[Ultrasound-targeted joint puncture in rheumatology]. / Ultraschallgezielte Gelenkpunktion in der Rheumatologie.

Joint punctures not only have a long tradition but are also an essential component in the diagnostic differentiation of various joint diseases. In addition, therapeutic injections are an essential component of an individual targeted treatment strategy in a disease-modifying antirheumatic drug (DMARD)-based treat-to-target concept. This article aims to convey to the reader the ultrasound-targeted joint puncture techniques in text and with many video clips that can be downloaded. This article therefore steps away from the conventional two-dimensional demonstration of anatomy-oriented puncture techniques and elucidates the diagnostic and therapeutic potency of ultrasound-targeted techniques in the daily routine. Furthermore, special importance is given to a sterile working technique, puncture material and synovial analysis.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 2: clinical features, diagnosis and differential diagnostics.

Gout develops in four stages beginning with an asymptomatic increase in blood levels of uric acid. An acute gout attack is an expression of an underlying inflammatory process, which in the course of time is self-limiting. Without therapy monosodium urate crystals remain in the synovial fluid and synovial membrane and trigger more acute attacks. In the course of the disease monosodium urate crystals form deposits (tophi) leading in severe forms to irreversible joint deformities with loss of functionality. In 20% of cases gout leads to involvement of the kidneys. Overproduction of uric acid can cause nephrolithiasis. These stones can be composed of uric acid or calcium phosphate. Another form of kidney disease caused by gout is uric acid nephropathy. This is a form of abacterial chronic inflammatory response with deposition of sodium urate crystals in the medullary interstitium. Acute obstructive nephropathy is relatively rare and characterized by renal failure due to uric acid precipitation in the tubules because of rapid cell lysis that occurs, for example, with chemotherapy. There is a causal interdependence between the occurrence of hyperuricemia and hypertension. Uric acid activates the renin-angiotensin-aldosterone (RAA) system and inhibits nitric oxide (NO) with the possible consequence of a rise in systemic vascular resistance or arteriolar vasculopathy; however, uric acid is also an apparently independent risk factor for atherosclerosis. In contrast to young patients, the diagnosis of an acute gout attack in the elderly can be a challenge for the physician. Polyarticular manifestations and obscure symptoms can make it difficult to differentiate it from rheumatoid arthritis and calcium pyrophosphate deposition disease (CPPD). Aspiration of synovial fluid with visualization of urate crystals using compensated polarized light microscopy is the gold standard for diagnosis of acute gout. Moreover, analysis of synovial fluid enables a distinction from septic arthritis by Gram staining and bacterial culture. Soft tissue ultrasonography is useful to detect affected synovial tissue and monosodium urate crystals within the synovial fluid. Involvement of bone occurs relatively late in the disease so that x­ray images are not useful in the early stages but might be helpful in differential diagnostics. Dual energy computed tomography (CT) and magnetic resonance imaging (MRI) can be used for certain indications.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 1: Epidemiology and pathophysiology.

Gout and calcium pyrophosphate deposition disease (CPPD, pseudogout) are still the most frequent inflammatory arthritides in multimorbid elderly patients. Gout and CPPD are different diseases and based on different pathophysiological principles. Gout is closely associated with the metabolic syndrome and is an independent risk factor for cardiovascular mortality. The prevalence of asymptomatic hyperuricemia is estimated to be 10-20% of adults in industrial nations and prevalence is strongly associated with age. More than 7% of persons aged over 65 years suffer from clinically manifest gout. The underlying pathophysiological principle is an imbalance between the formation and elimination of uric acid. The degradation of the purine bases adenine and guanosine to uric acid is catalysed by xanthine oxidase and genetic polymorphisms and mutations play an important role in absorption and excretion processes. Furthermore, carrier proteins, such as URAT-1 or OAT-4 also have an influence on these processes. An imbalance of the physiological processes results in the solubility product being exceeded, which in consequence leads to crystallization of urate. This induces a cascade of massive inflammatory reactions at the molecular and cellular level with the activation of cytokines. The inflammatory process can be stopped by neutrophil extracellular traps (NETs) that modulate aggregation and degradation of chemokines and cytokines and partitioning of crystallized urate against immune cells. Calcium pyrophosphate dehydrate (CPP) crystals are formed in the cartilage and CPP deposition can be found in 30% of people aged over 80 years. Inorganic pyrophosphate (PPi) is synthesized in chondrocytes and plays an important part in the formation of calcium pyrophosphate crystals. The degradation is catalyzed by inorganic pyrophosphatases. If there is dysregulation of this homeostasis more PPi is produced, which ultimately contributes to the formation of the CPP crystals.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part 3: Treatment.

