[Development of quality standards for patients with rheumatoid arthritis for use in Germany]. / Entwicklung von Qualitätsstandards für die Versorgung von Patient*innen mit rheumatoider Arthritis zur Anwendung in Deutschland.

Despite a qualitatively and structurally good care of patients with rheumatoid arthritis (RA) in Germany, there are still potentially amendable deficits in the quality of care. For this reason, the German Society for Rheumatology (DGRh) has therefore decided to ask a group of experts including various stakeholders to develop quality standards (QS) for the care of patients with RA in order to improve the quality of care. The QS are used to determine and quantitatively measure the quality of care, subject to relevance and feasibility. The recently published NICE and ASAS standards and a systematic literature search were used as the basis for development. A total of 8 QS, now published for the first time, were approved with the intention to measure and further optimize the quality of care for patients with RA in Germany.

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.

OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

[Lyme borreliosis]. / Lyme-Borreliose.

Lyme borreliosis is a multisystem infectious disease affecting mainly the skin, nervous system, joints and heart. It is caused by spirochetes of the Borrelia burgdorferi sensu lato complex which are transmitted by ticks. The diagnosis of Lyme borreliosis is based primarily on typical clinical symptoms and signs with serological confirmation. Antibiotic therapy is beneficial for all manifestations and treatment refractory cases are rare. The diagnosis "chronic Lyme borreliosis" is increasingly being misused for all conceivable medically unexplained symptoms.

Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra.

The triad of sterile pyogenic arthritis, pyoderma gangrenosum and acne is known by the acronym of PAPA syndrome. It is a rare autosomal dominant disease of early onset. The treatment of pyoderma gangrenosum is challenging as there is often only partial response to systemic glucocorticosteroids and immunosuppressive therapies. We report the rapid and lasting response of pyoderma gangrenosum to the targeted treatment with the recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) anakinra in a patient with PAPA syndrome.

Cellular immune reactivity to recombinant OspA and flagellin from Borrelia burgdorferi in patients with Lyme borreliosis. Complexity of humoral and cellular immune responses.

Patients with Lyme borreliosis (LB) usually develop a vigorous T cell response against the causative pathogen Borrelia burgdorferi, but little is known about the antigens recognized in the cellular response. Therefore, T cell reactivities against whole bacteria, recombinant 31-kD (outer surface protein A, [OspA]), and 41-kD proteins (flagellin) from B. burgdorferi were studied in patients with LB, non-LB patients, and healthy donors. In parallel, specific antibodies were determined by Western blot analysis. Virtually all patients with LB exhibited marked cellular responses to whole B. burgdorferi, which were significantly elevated compared with the control groups in both early and late disease stages. However, analyses using the purified antigens OspA and flagellin revealed considerable heterogeneity in the cellular reactivities among individuals as well as variations during the course of infection. T cell responses to OspA were significantly increased in patients with early LB compared with both control groups whereas in late-stage disease responses only exceeded those of non-LB patients and were not different from normal donors. Cellular immune reactivities to flagellin were significantly higher only in early LB compared with both control groups. Reciprocally, several control subjects demonstrated marked cellular responses to OspA and flagellin, suggesting that reactions to these proteins may not always be related to LB. T cell reactivity did not correlate well with the presence of specific antibodies. Almost all seropositive patients in both early and late stage LB had serum antibodies against flagellin, but antibodies to OspA were detectable only in a subset of late LB sera. These data demonstrate the complexity of the humoral and the cellular immune responses to components of B. burgdorferi.

[Two children with intermediate uveitis and granuloma annulare from the same neighbourhood]. / Zwei Kinder mit intermediärer Uveitis und Granuloma anulare in derselben Nachbarschaft.

Two children from the same neighbourhood presented with concomitant granuloma annulare (GA) and intermediate uveitis (IU) at an interval of 2 weeks. A coincidence seemed unlikely, as IU is very rare in children and even more so in connection with GA. Thorough diagnosis was performed to exclude other associated diseases. No systemic disease, no special features of vaccination or medication, no history of infection, and no toxic cause could be found. An association between GA and IU based on other, as yet undiagnosed factors, is still possible. Therefore, when evaluating patients with newly diagnosed IU, clinical work-up should also include medical history and examination to rule out GA.

Inhibition of granulocyte function by prednisolone and non-steroid anti-inflammatory drugs. Quantitative evaluation with NBT test and its correlation with phagocytosis.

