond to an anti-CD40L antibody treatment remains to be elucidated.