The treatment of gout is based on several principles. Symptom control and termination of the inflammatory process are important early goals, whereas the urate level should be lowered in the long term to prevent further gout attacks and complications. The non-pharmacological approach is based on individually informing the patient on dietary measures and changes of life style. Besides physical measures, such as cold applications on the affected joint, various medications are available for treatment of an acute gout attack. The choice of drug depends on the individual risk profile. If non-steroidal anti-inflammatory drugs (NSAID) and coxibs are chosen it should be taken into account that the use is restricted in patients with renal insufficiency. Moreover, these drugs may have gastrointestinal side effects and are associated with increased cardiovascular morbidity and mortality. Colchicine has gastrointestinal side effects at high dosages but can also be used for differential diagnostics if there is a quick response to treatment. Steroids are an effective alternative and can be given orally or parenterally in patients with dysphagia. Moreover, steroids can be used in cases of renal insufficiency. After symptoms of the acute attack have subsided, urate lowering therapy should be initiated to prevent further attacks. Low-dose urate lowering therapy can be started during an acute gout attack when acute therapy is initiated. Allopurinol is still the medication of choice but its use is restricted in patients with renal insufficiency. A rare but serious side effect is allopurinol hypersensitivity syndrome. Febuxostat can be an alternative in patients who do not tolerate allopurinol. In February 2016, lesinurad, an URAT-1 and OAT-4 inhibitor, was approved in combination with allopurinol or febuxostat. Data on the effectiveness and safety of synthetic uricases and biologicals are still sparse for elderly patients. These substances are reserved for severe cases of gout.

[Combination of biologics : where do we stand?]. / Kombination von Biologika : Wo stehen wir?

INTRODUCTION: Data with respect to safety and therapeutic efficacy for the combination of biological DMARDs is scarce and inhomogeneous in order to make final conclusions. To this end, data to biologic combinations is disappointing due to relatively low therapeutic efficacy and partially enhanced rates of severe infectious events. METHODS: Combining biologics is an option only in very special situations (RTX plus TNFi). In addition, the relation of financial effort to therapeutic efficacy is questionable, especially in the situation of numerous drug options (anti-cytokine principle, T-cell inhibition, B-cell depletion) and therapeutic strategies of combining biologics with DMARDs. Generally speaking, combinations of biological should only be used in clinical trials. New drugs influencing intracellular signaling pathways (small molecules) are going to be approved or are already approved by the drug agencies, thus, adding to the existing armamentarium. Furthermore, combinations with these new molecules are going to be interesting. CONCLUSIONS: This review summarizes the available studies concerning combination of biologicals in a tabular fashion.

[Screening and early diagnosis of psoriasis arthritis]. / Screening und Frühdiagnostik der Psoriasisarthritis.

Psoriasis arthritis (PsA) encompasses many diverse clinical symptoms. Epidemiological data about the prevalence in general, predisposed age groups, prevalence of joint, spine, enthesis, and extra-articular manifestations are very heterogeneous. Even for the PsA specialist the clinical picture is not always easy to differentiate from other overlapping or clinically similar disease entities. This paper tries to give some guidance on how to screen for and how to detect PsA early in the population of psoriasis patients on the basis of the Mainz PsA screening and early diagnosis algorithm.

