[Gout]. / Gicht.

Gout is the most common inflammatory arthritis in men with a rising incidence worldwide. It is a metabolic disease caused by hyperuricemia. Common causes of hyperuricemia, in addition to hereditary reduced renal excretion of urate, include purine over-nutrition, aging, comorbidities and associated medications, some of which increase serum urate levels. The first gout flare represents the signal for deposited urate crystals. If hyperuricemia remains untreated, crystal deposition proceeds and can cause recurrent gout flares, joint destruction and tophi. There is evidence that silent inflammation is ongoing even during asymptomatic stages. Gout patients often exhibit other metabolic, renal and cardiovascular co-morbidities and have higher (cardiovascular) mortality. Therefore, guidelines call for consequent urate lowering strategies to bring serum urate levels to a target at least below 360 µmol/l. The following article summarizes the recent state of knowledge regarding the diagnosis and therapy of gout.

[Evidence-based recommendations for diagnostics and treatment of gouty arthritis in the specialist sector : S2e guidelines of the German Society of Rheumatology in cooperation with the AWMF]. / Evidenzbasierte Empfehlung zur Diagnostik und Therapie der Gichtarthritis im fachärztlichen Sektor : S2e-Leitlinie der Deutschen Gesellschaft für Rheumatologie (DGRh) in Kooperation mit der AWMF.

Due to the increasing prevalence of gout, particularly in old age, the disease is becoming of increasing importance in Germany. Gout is one of the most common forms of recurrent inflammatory arthritis and is induced by the deposition of monosodium urate crystals in synovial fluid and other tissues. The principal goals of therapy in chronic gout are the symptomatic treatment of the acute joint inflammation and the causal treatment of the underlying metabolic cause, the hyperuricemia. Only a consistent and permanent reduction of the serum uric acid level ultimately results in an efficient avoidance of further gout attacks and therefore the prevention of structural damage. Due to an often inadequate treatment of gout, the target of healing the disease is often not achieved. A correct and timely diagnosis and adequate assessment of comorbidities associated with gout are, however, of substantial importance for patient and physician to achieve remission of the disease. In order to create a solid basis for a timely and effective treatment of affected patients, in 2016 the German Society of Rheumatology (DGRh) initiated the development of S2e guidelines on gouty arthritis for specialists. This article summarizes these S2e guidelines on the management of gouty arthritis in the specialist sector.

2016 updated EULAR evidence-based recommendations for the management of gout.

BACKGROUND: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. METHODS: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. RESULTS: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. CONCLUSIONS: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

[Gouty arthritis]. / Gicht.

Gouty arthritis is the most common form of arthritis in men. As a consequence of persisting hyperuricemia, uric acid crystals are deposited in the intra-articular and periarticular spaces and activate the innate immune system. The clinically impressive abrupt onset monoarticular arthritis in the lower extremities is highly suggestive of a gout attack. Arthrosonography can be used for early detection of crystal deposition on joint cartilage. In synovial fluid the detection of uric acid crystals in polarization microscopy is proof of gout even without the detection of intracellular uric acid crystals. Rapidly acting anti-inflammatory drugs are available for acute treatment of attacks; however, the essential therapy is the effective and life-long drug treatment of hyperuricemia from the first attack onwards, typically with allopurinol or febuxostat. This review delineates the clinically relevant knowledge on the pathogenesis, diagnosis and therapy of gout based on the currently available evidence.

[Do we still need clinical studies in rheumatology?]. / Brauchen wir noch klinische Studien in der Rheumatologie?

Despite a large number of approved therapies demonstrating efficacy in the treatment of rheumatic diseases, only 60-85 % of patients with the indications for rheumatoid arthritis are adequately treated in Germany. Additionally, approved therapies for other immune-mediated diseases are often entirely lacking, indicating the great medical need for the development of new innovative therapies in this specialized field. The development of new drugs is expensive due to the high costs of conducting clinical trials in all phases of development up to obtaining approval; therefore, pharmaceutical companies are looking for ways to save costs in the particular developmental stages. Although the classical regions for drug development (i.e. western Europe, the USA and Japan) offer both a high level of data quality and a good infrastructure to conduct clinical trials due to high standards of education and quality, clinical trials are expensive in these regions. Beside high costs, the comparatively low recruitment rates in these regions are one of the main reasons for the shifting of drug developmental stages from classical regions to eastern European, Latin American and Asian countries, which provide services for drug development and high recruitment rates for comparatively less money. However, there are many strong arguments for the participation of regions in western Europe, especially German sites in clinical trials. In this article these arguments are discussed and possible solutions and strategies for conducting and compensation of study centers in Germany for clinical trials in the field of rheumatology are provided.

