Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies

Evidence of no protection for a recurrent case of pathogen specific clinical mastitis from a previous case

The objective of this study was to determine whether the occurrence of a previous case of pathogen-specific clinical mastitis (CM) protects Holstein dairy cows against a recurrent case. Pathogens studied were Escherichia coli, Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., Klebsiella spp., and Trueperella pyogenes. A total of 40 864 lactations (17 265 primiparous and 23 599 multiparous) from 19 835 cows from 5 large, high milk producing New York State dairy herds were analysed. We estimated the effects of parity, calving diseases, milk yield, current season and number of CM cases in the previous lactation on the risk of a first CM case using generalised linear mixed models with a log link and Poisson error distribution. The aforementioned risk factors and the occurrence of previous cases of pathogen-specific CM within the current lactation were evaluated as risks for second and third cases of pathogen-specific CM. Cows with more CM cases in the previous lactation were at greater risk of pathogen-specific CM in the current lactation. Multiparous cows were at greater risk of a second CM case if they had suffered from a first CM case that was caused by the same pathogen as the second case. In contrast, a second CM case generally put cows at greater risk of a third case, irrespective of whether the third case was caused by the same or a different pathogen. Our results showed that a previous case of pathogen specific CM does not generally protect against a recurrent case

Does clinical mastitis in the first 100 days of lactation 1 predict increased mastitis occurrence and shorter herd life in dairy cows?

The objectives of this study were to estimate the direct effects of clinical mastitis (CM) occurring in early productive life (defined as the first 100 d of the first lactation) of Holstein dairy cows on the future rate of CM occurrence and on the length of total productive lifetime. Information on CM cases and other data occurring in 55,144 lactations in 24,831 cows in 5 New York State Holstein herds was collected from January 2004 until February 2014. For the first objective, a generalized linear mixed model with a Poisson distribution was used to study the effects of CM cases occurring in the first 100 d of a cow's first lactation, as well as farm indicator and number of days in the cow's lifetime, on the future lifetime rate of CM. Only cows that had completed their productive life [i.e., all had been culled (or sold) or had died; n = 14,440 cows] were included in this analysis. For the second objective, a Cox proportional hazards model was used to study the effects of CM cases occurring in the first 100 d of a cow's first lactation on the length of total productive lifetime. The model was stratified by farm. All 24,831 cows were included in this analysis with right censoring. Cows experienced between 0 and 4 CM cases in the first 100 d of lactation 1. Over their lifetime, cows experienced between 0 and 25 CM cases. During the study period, 10% of all cows died and nearly half of all cows were culled. The average length of productive life, including censored observations, was 2.0 yr after first calving. Compared with cows having no CM cases in the first 100 d of lactation 1, cows with 1 CM case in that time period had a 1.5 times higher rate of total number of CM cases over their lifetime. Cows with 2 (or 3 or more) CM cases in the first 100 d of lactation 1 had a 1.7 times (or 2.6 times) higher rate of total number of CM cases over their lifetime. For each additional CM case occurring in the first 100 d of lactation 1, the hazard rate of culling increased by 34%. Given economic conditions for preferentially culling mastitic cows, the study findings may help farmers make optimal decisions with regard to culling of such cows

Effects of pathogen-specific clinical mastitis occurrence in the first 100 days of lactation 1 on future mastitis occurrence in Holstein dairy cows: An observational study

The objective of this observational study was to estimate effects of clinical mastitis (CM) cases caused by different pathogens (Streptococcus spp., Staphylococcus aureus, Staphylococcus spp., Escherichia coli, Klebsiella spp., and CM cases with no growth) occurring in the first 100 d in lactation 1, of a dairy cow on the future rate of occurrence of different types of CM during a cow's full lifetime. The outcomes were occurrence of Streptococcus spp., Staphylococcus aureus, Staphylococcus spp., Escherichia coli, Klebsiella spp., and CM cases with no growth, after the first 100 d of lactation 1, until a cow's removal through death or sale in that or a subsequent lactation. Data, including information on CM cases, milk production, and event dates (including death or sale dates), were collected from 14,440 cows in 5 New York State Holstein herds from January 2004 until February 2014. Generalized linear mixed models with a Poisson distribution and log link function were fit for each pathogen. The individual cow was the unit of analysis. Escherichia coli was a predictor of future occurrence of E. coli, Klebsiella spp., and CM cases with no growth. Early-occurring Klebsiella spp. was a predictor of future cases of Klebsiella spp. Cases with no growth were predictors of future occurrence of Staphylococcus spp., E. coli, Klebsiella spp., and cases with no growth. Thus, E. coli and cases with no growth occurring early in lactation 1 appear to be consistent risk factors for future cases of CM, whether cases with the same pathogen or a different pathogen. In this study, farm effects on later pathogen occurrence differed somewhat, so treatment protocol and culling strategy may play a role in the findings. Nevertheless, the findings may help farmers in managing young cows with CM in early productive life, especially those with E. coli or cases with no growth, in that they may be more susceptible to future CM cases in their later productive life, thus meriting closer attention

Association of pathogen-specific clinical mastitis in the first 100 days of first lactation with productive lifetime : An observational study comparing competing risks models for death and sale with the Cox model