[Ultrasound-guided joint injections in patients with rheumatic diseases]. / Sonographisch geführte Gelenkpunktionen in der Rheumatologie.

Joint and soft tissue injections are routinely performed in daily rheumatology practice to establish the diagnosis or as part of the treatment in patients suffering from rheumatic diseases. Consequently, joint injections have been included in the rheumatology further training curriculum. Despite numerous studies demonstrating a poor accuracy and outcome of joint injections guided only by clinical examination, most of the injection procedures are still performed in a "blind" fashion based on clinical judgment. Ultrasound has evolved as an established imaging method in rheumatology within the past decade and is considered the preferred imaging modality for joint interventions due to its availability and lack of radiation exposure. In this article the indications and important aspects of the practical management of ultrasound-guided injections performed in daily rheumatology practice are summarized.

[Ultrasound-guided puncture : an inexpensive and effective learning model]. / Ultraschallgesteuerte Punktion : Ein kostengünstiges und effektives Lernmodell.

Ultrasound is present in almost any practice and hospital clinic today. In clinical practice, puncture of structures, injections of local anesthetics or glucocorticoids are frequently performed. However, unguided puncture into tissue may have deleterious side-effects if the target is not reached or the drug is not injected properly, such as bleeding, traumatization of delicate structures, glucocorticoid-induced tendon rupture and skin necrosis. Coordination of eye, probe and the manipulation hand needs practice before being used on patients.Therefore, we developed an inexpensive, easy to make and effective learning model for ultrasound-guided puncture and injections. We describe how the model is made and how it can be used to efficiently enhance learning success. It was found that a person unskilled in ultrasonography needs about 40-60 coached punctures in order to confidently hit the target.This model has already been used in our medical education program for rheumatologists, internists, surgeons, orthopedic specialists, anesthetists and general practitioners with great success.

Serum BAFF strongly correlates with PsA activity in male patients only--is there a role for sex hormones?

OBJECTIVES: To determine the relationship between serum levels of B cell activating factor belonging to the TNF family (BAFF) and disease activity (DAS28) in psoriatic arthritis (PsA) patients. METHODS: Twenty-two male and 31 female psoriasis patients fulfilling the CASPAR criteria for PsA were recruited for the study. Disease activity was recorded using the disease activity score for 28 joints (DAS28). Whole blood and serum samples were analysed for serum BAFF, estradiol, and testosterone levels. RESULTS: Serum BAFF levels were positively correlated with DAS28 only in male PsA patients (r=0.669, p<0.001). In male but not female patients, serum testosterone was negatively correlated with DAS28 (r=-0.632, p=0.002), and serum BAFF (r=-0.520, p=0.018), respectively. The serum BAFF/ serum testosterone (B/T) ratio showed a strong correlation with DAS28 in male patients (r=0.743, p<0.0001) and, again, no correlation was found in female participants (r=0.019, p=0.93). A linear regression analysis showed that the B/T is a good predictor of DAS28 (r2=0.586, p<0.001). On the other hand, estradiol levels did neither correlate with PsA activity in male nor female patients in our study population. CONCLUSIONS: Even though a role for B cells in the pathogenesis of PsA has not been established, BAFF levels correlate with disease activity in male PsA patients. Furthermore, serum testosterone in male patients negatively correlates with disease activity and BAFF, respectively. The serum BAFF/serum testosterone ratio might be used as predictor of disease activity in male PsA patients.

[Detection of psoriasis arthritis with the GEPARD patient questionnaire in a dermatologic outpatient setting]. / GEPARD-Patientenfragebogen: Erfassung von Patienten mit Psoriasisarthritis aus einem ambulanten dermatologischen Patientenpool.

