Complications After Orthopedic Surgeries in Patients with Rheumatoid Arthritis Treated with Janus Kinase Inhibitors: a Retrospective Observational Study.

OBJECTIVES: The current study compared the outcome after orthopedic surgeries in patients with RA receiving JAKi versus biologic disease-modifying anti-rheumatic drugs (bDMARDs). METHODS: This was a retrospective observational study of Japanese patients with RA. Sixty-two patients with RA using JAKi preoperatively underwent orthopedic surgeries. Using propensity score matching, these 62 patients were matched with 62 patients using bDMARDs preoperatively. The number of adverse events was counted. We also examined whether the drug-withholding period in the JAKi-treated group was associated with the occurrence of major postoperative adverse events, namely inflammatory flares and delayed wound healing (DWH). RESULTS: JAKi-treated patients had a higher incidence of postoperative flares than bDMARDs-treated patients (29% vs 12.1%, p=0.01). The incidences of postoperative complications other than flares were not significantly different between the two groups. Among the JAKi-treated group, a longer perioperative drug-withholding period (≥11 days) was associated with a higher incidence of postoperative flares (p=0.04). The incidences of DWH and SSI were not associated with the duration of the JAKi withholding period. CONCLUSION: JAKi-treated patients had a higher incidence of postoperative flares than bDMARDs-treated patients. A total of 11 days or more of drug withdrawal was associated with postoperative flares.

Comparison of the peripheral blood leukocyte population between Japanese Black and Holstein calves.

Japanese black (JB) calves have greater susceptibility to infectious diseases compared to Holstein (Hol) calves. In order to clarify the differences in cellular immune status between JB and Hol calves, the leukocyte population and lymphocyte proliferative ability were analyzed. In total 200 healthy calves, 1 day to 14 weeks of age, were examined: 105 JB and 95 Hol calves. Lower numbers in peripheral blood and percentage in peripheral blood mononuclear cells of CD3(+)TcR1-N12(+) T cells and major histocompatibility complex class-II(+)CD14(-) B cells were observed in the JB compared to the Hol. The percentage of TcR1-N12(+)CD25(+) T cell in the JB was significantly lower than that of the Hol at 4-6, and 8-10 weeks. Interleukin (IL)-2 sensitivity in the JB was lower than that in the Hol, and significant differences were observed in age groups of 6-8 weeks and 10-14 weeks. These findings indicated that the lower numbers of γδ T cells and B cells in the JB compared to the Hol might be associated with the specificity of the immune systems in JB calves.

Blood free amino acids in the postpartum dairy cattle with left displaced abomasum.

In order to decipher the amino acid (AA) balance in the dairy cattle with left displaced abomasum (LDA), blood samples were obtained from thirty LDA and 12 healthy control cattle. Plasma from LDA cattle exhibited significantly higher free fatty acid and ß-hydroxybutyrate, lower glucogenic AA, such as methionine, alanine and serine, and higher ratio of ketogenic AA among blood free AA, such as leucine and lysine. The Fischer ratio, phenylalanine and albumin were similar to control cattle. These results suggested that LDA cattle were in negative energy balance, but AA metabolism and protein synthesis were within a normal range. Lower glucogenic AA was due to the higher gluconeogenesis, and higher ketogenic AA was due to higher ketogenesis.

Age-related alterations in peripheral leukocyte population of healthy Holstein dairy cows during the pre-calving period.

Older cows show a high incidence of infectious diseases during the periparturient period. The periparturient infectious diseases are closely associated with the immune function of dairy cows during the pre-calving period. In order to evaluate the relationship between the immune cell population and age in the cows during the pre-calving period, we obtained blood samples from 170 dairy cows during the pre-calving period. We chose only healthy cows, which did not develop clinical diseases within 2 weeks after the calving in this study. The animals were divided into 4 groups based on their parity: in their 1st pregnancy (Group 1), in their 2nd pregnancy (Group 2), in their 3rd calving (Group 3) and in more than 3rd pregnancy (Group 4). The numbers of the peripheral blood CD3(+)TcR1-N12(+) and MHC class-II(+)CD14(-) lymphocytes were significantly higher in Group 1 compared to Group 4. This result indicated that the lower gammadeltaT cells and B cells in older cows compared with heifer during pre-calving period.

