Peter Härle

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 (RRank = 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.

A patient with arthritis, severe back pain, impaired wound healing, and perforated sigmoid colon

In November, 2004, a 65-year-old man presented to our interdisciplinary emergency department with an acute abdomen, arthritis in several large and small joints, and many white skin lesions, predominantly on his hands (fi gure, A). An exploratory laparotomy showed bacterial peritonitis due to perforation of the sigmoid colon of unknown aetiology. Hemicolectomy with iliostomy construction was done. White plaques all over the sigmoid and other parts of the colon were noticed intraoperatively. Fluid obtained from arthrocentesis of the right shoulder joint showed a tophaceous white mass and birefringent crystals on compensated polarisation microscopy. Urate crystals were also found in the fl uid of the surgical draining tubes and in the urine. These fi ndings indicated advanced tophaceous gout, and we wondered whether the colonic perforation was caused by urate-induced abdominal infl ammation. Indeed, histology of the sigmoid colon supported this hypothesis (fi gure, B). Despite various antibiotic regimens, daily fever (38·0–39·5°C), leucocytosis (16×109/L), and high concentrations of C-reactive protein (100–200 mg/L) persisted. Because the patient remained febrile despite paracetamol administration, metamizole was initiated; colchicum (0·5 mg twice daily) was also started to treat gout-induced infl ammation. However, the patient developed severe (possibly drug-induced) neutropenia (0·19×109/L) and medications were discontinued until the blood count recovered 10 days later. 32 days after admission, our patient had creatinine clearance of 38 mL/min. We administered allopurinol 100 mg daily; as a result of a drug-related rash this treatment was replaced by benzbromarone 50 mg daily and then probenecid 250 mg daily—both of which also caused a rash. Therefore, on day 55 of admission, rasburicase, a recombinant uricase, was given in a daily dose of 0·2 mg/kg intravenously over 7 days. The uric acid concentration fell from 713·8 μmol/L to below the detection limit. Fever and C-reactive protein (127 mg/L) decreased within 4 days. Uric acid con centration slowly increased thereafter to a maximum of 386·6 μmol/L on day 74 under concomitant low purine diet and intravenous fl uids. Because repeated blood cultures were negative, we concluded that high systemic concentrations of infl ammatory markers and fever were caused by diff use urate crystal deposition and not by presumptive bacterial infection. Our patient was started on prednisolone on day 63 (tapered from 40 mg to 10 mg daily over 10 days) with further improvement in his condition. On day 70, he complained of severe back pain. MRI of the spine ruled out vertebral fracture, spondylodiscitis, or vertebral tophi. Many abscess-like lesions in the psoriatic muscle and in L3/4 vertebrae were seen, and CT-guided biopsy of the lesions showed tophi with negative bacterial cultures. Over the next few weeks, repeated intestinocutaneous fi stulas and impaired wound healing occurred with histology showing birefringent material with infl ammatory infi ltrates, suggesting that this was the cause of impaired wound healing. 4 months after the initial admission, the patient died of bacterial peritonitis with septic multiorgan failure. Tophus formation in untreated chronic gout can cause lesions that mimic malignant disease, abscess, neurological compression syndromes, heart-valve defects, and cutaneous calcinosis. Defi nitive diagnosis can be achieved by use of polarised microscopy of tissue and fl uids. Our case report documents urate-induced intestinal perforation in conjunction with impaired wound healing. In our patient, side-eff ect-driven discontinuation of common gout drugs and high infl ammatory activity led us to use a recombinant urate oxidase, which greatly improved his clinical condition and infl ammatory markers. Continuous administration of rasburicase might have consolidated the initial eff ect. However, because high therapeutic costs are a consideration with this drug, pegylated urate oxidase formulations or febuxostat, a novel selective non-purine xanthine oxidase inhibitor, might be possible therapeutic options for continuous treatment of severe cases of tophaceous gout in the future.

Rheumatoide Arthritis: pathogenetische Bedeutung der neuroendokrinen Achsen und des peripheren Nervensystems