[Chondrocalcinosis due to calcium pyrophosphate deposition (CPPD). From incidental radiographic findings to CPPD crystal arthritis]. / Chondrokalzinose durch Kalziumpyrophosphat-Dihydrat-Ablagerung (CPPD) : Vom radiologischen Zufallsbefund zur CPPD-Kristallarthritis.

If acute arthritis occurs in the elderly in addition to typical degenerative, load-related joint complaints, this is often induced by crystal deposition. The crystals lead to activation of the immune system resulting in acute inflammation. In addition to gout, calcium pyrophosphate deposition (CPPD) disease in particular must also be taken into consideration. Diagnostically important are imaging techniques, e.g. early specific alterations of cartilage can be shown by joint sonography and later calcium pyrophosphate crystals can be detected as cartilage calcification (chondrocalcinosis) by radiography. Important for the diagnosis of crystal arthropathy is usually the microscopic detection of specific crystals in the synovial fluid and is supported by exclusion of septic arthritis by arthrocentesis. In contrast to gout, which can be well controlled by the pharmaceutical lowering of uric acid levels, there is no causal therapy for CPPD disease so far. As CPPD may occur as a secondary effect in metabolic disorders, such as hyperparathyroidism or hemochromatosis, it seems to be important to search for the underlying disease. The following article presents the current knowledge on clinically relevant aspects of the pathogenesis, diagnosis and therapy of CPPD disease.

As compared to allopurinol, urate-lowering therapy with febuxostat has superior effects on oxidative stress and pulse wave velocity in patients with severe chronic tophaceous gout.

We prospectively evaluated whether an effective 12-month uric acid-lowering therapy (ULT) with the available xanthine oxidase (XO) inhibitors allopurinol and febuxostat in patients with chronic tophaceous gout has an impact on oxidative stress and/or vascular function. Patients with chronic tophaceous gout who did not receive active ULT were included. After clinical evaluation, serum uric acid levels (SUA) and markers of oxidative stress were measured, and carotid-femoral pulse wave velocity (cfPWV) was assessed. Patients were then treated with allopurinol (n = 9) or with febuxostat (n = 8) to target a SUA level ≤ 360 µmol/L. After 1 year treatment, the SUA levels, markers of oxidative stress and the cfPWV were measured again. Baseline characteristics of both groups showed no significant differences except a higher prevalence of moderate impairment of renal function (estimated glomerular filtration rate <60 ml/min) in the febuxostat group. Uric acid lowering with either inhibitors of XO resulted in almost equally effective reduction in SUA levels. The both treatment groups did not differ in their baseline cfPWV (allopurinol group: 14.1 ± 3.4 m/s, febuxostat group: 13.7 ± 2.7 m/s, p = 0.80). However, after 1 year of therapy, we observed a significant cfPWV increase in the allopurinol group (16.8 ± 4.3 m/s, p = 0.001 as compared to baseline), but not in the febuxostat patients (13.3 ± 2.3 m/s, p = 0.55). Both febuxostat and allopurinol effectively lower SUA levels in patients with severe gout. However, we observed that febuxostat also appeared to be beneficial in preventing further arterial stiffening. Since cardiovascular events are an important issue in treating patients with gout, this unexpected finding may have important implications and should be further investigated in randomized controlled trials.

[Gout as a systemic disease. Manifestations, complications and comorbidities of hyperuricaemia]. / Die Gicht als Systemerkrankung. Manifestationen, Begleit- und Folgeerkrankungen der Hyperurikämie.

Of all inflammatory rheumatic diseases gout has the highest prevalence. Patients with intermittent acute gout attacks are usually treated by primary care physicians. However, in cases of insufficient long-term control of serum uric acid levels, complications or atypical clinical manifestations may necessitate consultation with a rheumatologist in the further course of the disease. An oligoarticular or polyarticular presentation can give rise to the initial suspicion of rheumatoid or psoriatic arthritis. In these cases a careful clinical work-up supported by laboratory and imaging investigations is necessary and synovial fluid analysis is usually required. As in other rheumatic diseases extra-articular manifestations are of utmost importance for morbidity and mortality. Gout is a complex metabolic and inflammatory disease and besides articular symptoms the renal and cardiovascular effects of hyperuricemia are particularly relevant for the overall prognosis.