Relationship between immune function and serum vitamin A in Japanese black beef cattle.

This study evaluated the relationship between the serum vitamin A level and immune function in seventy non-diseased Japanese Black (JB) cattle during their fattening stages. The animals were divided into two groups, a Low Vitamin A (VA) group (N=9) with below 30 IU/dl of serum VA and a Control group (N=61). Blood samples were collected for biochemical analysis and examination of the leukocyte population and cytokine mRNA expression. The numbers of CD3(+)WC1(+) T cells and MHC class-ll(+)CD14(-) B cells were significantly lower in the Low VA group than in the Control group (P<0.05). The IFN-gamma/IL-4 rate was significantly lower in the Low VA group, while IL-4 was higher and IFN-gamma was lower in the Low group compared with the Control group. This study indicated that immune function imbalance was present in JB cattle with low serum VA levels during the fattening stage.

Effects of active egg white product/ Clostridium butyricum Miyairi 588 additive on peripheral leukocyte populations in periparturient dairy cows.

The leukocyte populations of periparturient dairy cows were analyzed after administration of active egg white/Clostridium butyricum Miyairi additive. Sixty-eight Holstein milking cows were divided into 3 groups. Group A was administered active egg white product (AEWP)/Clostridium butyricum Miyairi 588 (Miyairi 588) additive (n=23). Group B was administered Miyairi 588 only (n=23), and Group C was the control group (n=22). The challenged groups were administered 100 g of AEWP + Miyairi 588, or Miyairi 588 alone, daily for 60 days from 1 month before until 1 month after paturition. Blood samples were collected from all groups three times (1 month before, 1 week after and 1 month after parturition) for analysis of the peripheral leukocyte population. The results showed significantly higher numbers of CD4+ cells in Group A compared with Group C 1 week after paturition. AEWP/Miyairi 588 additive may enhance the number of CD4+ T cells in periparturient dairy cows.

Changes in peripheral blood mononuclear cells after calving in lactating cows with serious decrease of body weight before and after calving.

The aim of this study was to clarify the hormonal and immunological changes in periparturient dairy cows with excessive weight loss following calving. We analyzed leukocyte populations and the peripheral blood mononuclear cell (PBMC) mRNA of IFN-gamma, IL-4, growth hormone (GH)-receptor (R) and insulin -R and measured the GH and insulin concentrations. Ten dairy cows fed in one herd were used in this study and were divided into two groups. Five cows that experienced loss of body weight following calving of over 10% comprised the Weight Loss Group, and the remaining five cows, which experienced loss of body weight of 5% or less following calving, served as the Control Group. The Weight Loss Group had high serum cholesterol and low blood urea nitrogen levels compared with the Control Group throughout the period of observation. In regard to the leukocyte populations, there were significantly fewer CD4(+)CD45R-T cells in the Weight Loss Group 1 to 2 months after calving compared with the Control Group. The percentage of IFN-gamma/IL-4 among PBMCs in the Weight Loss Group tended to be lower than in the Control Group throughout the observation period. In the Weight Loss Group, the levels of GH-R during month 2 were lower than in the Control Group. We concluded that excessive loss of body weight in dairy cows following calving is associated with depressed cellular immune function.

Effects of mycotoxins on mitogen-stimulated proliferation of bovine peripheral blood mononuclear cells.

The effects of mycotoxins on mitogen-stimulated proliferation of bovine peripheral blood mononuclear cells (PBMCs) were investigated. Aflatoxin B(1) (AFB(1)), deoxynivalenol (DON) and zearalenone (ZEN) were added to cultures of PBMCs, and the proliferation responses were measured using MTT bioassays. Suppression of the proliferation of calf PBMCs by AFB(1) and DON was significantly stronger than that of cow PBMCs, whereas there were no differences in suppressive effects on PBMCs from Holstein and Japanese Black calves and cows. The suppressive effect was greatest in the order of DON, AFB(1) and ZEN, and the effects of DON and AFB(1) seemed to be dose-dependent. The results suggest that some mycotoxins directly suppress proliferation of bovine PBMCs.

Comparison of two different nutritive conditions against the changes in peripheral blood mononuclear cells of periparturient dairy cows.