BACKGROUND: Diagnosis of psoriasis arthritis (PsA) is often delayed in an outpatient dermatological setting. Therefore, we compiled a patient questionnaire (GEPARD, GErman Psoriasis ARthritis Diagnostic questionnaire) to detect PsA in psoriasis outpatients. PATIENTS AND METHODS: Initially, between 2005 and 2007, we evaluated GEPARD in the outpatient setting of our Department of Dermatology with the Vasey and Espinoza criteria. In May 2008, the questionnaire was distributed to practices in the Regensburg area, Germany. Patients who filled out the GEPARD questionnaire were invited for a rheumatological work-up and, where indicated, arthrosonography, conventional X-ray, MRI, and scintigraphy examinations were performed. PsA was classified on the basis of the CASPAR criteria. RESULTS: We calculated a sum cut-off score of >or= 4 positive answers in the first cohort. Of all 54 patients examined 63% could be diagnosed with PsA according to the CASPAR criteria. After a complete work-up with all diagnostic means 79.6% (43 patients) could be detected with inflammatory joint manifestations. CONCLUSION: It is possible to detect PsA patients in a dermatologic outpatient setting with the GEPARD questionnaire.

[Treatment of osteoarthritis with drugs and other modalities]. / Medikamentöse oder nicht medikamentöse Therapie der Osteoarthrose.

There is an increasing incidence in osteoarthritis, particularly following the 5th life-decade. However, also young people may suffer from severe osteoarthritis, which is estimated to be the most common cause of disability in adults resulting in substantial economic burden. To this end, effective therapies are needed. Therapeutic options are very comprehensive, which are presented in this review as non-pharmacological, pharmacological and surgical treatment modalities. Treatment efficacy will be discussed with regard to alleviation of symptoms and potential prevention of disease progression according to the given evidence.

Lack of dehydroepiandrosterone in type I and II hereditary angioedema and role of danazol in steroid hormone conversion.

BACKGROUND: Hereditary angioedema (HAE) is successfully treated with danazol, a therapeutic steroid compound. To investigate hormones of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis in patients with HAE with and without danazol. METHODS: We included 16 patients with type I HAE, nine patients with type II HAE, and 16 healthy subjects. Serum levels of adrenocorticotropic hormone (ACTH), cortisol, androstenedione, dehydroepiandrosterone (DHEA), free testosterone, and 17beta-oestradiol were measured. RESULTS: Serum levels of ACTH were markedly decreased in patients with type II HAE compared to the other groups (P < 0.001). Serum cortisol was similar between groups but danazol treatment decreased cortisol levels, particularly in women (P = 0.019). Serum levels of DHEA were significantly decreased in all patients with type I and II HAE compared to controls (P < 0.05), which was only partly dependent on prior danazol therapy as patients without danazol had also decreased serum levels of DHEA (P < 0.05). Furthermore, free testosterone serum levels were markedly increased in patients under danazol (P < 0.005) and the ratio of 17beta-oestradiol/free testosterone was significantly decreased in these patients (P < 0.005). CONCLUSIONS: This study demonstrated decreased DHEA in patients with type I and II HAE independent of danazol therapy, which was particularly evident in women. It also demonstrates that danazol induced a marked up-regulation of free testosterone in relation to precursors and downstream 17beta-oestradiol. In HAE, there seems to be a primary lack of the adrenal androgen DHEA.

Citrullination in extra-articular manifestations of rheumatoid arthritis.

BACKGROUND: Anti-citrullinated protein antibodies have been detected with high specificity in serum of patients with rheumatoid arthritis (RA), and citrullination of proteins may play a key role in the pathogenesis of RA. We therefore investigated the presence of citrullination in two extra-articular manifestations of RA, interstitial pneumonia (IP) and rheumatoid nodules. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), idiopathic IP (n = 20) and controls (n = 10), as well as specimens of rheumatoid nodules from 26 patients, were examined. All sections were incubated with an anti-modified citrulline antibody. Masked scoring of stained sections and analysis of results by stratification according to demographic and clinical characteristics was performed. RESULTS: Presence of citrulline could be detected in eight lung specimens of patients with RA-associated IP (44%) and nine patients with idiopathic IP (46%). Conversely, lung tissue from control patients showed weak extracellular citrullination in only two cases (20%). Citrullination did not show any significant associations with demographic or clinical characteristics such as age, gender, smoking habits, disease severity, histological subtype, degree of inflammation or steroid use. Rheumatoid nodules were citrulline positive in a majority of cases (70%). CONCLUSION: Citrullination is present in extra-articular manifestations of RA such as IP and nodules. In contrast to the high specificity of anti-citrulline antibodies in RA, citrullination is not only restricted to RA but can also be observed in idiopathic IP. Whether citrullination significantly contributes to the initiation or perpetuation of autoimmunity or merely reflects ongoing inflammation remains to be clarified.

