Objective. To estimate the incidence rates of serious and nonserious infections in patients with rheumatoid arthritis (RA) who start treatment with a biologic agent, and to compare these rates with those in patients with RA who receive conventional treatment.Methods. Patients enrolled in the German biologics register between May 2001 and September 2003 were included. Treating rheumatologists assessed adverse events and serious adverse events. All adverse events and serious adverse events experienced within 12 months after study entry were analyzed. Propensity score methods were applied to estimate which part of a rate increase was likely to be attributable to differences in patient characteristics.Results. Data were available for 512 patients receiving etanercept, 346 patients receiving infliximab, 70 patients receiving anakinra, and 601 control patients treated with disease-modifying antirheumatic drugs.The total number of adverse events per 100 patientyears was 22.6 (95% confidence interval [95% CI] 18.7-27.2) among patients receiving etanercept, 28.3 (95% CI 23.1-34.7) among patients receiving infliximab, and 6.8 (95% CI 5.0-9.4) among controls (P < 0.0001). Significant differences in the rate of serious adverse events were also observed. For patients receiving etanercept, those receiving infliximab, and controls, the total numbers of serious adverse events per 100 patient-years were 6.4 (95% CI 4.5-9.1), 6.2 (95% CI 4.0-9.5), and 2.3 (95% CI 1.3-3.9), respectively (P ‫؍‬ 0.0016). After adjusting for differences in the case patient mix, the relative risks of serious adverse events were 2.2 (95% CI 0.9-5.4) for patients receiving etanercept and 2.1 (95% CI 0.8-5.5) for patients receiving infliximab, compared with controls.Conclusion. Patients treated with biologic agents have a higher a priori risk of infection. However, our data suggest that this risk is increased by treatment with tumor necrosis factor inhibitors.

Context The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor ␣ (TNF-␣). Little is known about the reactivation of latent viral infections during treatment with TNF-␣ inhibitors. Objective To investigate whether TNF-␣ inhibitors together as a class, or separately as either monoclonal anti-TNF-␣ antibodies (adalimumab, infliximab) or a fusion protein (etanercept), are related to higher rates of herpes zoster in patients with rheumatoid arthritis. Design, Setting, and Patients Patients were enrolled in the German biologics register RABBIT, a prospective cohort, between May 2001 and December 2006 at the initiation of treatment with infliximab, etanercept, adalimumab, or anakinra, or when they changed conventional disease-modifying antirheumatic drug (DMARD). Treatment, clinical status, and adverse events were assessed by rheumatologists at fixed points during follow-up. Main Outcome Measures Hazard ratio (HR) of herpes zoster episodes following anti-TNF-␣ treatment. Study aims were to detect a clinically significant difference (HR, 2.0) between TNF-␣ inhibitors as a class compared with DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-␣ inhibitors, the monoclonal antibodies or the fusion protein, compared with conventional DMARDs. Results Among 5040 patients receiving TNF-␣ inhibitors or conventional DMARDs, 86 episodes of herpes zoster occurred in 82 patients. Thirty-nine occurrences could be attributed to treatment with anti-TNF-␣ antibodies, 23 to etanercept, and 24 to conventional DMARDs. The crude incidence rate per 1000 patient-years was 11.1 (95% confidence interval [CI], 7.9-15.1) for the monoclonal antibodies, 8.9 (95% CI, 5.6-13.3) for etanercept, and 5.6 (95% CI, 3.6-8.3) for conventional DMARDs. Adjusted for age, rheumatoid arthritis severity, and glucocorticoid use, a significantly increased risk was observed for treatment with the monoclonal antibodies (HR, 1.82 [95% CI, 1.05-3.15]), although this risk was lower than the threshold for clinical significance. No significant associations were found for etanercept use (HR, 1.36 [95% CI, 0.73-2.55]) or for anti-TNF-␣ treatment (HR, 1.63 [95% CI, 0.97-2.74]) as a class. Conclusion Treatment with monoclonal anti-TNF-␣ antibodies may be associated with increased risk of herpes zoster, but this requires further study.