Zusammenfassung.Hintergrund: Die lokalen Prozesse des angeborenen und adaptiven Immunsystems haben in der akuten Phase der rheumatoiden Arthritis (RA) eine wichtige pathogenetische Bedeutung. Neben dem Immunsystem könnten die Veränderungen entzündungshemmender neuroendokriner und neuronaler Systeme wichtige Komponenten darstellen, die für die Chronifizierung der Entzündung verantwortlich sind. Veränderungen: Wie bei vielen chronisch-entzündlichen Erkrankungen findet man bei der RA eine in Relation zum Grad der systemischen Entzündung zu niedrige Cortisol- und Androgensekretion. Zusätzlich ist im Synovialgewebe die Anzahl der entzündungshemmenden sympathischen Nervenfasern deutlich reduziert, wohingegen entzündungsfördernde sensible Nervenfasern vermehrt vorhanden sind. Das Gleichgewicht der synergistisch wirkenden entzündungshemmenden Systeme (Cortisol, Dehydroepiandrosteron, Androgene, sympathische Neurotransmitter) wird zugunsten von entzündungsfördernden Systemen (sensible Neurotransmitter, Östrogene) verschoben. Schlussfolgerung: Neue therapeutische Strategien könnten aus diesen Betrachtungen zur Pathogenese abgeleitet werden.Abstract.Background: Local innate and adaptive immune processes are of importance during the acute phase of rheumatoid arthritis (RA). In the advanced inflammatory phase alterations of systemic anti-inflammatory feedback mechanisms might be important features which may support chronic inflammation. Alterations: Similarly, like in other chronic inflammatory diseases, inadequately low cortisol and androgen serum levels can be detected in RA patients. In addition, there is a marked reduction of anti-inflammatory sympathetic nerve fibers in the inflamed joints paralleled by an enhanced number of pro-inflammatory sensory nerve fibers. Thus, an uncoupling of synergistically acting endocrine and neuronal, anti-inflammatory mechanisms (cortisol, dehydroepiandrosterone, androgens, sympathetic neurotransmitters) and a preponderance of pro-inflammatory mechanisms (estrogens, sensory neurotransmitters) may lead to chronic inflammatory disease. Conclusion: From this pathogenetic point of view new therapeutic strategies could be developed for the treatment of patients with RA.

Fatal outcome of constrictive pericarditis in rheumatoid arthritis

This is a report of a 39-year-old patient diagnosed with seropositive rheumatoid arthritis at the age of 17. The patient died 2 years after the onset of extra-articular cardiac symptoms. This case demonstrates the devastating course of progressive constrictive pericarditis under sole medical therapy and emphasizes the importance of early radical pericardectomy to avoid progression of disease and secondary complications with fatal outcome. Further, we discuss risk factors, diagnostic caveats, diagnostic tests and therapy of hemodynamically relevant contrictive pericarditis.

Stress, Hormone und neuronale Signale bei rheumatoider Arthritis

ZusammenfassungDiese Übersichtsarbeit zeigt, wie hormonelle und neuronale Faktoren, die im Stress verstärkt freigesetzt werden, die rheumatoide Arthritis und die juvenile idiopathische Arthritis ungünstig beeinflussen können. Dabei wird das Hauptaugenmerk auf Cortisol und Noradrenalin gelegt. Es wird dargelegt, dass zur Erklärung der durch Stress hervorgerufenen Veränderungen bei diesen beiden chronischen Krankheiten neben dem Immunsystem auch das endokrine System und das Nervensystem in die Überlegungen aufgenommen werden müssen. Die Defekte des endokrinen Systems und des Nervensystems bei rheumatoider Arthritis und juveniler idiopathischer Arthritis können an der Auslösung und Chronifizierung dieser Krankheiten maßgeblich beteiligt sein.AbstractThis review demonstrates that hormonal and neuronal factors, which are released during stressful situations, can unfavorably influence the two chronic diseases of rheumatoid arthritis and juvenile idiopathic arthritis. Noradrenaline and cortisol are in the focus of this review. In the said two chronic inflammatory diseases, it is obvious that apart from the immune system also the endocrine and nervous system play an essential role in the stress-induced initiation and aggravation of these diseases.

Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis

OBJECTIVE Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti-TNF therapy. This study investigated the influence on steroidogenesis of an interleukin-6 (IL-6)-neutralizing strategy using IL-6 receptor monoclonal antibodies (referred to as MRA). METHODS In a placebo-controlled, double-blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17beta-estradiol, as well as their respective molar ratios, were determined. RESULTS MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA-treated patients (minimum P < 0.004). Serum levels of estrone and 17beta-estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001). CONCLUSION Neutralization of IL-6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.

Stress, Hormone und neuronale Signale bei rheumatoider Arthritis@@@Stress, Hormones, and Neuronal Signals in the Pathophysiology of Rheumatoid Arthritis. The Negative Impact on Chronic Inflammation: Der negative Einfluss auf das chronische Entzündungsgeschehen

ZusammenfassungDiese Übersichtsarbeit zeigt, wie hormonelle und neuronale Faktoren, die im Stress verstärkt freigesetzt werden, die rheumatoide Arthritis und die juvenile idiopathische Arthritis ungünstig beeinflussen können. Dabei wird das Hauptaugenmerk auf Cortisol und Noradrenalin gelegt. Es wird dargelegt, dass zur Erklärung der durch Stress hervorgerufenen Veränderungen bei diesen beiden chronischen Krankheiten neben dem Immunsystem auch das endokrine System und das Nervensystem in die Überlegungen aufgenommen werden müssen. Die Defekte des endokrinen Systems und des Nervensystems bei rheumatoider Arthritis und juveniler idiopathischer Arthritis können an der Auslösung und Chronifizierung dieser Krankheiten maßgeblich beteiligt sein.AbstractThis review demonstrates that hormonal and neuronal factors, which are released during stressful situations, can unfavorably influence the two chronic diseases of rheumatoid arthritis and juvenile idiopathic arthritis. Noradrenaline and cortisol are in the focus of this review. In the said two chronic inflammatory diseases, it is obvious that apart from the immune system also the endocrine and nervous system play an essential role in the stress-induced initiation and aggravation of these diseases.