The objective of this observational study was to study the association between clinical mastitis (CM) (Streptococcus spp., Staphylococcus aureus, Staphylococcus spp., Escherichia coli, Klebsiella spp., cases with other treated or other not treated organisms, CM without growth) occurring in a dairy cow's first 100 days (d) of her first lactation and her total productive lifetime, ending in death or sale (for slaughter). Data were collected from 24,831 cows in 5 New York Holstein herds from 2004 to 2014. Two analytical approaches were compared. First, removals (death, sale) were treated as competing events in separate survival analyses, in proportional subdistribution hazards models. In one, death was coded as the event of interest and sale as the competing event; in another, sale was the event of interest and death the competing event. Second, traditional survival analysis (Cox proportional hazards) was conducted. In all models, the time variable was number of days from date of first calving until event (death or sale) date; if the cow was alive at study end, she was censored. Models were stratified by herd. Ten percent of cows died; 48.4 % were sold. In the competing risks analysis, E. coli and CM without growth were associated with death; the former with an increased hazard rate of death, the latter with a lower one. Streptococcus spp., Staph. aureus, Klebsiella spp., cases with other treated or untreated organisms, and CM without growth were associated with higher hazard rates of sale. The Cox proportional hazards model's hazard rates were higher than those in the competing risks model in which death was the event of interest, and resembled those in the model in which sale was the event of interest. Four additional Cox models, omitting dead or sold cows, or censoring each, were also fitted; hazard ratios were similar to the above models. Proportional subdistribution hazards models were appropriate due to competing risks (death, sale); they produce less-biased estimates. A study limitation is that while proportional subdistribution hazards models were appropriate, they have the illogical feature of keeping subjects at risk for the event of interest even after experiencing the competing event. This is, however, necessary in estimating cumulative incidence functions. Another limitation concerns pathogen variability among study farms, implying that CM decisions are farm-specific. Misclassification of ‘dead’ vs. ‘sold’ cows was also possible. Nevertheless, the findings may help in optimizing management of cows contracting specific types of CM early in productive lifetime

Does clinical mastitis in the first 100 days of lactation 1 predict increased mastitis occurrence and shorter herd life in dairy cows?

The objectives of this study were to estimate the direct effects of clinical mastitis (CM) occurring in early productive life (defined as the first 100 d of the first lactation) of Holstein dairy cows on the future rate of CM occurrence and on the length of total productive lifetime. Information on CM cases and other data occurring in 55,144 lactations in 24,831 cows in 5 New York State Holstein herds was collected from January 2004 until February 2014. For the first objective, a generalized linear mixed model with a Poisson distribution was used to study the effects of CM cases occurring in the first 100 d of a cow's first lactation, as well as farm indicator and number of days in the cow's lifetime, on the future lifetime rate of CM. Only cows that had completed their productive life [i.e., all had been culled (or sold) or had died; n = 14,440 cows] were included in this analysis. For the second objective, a Cox proportional hazards model was used to study the effects of CM cases occurring in the first 100 d of a cow's first lactation on the length of total productive lifetime. The model was stratified by farm. All 24,831 cows were included in this analysis with right censoring. Cows experienced between 0 and 4 CM cases in the first 100 d of lactation 1. Over their lifetime, cows experienced between 0 and 25 CM cases. During the study period, 10% of all cows died and nearly half of all cows were culled. The average length of productive life, including censored observations, was 2.0 yr after first calving. Compared with cows having no CM cases in the first 100 d of lactation 1, cows with 1 CM case in that time period had a 1.5 times higher rate of total number of CM cases over their lifetime. Cows with 2 (or 3 or more) CM cases in the first 100 d of lactation 1 had a 1.7 times (or 2.6 times) higher rate of total number of CM cases over their lifetime. For each additional CM case occurring in the first 100 d of lactation 1, the hazard rate of culling increased by 34%. Given economic conditions for preferentially culling mastitic cows, the study findings may help farmers make optimal decisions with regard to culling of such cows

Evidence of no protection for a recurrent case of pathogen specific clinical mastitis from a previous case

The objective of this study was to determine whether the occurrence of a previous case of pathogen-specific clinical mastitis (CM) protects Holstein dairy cows against a recurrent case. Pathogens studied were Escherichia coli, Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., Klebsiella spp., and Trueperella pyogenes. A total of 40 864 lactations (17 265 primiparous and 23 599 multiparous) from 19 835 cows from 5 large, high milk producing New York State dairy herds were analysed. We estimated the effects of parity, calving diseases, milk yield, current season and number of CM cases in the previous lactation on the risk of a first CM case using generalised linear mixed models with a log link and Poisson error distribution. The aforementioned risk factors and the occurrence of previous cases of pathogen-specific CM within the current lactation were evaluated as risks for second and third cases of pathogen-specific CM. Cows with more CM cases in the previous lactation were at greater risk of pathogen-specific CM in the current lactation. Multiparous cows were at greater risk of a second CM case if they had suffered from a first CM case that was caused by the same pathogen as the second case. In contrast, a second CM case generally put cows at greater risk of a third case, irrespective of whether the third case was caused by the same or a different pathogen. Our results showed that a previous case of pathogen specific CM does not generally protect against a recurrent case