The role of the sympathetic nervous system in intestinal inflammation.

The nervous system in the intestine controls motility, secretion, sensory perception, and immune function. Peptidergic neurones with neurotransmitters such as substance P and nerve growth factors have been the main focus of neuroimmunomodulation research in the gut. This review summarises the present knowledge concerning the role of the sympathetic nervous system (SNS) in modulating intestinal inflammation. The role of the SNS for gut inflammation is compared with its role in rheumatoid arthritis which demonstrates notable similarities. Nerve fibres of the SNS not only enter the enteric plexuses but also innervate the mucosa and gut associated lymphoid tissue (GALT). The SNS has pro- and anti-inflammatory functions. Neurotransmitters such as norepinephrine, adenosine, and others can evoke remarkably different opposing effects depending on concentration (presence of sympathetic nerve fibres and extent of neurotransmitter release), receptor affinity at different receptor subtypes, expression of adrenoceptors, availability of cotransmitters, and timing of SNS activity in relation to the inflammatory course. This review attempts to integrate the different perspectives of the pro- and anti-inflammatory effects of the SNS on inflammatory disease of the gut.

Increase of sympathetic outflow measured by neuropeptide Y and decrease of the hypothalamic-pituitary-adrenal axis tone in patients with systemic lupus erythematosus and rheumatoid arthritis: another example of uncoupling of response systems.

OBJECTIVE: To study in parallel the outflow of the sympathetic nervous system (SNS) and the hypothalamic-pituitary adrenal (HPA) axis tone in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: 32 patients with SLE, 62 with RA, and 65 healthy subjects (HS) were included. To measure the tone of the HPA axis, plasma ACTH and serum cortisol were determined. Serum neuropeptide Y (NPY) was used to evaluate the sympathetic outflow. RESULTS: Patients with SLE had increased NPY levels in comparison with HS, irrespective of prior prednisolone treatment (p<0.001). For patients with RA, only those with prednisolone treatment had increased NPY levels in comparison with HS (p = 0.016). Daily prednisolone dose correlated positively with serum NPY in RA (R(Rank) = 0.356, p = 0.039). In contrast, plasma ACTH levels were generally decreased significantly in comparison with HS in SLE with prednisolone, and in RA with/without prednisolone. Similarly, serum cortisol levels were also decreased in SLE with/without prednisolone, and in RA with prednisolone. The NPY/ACTH ratio was increased in SLE and RA, irrespective of prior prednisolone treatment. The NPY/cortisol ratio was increased in SLE with/without prednisolone, and in RA with prednisolone. Twelve weeks' anti-TNF antibody treatment with adalimumab did not decrease NPY levels in RA, irrespective of prednisolone treatment. CONCLUSIONS: An increased outflow of the SNS was shown and a decreased tone of the HPA axis in patients with SLE and RA. Low levels of cortisol in relation to SNS neurotransmitters may be proinflammatory because cooperative anti-inflammatory coupling of the two endogenous response axes is missing.

Key role of the sympathetic microenvironment for the interplay of tumour necrosis factor and interleukin 6 in normal but not in inflamed mouse colon mucosa.