Multicopy single-stranded DNA (msDNA), a branched DNA-RNA molecule, has been shown in Escherichia coli B and clinical strain Cl-1 to be synthesized by reverse transcriptase. We report that 13% of the strains of the ECOR collection, a sample of 72 E. coli isolates representing the breadth of genetic variation of the species, produce msDNA. Three of the four major subspecific groups include msDNA-producing strains. Screening of 25 isolates that are genetically related to msDNA-producing clinical strains uncovered 22 additional msDNA-producing strains. A phylogenetic tree based on allelic variation detected electrophoretically at 20 enzyme-encoding loci revealed two major clusters and several deep branches composed of strains that synthesize msDNA. Although E. coli K-12 does not harbor msDNA, other closely related strains of the K-12 family do. The results support the hypothesis that msDNA-synthesizing systems, including reverse transcriptase genes, were acquired recently and independently in different lineages of E. coli.The recent discovery of bacterial reverse transcriptases (RTs) was engendered by the observation of a peculiar satellite DNA, now called multicopy single-stranded DNA (msDNA), in the soil bacterium Myxococcus xanthus (26). The satellite (msDNA-Mxl62) is unusual because it consists of a 162-base single DNA strand linked to a 77-base RNA (msdRNA) sequence by a 2',5'-phosphodiester linkage and occurs in hundreds of copies per cell (4). An msDNA of a similar structure (msDNA-Sa163) has been found in the closely related myxobacterium Stigmatella aurantiaca (5, 6). Recently it has been reported that M. xanthus contains another species of msDNA (msDNA-Mx65) in addition to msDNA-Mxl62 (3). Most recently, msDNA molecules with structural features similar to those of myxobacterial msDNAs have been found in clinical isolate Cl-1 (9), strain B (10), and several other clinical isolates (21) of Escherichia coli.In M. xanthus (8), E. coli clinical isolate Cl-1 (9), and E. coli B (10), the synthesis of msDNA depends on RT encoded by a sequence adjacent to the chromosomal region specifying msdRNA. Although the three bacterial RTs are substantially divergent in size and amino acid sequence, as inferred from the nucleotide sequences, they exhibit the common amino acid motifs of retroviral reverse transcriptases (22).The objective of the study reported here was to determine the frequency of occurrence and genetic relationships among strains that harbor msDNA synthesized by RT in natural populations of E. coli. To accomplish this, we examined the 72 strains of the ECOR collection (13), a sample of natural isolates chosen to represent the major subspecific groups of the E. coli species as a whole. These groups have been identified on the basis of allelic variation at enzyme-encoding genes detected by multilocus enzyme electrophoresis (14, 23) and include isolates recovered from a variety of human and animal hosts in diverse geographic areas (13). In addition, we characterized the multilocus genotypes of previously repor...

The long-term prognosis for SLE has improved markedly in recent decades because of earlier diagnosis and optimized treatment. Further research and randomized controlled trials are needed for the development of specifically targeted therapies.

ObjectiveTo investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ).MethodsIn 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.Results37 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.ConclusionsThe 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.

Objective. Randomized clinical trials (RCTs) evaluate the efficacy of treatments in selected groups of patients defined by strict inclusion criteria. The value of these trials in predicting therapeutic effectiveness in "real world" patients is limited. This observational cohort study was designed to complement the knowledge obtained in RCTs by evaluating the effectiveness of tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) according to their eligibility for the major trials.Methods. Using the data from the German biologics register Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT [in German]), we investigated how many of the RA patients who were treated with a TNF inhibitor (infliximab, etanercept, or adalimumab) would have been eligible for the major clinical trials that led to approval of the drugs. In addition, therapeutic effectiveness was compared in the eligible and ineligible patients using the American College of Rheumatology 20% (ACR20) and 50% (ACR50) improvement response criteria.Results. Only 21-33% of the patients in the RAB-BIT register would have been eligible for the major trials. In these patients, the ACR20 and ACR50 improvement responses, indicating therapeutic effectiveness, were comparable with the response rates in the published trials. ACR response rates were lower in those patients considered ineligible for the trials; however, absolute improvement was similar to that in eligible patients. Ineligible patients had lower baseline disease activity, more comorbidity, and lower functional status.Conclusion. RCT cohorts reflect only a minor proportion of the patients treated with biologic agents in routine care. In the clinic setting, the indications for treatment with biologic agents are not identical to the inclusion criteria for trials. Despite the smaller relative improvement achieved in these patients with longstanding, severe RA who would not fulfill the inclusion criteria of a major trial, the majority of such patients would nevertheless benefit from biologic therapy.Randomized clinical trials (RCTs) are generally considered the gold standard for evaluating the efficacy of new therapeutic interventions for defined medical conditions. Standardized trial designs are necessary to ensure that patients randomly allocated to the treatment arms are as similar as possible. The setting of the RCT is therefore artificial, due to restrictive inclusion and exclusion criteria, fixed treatment regimens, and rigidity of followup (1,2). In rheumatology, as in many other fields of medicine, trials cannot reflect effectiveness of treatments in the real world (3), since a majority of

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.

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.