The effect of prednisolone and non-steroid anti-inflammatory drugs on PMNL (polymorphonuclear leucocytes) oxidative metabolism was quantified with a newly standardized NBT test, and it was investigated whether these effects correlate with phagocytosing capacity of PMNL. Prednisolone inhibits NBT reduction in dose dependency already at concentrations, which do not interfere with phagocytosis. Thus prednisolone dissociates phagocytosis and phagocytosis-associated oxidative metabolism. High doses of prednisolone also inhibit phagocytosis. These effects of prednisolone are still demonstrable when PMNL are washed after pre-incubation with the drug. The non-steroid anti-inflammatory drugs (indomethacin, phenylbutazone and pyrazinobutazone) inhibit phagocytosis and NBT reduction at equivalent doses. When PMNL are washed after incubation with the drugs, they regain normal capacity to phagocyse and to reduce NBT. It is suggested that these drugs inhibit phagocytosis directly, and consequently the phagocytosis-associated oxidative metabolism is suppressed.

Antibiotic therapy of early European Lyme borreliosis and acrodermatitis chronica atrophicans.

In a study on 121 consecutive patients with erythema migrans, 65 patients obtained oral penicillin, 36 tetracyclines, and 20 amoxicillin-clavulanic-acid. Follow-up was carried out for a median of 29, 17, and 7 months, respectively. In another limited trial on 29 patients with acrodermatitis chronica atrophicans (ACA), 14 patients received oral penicillin, 9 parenteral penicillin, and 6 tetracyclines. There was no statistically significant difference among treatment groups in both therapeutic trials, with the exception of different follow-ups due to the nonrandomized study design and different occurrence of the Jarisch-Herxheimer reaction in patients with erythema migrans. Later extracutaneous manifestations developed in 27% of the patients with erythema migrans and in 47% of the patients with ACA despite antibiotic therapy. We could not prove the superiority of any antibiotic tested in either early or late European Lyme borreliosis.

[Diagnosis and therapy of Lyme arthritis]. / Diagnostik und Therapie der Lyme-Arthritis.

Several distinct patterns of rheumatic manifestations can be seen throughout the course of Lyme borreliosis: intermittent and migratory musculoskeletal pain without objective findings, intermittent arthritis, chronic erosive arthritis, and joint deformities under affected skin in acrodermatitis chronica atrophicans. Commonly, Lyme arthritis is a late disease manifestation. A clinical history of extra-articular disease manifestations is the most reliable key to Lyme arthritis. However, arthritis often occurs without antecedent early-disease manifestations. The diagnostic significance of serological findings suggesting Lyme arthritis must be considered carefully with regard to the typical clinical features of Lyme arthritis and its potential differential diagnoses. Otherwise, Lyme arthritis will be frequently over-diagnosed. Lyme arthritis can be cured with antibiotics. However, treatment failures occur with any of the hitherto recommended regimens.

[Early diagnosis of Lyme arthritis]. / Frühdiagnostik der Lyme-Arthritis.

Lyme-Arthritis is one of the most frequent manifestations of Lyme disease. Transient arthritides may already develop in the early disease stage. However, typical Lyme arthritis manifests weeks to months after the infection as intermittent mon- or oligoarthritis predominantly affecting the knees. Massive knee effusions may lead to popliteal cysts that often rupture. Chronic arthritides are rare. The diagnosis of Lyme arthritis mainly is based on clinical grounds and confirmed by laboratory tests. Direct detection of the causing agent by culture is difficult and not suitable for clinical use. With polymerase chain reaction based assays in up to 80% of untreated patients with Lyme arthritis B. burgdorferi DNA can be detected in joint fluid or synovial membrane specimens. While this method is not widely available yet it will become a routine diagnostic tool in Lyme arthritis in the near future. Borrelia serology is still the most important laboratory test. A negative serology almost certainly rules out Lyme arthritis. A positive serology alone, however, does not proof Lyme disease and must be critically interpreted in context with clinical symptoms.

Treatment continuation in patients receiving biological agents or conventional DMARD therapy.

OBJECTIVE: To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure. METHODS: Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases. RESULTS: Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate. CONCLUSIONS: Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.

Joint manifestations of Lyme borreliosis in Europe.