BACKGROUND: In the intestinal tract, the role of sympathetic neurotransmitters has been largely ignored in mucosal neuroimmunology. AIM: Our aim was to investigate the influence of the sympathetic microenvironment on the mucosal interplay of tumour necrosis factor (TNF) and interleukin 6 (IL-6). METHODS: Colon strips of normal and colitic BALB/c mice were superfused in vitro. Tissue was electrically stimulated to investigate the influence of endogenous norepinephrine (NE) on secretion of IL-6, with or without anti-TNF antibodies (anti-TNF) and adrenoceptor antagonists. IL-6 was secreted from macrophages. RESULTS: Superfusion with anti-TNF stimulated IL-6 secretion in normal but not in colitic colon (p<0.005). Parallel superfusion with a beta-adrenergic antagonist abrogated this phenomenon. Anti-TNF increased release of NE from normal colonic strips (p<0.05), which demonstrates TNF induced inhibition of preterminal NE release. In colitic mice, anti-TNF did not change NE release. In the presence of anti-TNF, exogenous and endogenous NE stimulated colonic IL-6 secretion via beta-adrenoceptors in normal (p<0.001) but not in colitic mice. In the absence of anti-TNF, endogenous and exogenous NE inhibited IL-6 secretion via the beta-adrenoceptor in normal but not in colitic mice (p<0.01). Colitic mice demonstrated loss of sympathetic nerve fibres. CONCLUSIONS: Modulation of mucosal IL-6 is largely dependent on the sympathetic microenvironment and availability of local TNF in normal but not in colitic mice. Anti-TNF strategies may lead to an increase in the proinflammatory cytokine depending on adrenergic tone. This would be relevant with normal sympathetic innervation, which is lost in colitic mice. We present a model of sympathetic regulation of colonic macrophage TNF and IL-6 secretion.

Predictive and potentially predictive factors in early arthritis: a multidisciplinary approach.

OBJECTIVES: Rheumatoid arthritis (RA) is characterized by variable degrees of joint inflammation, joint destruction, progressive disability and premature death. Destruction of joint cartilage and bone may occur early during disease, as was shown in longitudinal studies of RA, and there is increasing consent among rheumatologists that early diagnosis and early initiation of therapy with disease-modifying anti-rheumatic drugs (DMARDs) can limit the severity of RA. Unfortunately, the currently used diagnostic and predictive indicators (clinical, laboratory and radiological) are of limited value for making an early diagnosis and prognosis of the disease course at the individual level, thus reducing optimal benefit from present and emerging therapies. Therefore, this review focuses on the multidisciplinary aspects of neuroendocrine-immune changes in RA. METHODS: A Medline search was performed using the search terms 'androgens', 'estrogens', 'sympathetic nervous system', 'sensory nervous system', 'prognosis', 'early rheumatoid arthritis', 'arthritis' and 'studies' in various combinations. For the tabular overview, we only listed clinical studies focusing on endocrine and neuronal aspects. RESULTS: In addition to the currently used predictive indicators, there is an abundant body of literature describing changes of the neuronal, endocrine and immune parameters during inflammatory diseases. Unfortunately, no longitudinal studies concerning neuroendocrine aspects have been done up to now. CONCLUSION: Parameters of the neuroendocrine system should be included in anticipated longitudinal clinical studies to find their true predictive value in early RA.

Successful treatment of psoriatic onycho-pachydermo periostitis (POPP) with adalimumab.

Psoriatic onycho-pachydermo periostitis (POPP) is recognized as a rare subset of psoriatic arthritis, characterized by psoriatic onychodystrophy, connective tissue thickening above the distal phalanx, and a periosteal reaction. Therapy for this rare disease is based on treatments used for psoriatic arthritis, but traditional disease-modifying antirheumatic drugs, such as sulfasalazine and methotrexate, have shown inconsistent and unsatisfactory results. We report herein a successful therapeutic approach for POPP using the fully human anti-tumor necrosis factor (TNF) antibody adalimumab in a 42-year-old male patient. After 4 months of anti-TNF treatment, a remarkable normalization of the clinical appearance was achieved and magnetic resonance imaging showed complete resolution of the initial inflammatory lesions. Therefore, we consider a TNF-blocking strategy as promising for treatment of POPP.