[Gout - regardless of therapeutic options a "forgotten" disease]. / Gicht - die "vergessene" Erkrankung trotz vieler therapeutischer Optionen.

Compared to other chronic inflammatory diseases, gout appears to based on a rather "simple" pathophysiology and therefore the amount of teaching time in medical school and during internship is rather limited. On the other hand, several problems in short- and long-term management still need to be solved - combined with the problem of an increased incidence in elderly people. However, there is significant advance in the knowledge of its pathophysiology including the fact that gout is more than a pure "crystal arthopathy" but rather within the spectrum of chronic inflammatory immunologic diseases. This includes cytokines such as interleukin-1 and intracellular signaling via the inflammasome. For treatment, the novel and effective xanthine oxidase inhibitor febuxostat has been added to the therapeutic armamentarium. Guidelines of EULAR and BSR support the physician in the long-term management of the numerous gout patients.

[Crystal-induced activation of the inflammasome: gout and pseudogout]. / Kristallinduzierte Inflammasomaktivierung: Gicht und Pseudogicht.

Crystals in tissues lead the innate immune system to the same kind of acute response seen with pathogens. Via activation of the inflammasome, interleukin-1 (IL-1) is released, which upregulates mediators such as cyclooxygenase, tumor necrosis factor, and IL-8 and induces an acute granulocytic inflammation. Therefore, in addition to nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and colchicine, IL-1 blockers appear to be effective. Large clinical trials have already been initiated. Such an approach could constitute a valuable alternative for patients with contraindications or insufficient response to NSAIDs. After the attack has subsided, control of uric acid metabolism is central. At least several of the responsible urate transporters have been unraveled, which could lead to more focused therapy in the future. At present, diet and blockade of uric acid synthesis remain the main pillars of therapy. The new xanthine oxidase inhibitor febuxostat constitutes a novel option for patients with renal insufficiency or intolerance to allopurinol.

[Molecular basis of primary renal hyperuricemia : role of the human urate transporter hURAT1]. / Molekulare Grundlagen der primär-renalen Hyperurikämie : Zur Rolle des humanen Urattransporters hURAT1.

In highly industrialized countries hyperuricemia is one of the most common metabolic disorders. High uric acid blood levels may lead to the manifestation of gout owing to the precipitation of urate crystals in connective tissue, the skeletal system and kidneys. A primary reduction of renal uric acid excretion can be detected in more than 90% of all cases of hyperuricemia. Despite the identification of several uric acid transporting proteins their pathogenetic role for the induction of primary reduced renal uric acid excretion has not yet been verified. As a result of a case-control study on individuals with normal and reduced renal uric acid excretion, an association of polymorphisms in the human urate transporter 1 gene (hURAT1) with primary reduced urate excretion has been demonstrated for the first time. The hURAT1 gene is an organic anion transporter (SLC22A12), which is preferentially expressed in the apical membrane of proximal renal tubule cells. Functioning as an antiporter, hURAT1 mediates the uptake of urate from the lumen into proximal tubule cells in exchange for organic and inorganic anions. Loss-of-function mutations in the hURAT1 gene are a cause of hereditary renal hypouricemia. The precisely regulated hURAT1 is a candidate gene for hyperuricemia and an important target for the development and optimization of new diagnostic approaches and pharmacological interventions of primary reduced renal uric acid excretion.

[Hyperuricemia and gout: diagnosis and therapy]. / Hyperurikämie und Gicht : Diagnostik und Therapie.

In our modern society hyperuricemia is one of the most frequent metabolism disturbances. So far, every fourth man and every tenth woman suffer from an asymptomatic or a symptomatic hyperuricemia named gout. Mostly, over nutrition and malnutrition as well as other secondary factors with a genetically determined renal secretion disturbance of uric acid lead to an increase of serum uric acid. By deposition of uric acid crystals in tissues with intermittent immunologic activation of inflammation cells a manifestation of gout can be seen. The clinical image of gout varies widely. It may manifest as acute or chronic arthritis, tophi on the skin, subcutaneous tissue and the skeletal system as well as urate nephropathy. To eliminate the consequences of hyperuricemia in the long term, apart from a thorough anamnesis of nutritional habits a general examination of metabolic parameters is necessary to exclude a metabolic syndrome and other causes for a secondarily caused hyperuricemia. As gout is very often primarily caused by a renal secretion disturbance of uric acid special diagnostics should be done. Basing on literature research and inclusion of experts opinions this article represents the therapeutically options in treatment of hyperuricemia and gout with their resulting side effects and contraindications.