Our clinical and serological studies have shown that Lyme arthritis is not a rare manifestation of Lyme borreliosis in Europe. The significance of serological findings for Lyme arthritis have more often remained uncertain in consideration of potential differential diagnoses than was to be expected on the basis of specificity controls. Various joint manifestations in the course of Lyme borreliosis have been distinguished. The succession or the coexistence of intermittent attacks of arthralgias and arthritis has been pointed out as particular indications of Lyme arthritis. We have noted diffuse hand and finger swelling as a striking feature of early Lyme arthritis. Generally, Lyme arthritis has been attributable to Stage 3 of the disease. The most pathognomonic manifestation has been intermittent knee arthritis. The pattern of joint involvement has shown similarities to that in postenteric and postveneral reactive arthritides, in particular as regards the occurence of dactylitis (sausage digits) and heel involvement. However, we have not seen sacroiliitis and Reiter's syndrome. As distinguished from typical Lyme arthritis, peculiar joint manifestations have been noted in association with acrodermatitis chronica atrophicans. Typing of Class I and II histocompatibility antigens did not give evidence of any immunogenetic basis for Lyme arthritis.

Starvation-induced expression of retron-Ec107 and the role of ppGpp in multicopy single-stranded DNA production.

Multicopy single-stranded DNA is found as a small single-stranded RNA-DNA complex in certain wild-type strains of Escherichia coli as well as in other gram-negative bacteria. Using the promoter region of the previously characterized retron-Ec107 from E. coli ECOR70, I constructed a chromosomally located lacZ operon fusion. Examination of expression from the PEc107 promoter showed that activity increased sharply when cells entered stationary phase in rich medium or when they were starved for phosphate. The nucleotide guanosine-3',5'-bispyrophosphate was found to be a positive regulator of retron-Ec107 expression. Its presence is required for starvation-induced transcription of retron-Ec107 and multicopy single-stranded DNA production. It was also found that expression from the retron promoter is independent of the sigma factor sigmaS.

Lyme arthritis in Germany.

Lyme arthritis appears not to be a rare manifestation of Borrelia burgdorferi infection in Germany. We report 20 cases of the illness occurring in South Germany. In eleven of our patients arthritis was the only clinical manifestation of the infection; the diagnosis in those cases has only been verified by the detection of specific antibodies to Borrelia burgdorferi with indirect immunofluorescence and IgG Western blot technique. In comparison with previous reports of Lyme arthritis the quota of chronic joint involvement in our patients was relatively high, 4 of the patients developed radiographic signs of erosive arthritis. We suggest that Lyme arthritis is still underrecognized in Germany, and that previously reported assertions concerning the relative frequency of the various disease manifestations of Borrelia burgdorferi infections reflect a patient-selection.

Ultrasound findings in Löfgren's syndrome: is ankle swelling caused by arthritis, tenosynovitis or periarthritis?

Arthritis of acute sarcoidosis or Löfgren's syndrome commonly affects the ankles. However, it is often difficult to determine by clinical means whether swelling of the ankles is due to frank arthritis or involvement of periarticular tissues. Therefore, sonographic examinations were performed in 24 consecutive patients with acute sarcoidosis, 16 of them with the typical triad of Löfgren's syndrome. Joint effusions could be demonstrated only by ultrasound in 6 patients. Sonographic findings consistent with tenosynovitis were found in 8 cases. In the majority of cases (20/24) the predominant abnormalities were hypoechogenic structures within the subcutis and periarticular tissues. Thus, frank arthritis is rather a rare cause of ankle swelling in Löfgren's syndrome; more often presumed joint manifestations can be attributed to subcutaneous or periarticular inflammation.

[Ultrasound findings in chondrocalcinosis]. / Sonographische Befunde bei der Chondrokalzinose.

The diagnosis of chondrocalcinosis is based on typical radiographic findings and synoviaanalysis. We examined 10 patients with chondrocalcinosis to see whether pathognomonic findings of the disease could also be seen by ultrasound. Ultrasound and x-ray findings were compared. Calcifications of the knee menisci were seen by ultrasound in all patients (10/10). Moreover, in three of six patients calcified carpal disci were observed by ultrasound. Joint mouse, exostosis and calcinosis of the capsula could be demonstrated by ultrasound in all instances. In one case the joint mouse was only seen by ultrasound; tomography finally confirmed this diagnosis. Though ultrasound findings in chondrocalcinosis cannot be considered pathognomonic, typical changes of the diseases can be found by this technique. Since ultrasound is a method of increasing interest in rheumatic diseases, those findings may initiate the consideration of the diagnosis.