[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.

[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.

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.

[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.

Heterogeneity of Borrelia burgdorferi sensu lato demonstrated by an ospA-type-specific PCR in synovial fluid from patients with Lyme arthritis.

Borrelia burgdorferi sensu lato, the etiological agent of Lyme borreliosis, has been divided into three genospecies: B. burgdorferi sensu stricto (OspA-type 1), B. afzelii (OspA-type 2) and B. garinii (OspA-type 3-7). Whereas in Europe B. afzelii (OspA-type 2) is predominant among human skin isolates and B. garinii (OspA-type 3-7) among human CSF isolates, some previous serological studies suggested that Lyme arthritis is also associated with B. burgdorferi sensu stricto in Europe. In the present study we designed ospA type-specific PCRs and identified four different ospA types associated with Lyme arthritis. Our study group consisted of 20 patients with positive serology (ELISA and immunoblotting) and clinical criteria for Lyme arthritis. B. burgdorferi DNA was detected in 13 patients and in none of 10 control patients from synovial fluid. We identified ospA-type 1 (26.6%), ospA-type 2 (33.3%), ospA-type 4 (6.6%) and ospA-type 5 (33.3%). Our conclusion is that in Europe B. burgdorferi sensu lato strains causing Lyme arthritis are considerably heterogeneous and that there is no prevalence of certain genospecies or OspA-types among this strains.

Sudeck's atrophy in Lyme borreliosis.

A patient with disseminated Lyme borreliosis is reported. The patient suffered from erythema migrans and radicular pain. Serologic tests routinely performed (IFT, ELISA, Western blots with different strains and Borrelia-LTT) were negative. However, Borrelia burgdorferi (genotype Borrelia afzelii) was cultivated from a skin biopsy. Western blot with the patient's isolate and sera showed strong reactivity only with the 60 kDa protein. In spite of immediate diagnosis and intravenous antibiotic treatment according to current recommendations he developed pain in the right ankle, which was resistant to further antibiotic and anti-inflammatory therapy. Sudeck's atrophy was diagnosed by X-ray. Treatment with calcitonin brought immediate relief from pain and led to radiographically demonstrable recalcification.

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.

Seronegative spondylarthropathies in HIV-infected patients: further evidence of uncommon clinical features.

Reiter's syndrome and reactive arthritis in individuals with human immunodeficiency virus (HIV) infection are characterized by severe and persistent arthritis, intense enthesopathy, and poor response to treatment. These uncommon clinical features suggest a direct role of HIV in the pathogenesis of seronegative spondylarthropathies. We report on widely differing clinical features in two HIV-infected patients with undifferentiated seronegative spondylarthropathy or reactive arthritis. Both patients were HLA-B27-positive. The first patient presented with heel swelling and dactylitis ("sausage" toes). Subsequently he developed polyarticular erosive arthritis. The clinical course was complicated by fulminant ulcerative colitis leading to hemicolectomy. After hemicolectomy, a temporary resolution of arthritis occurred. In the second patient, heel swelling and polyarticular arthritis occurred 2 months after Shigella dysentery. After 3 years of continuing joint inflammation, he presented with a Jaccoud-like arthropathy. In a cohort of 700 HIV-infected patients receiving continuous care in our department, these were the only patients with seronegative spondylarthropathy observed between 1984 and 1992.

Recombinant immunoblot in the serodiagnosis of Lyme borreliosis. Comparison with indirect immunofluorescence and enzyme-linked immunosorbent assay.

A recombinant immunoblot was developed for detection of IgM and IgG antibodies in patients with Lyme borreliosis. The recombinant antigens were the chromosomal-encoded Borrelia burgdorferi proteins p100, the flagellin and an internal flagellin fragment thereof as well as the plasmid-encoded outer surface proteins A (OspA) and C (OspC). A panel of 144 sera from patients with Lyme borreliosis (erythema migrans, n = 31; neuroborreliosis state II, n = 60; Lyme arthritis, n = 24 and acrodermatitis chronica atrophicans, n = 19) have been investigated and the results have been compared to the immunofluorescence absorption test (IFA-ABS) and to two different enzyme-linked immunosorbent assays [the flagellin ELISA and a newly developed ELISA (OGP-ELISA)]. The two ELISAs were comparable in sensitivity, whereas the IFA-ABS was less sensitive for IgM antibody but equally sensitive for IgG antibody detection. Immunoblot analysis revealed that IgG antibodies are mainly reactive with p100 and the internal flagellin fragment (sensitivity 51% and 32%, respectively) and rarely with OspC (14%). All patients with late Lyme borreliosis had IgG antibodies against the p100. IgM antibodies were predominantly directed against OspC (43%) and in a lower extent against the internal flagellin fragment and p100 (15% and 13%, respectively). The complete flagellin was not useful due to a high number of unspecific reactions with control sera and the OspA was only exceptionally reactive in Lyme borreliosis patients. The sensitivity of IgM antibody detection could be increased in cases with early Lyme borreliosis from 46% to 65% when the OspC blot was performed in addition to the flagellin ELISA, or from 56% to 65% when performed in addition to the OGP-ELISA. The recombinant blot is, therefore, a valuable diagnostic test to increase sensitivity of early antibody detection and is regarded as a valuable confirmatory test also in late disease.