To clarify the relationship between cellular immune status and nutritive condition in periparturient dairy cows, feeding content, blood profiles, and immune condition were observed in cows from two dairy herds with different types of feed content. Immunological analyses such as leukocyte population and peripheral blood mononuclear cell (PBMC) mRNA of IFN-gamma, TNF-alpha, IL-4, and IL-10, quantified by real-time RT-PCR were performed. With regard to feed content during dry periods, there were six cows in the herd with insufficient non-structural carbohydrate (NFC) intake (group I) and six cows in the herd with sufficient NFC intake (group II). Significantly lower levels of blood glucose were observed in group I between weeks -12 and 16 compared with group II. Serum cholesterol level was significantly lower in group I between weeks 2 and 10 than in group II. The numbers of CD3+ and CD4+ T cells in group I were significantly lower than those in group II in weeks 6 and 14. The numbers of CD21+ B cells were significantly lower in group I than in group II in weeks -16, -12, 2, and 10. On the other hand, the CD4+/CD8+ ratio in group II was significantly higher than group I between weeks 2 and 14. The IFNgamma/IL-4 mRNA rate in group I was significantly lower than group II in week 6. We concluded that cellular immune depression occurrs after calving in dairy cows with low nutritional status in the periparturient period.

Comparison of the insulin reaction of peripheral blood T cells between healthy Holstein dairy cows and JB during the periparturient period.

To compare the changes in the insulin reaction of Holstein dairy cows and Japanese Black cows (JB) during the periparturient period, the insulin resistance test in vivo and lymphocytes proliferation with insulin in vitro were performed. Ten healthy Holstein dairy cows (Holstein group) and 10 healthy JB cows (JB group) used in this study were observed on days 60, 40, and 20 before calving and days 7 and 20 after calving. In insulin resistance reaction in vivo and in vitro, a low insulin-stimulated glucose disposal rate and lymphocyte proliferation with insulin were observed in the Holstein group compared with the JB group during the experimental period. An analysis of the lymphocytes cultured with insulin showed that the percentage of CD4+CD45R- T cells in the Holstein group was significantly lower than that of the JB group before day 20. These findings indicate that T cells reaction to insulin in healthy periparturient Holstein cows is lower than that in Japanese Black.

Peripheral mononuclear cell response in Japanese black calves after oral administration of IFN-alpha.

To investigate the effects of oral administration of an interferon (IFN)-alpha drug on the immune reaction of healthy Japanese Black (JB) calves, peripheral leukocyte populations and their ability to produce cytokine mRNA were analyzed after oral administration of IFN-alpha. Fourteen calves fed in one herd were divided into two groups; seven calves were orally administered 0.1 g/day of IFN-alpha from the day of birth to day 5 on each day (group 1, N=7), and the other seven calves were used as the control (group 2, N=7). Blood samples were collected from the jugular veins of all calves before administration and in weeks 1, 2, 4, 8, and 16 after birth. The number of MHC class II+CD14+ monocytes in the leukocytes population of group 1 increased gradually after birth, and significantly higher numbers were detected in week 4 compared with group 2. MHC class II-CD14+ monocytes in group 1 peaked in week 1, and a significant increase was detected compared with group 2. The level of IL-12 in the cytokine mRNA of group 1 increased gradually between weeks 1 and 2, and a significantly higher level of IL-12 was found compared with group 2. These results suggest that oral administration of IFN-alpha induces activation of the monocyte functions in JB calves.

Evaluation by weight change rate of dairy herd condition.

The purpose of this study was to clarify whether weight change rate (WCR) is useful in evaluating herd health. Five herds (A, B, C, D, and E) were examined monthly for approximately 1 year to measure both WCR and BCS. WCR was calculated using the following equation: WCR (%) = (body weight of current month-body weight of the preceding month)/body weight of current month x 100. In addition, blood profiles were performed in each herd before and after calving. The incidence of periparturient diseases was higher in Herds A, B, and C compared with Herds D and E. Reproductive performance in Herds A and B was rather poor compared with Herds C, D, and E. There were significantly lower WCRs in Herd A compared with Herd C during the period of day -30 to day 30 after calving. According to the blood profiles, high levels of non-essential fatty acids (NEFA) were observed during the period of day -30 to -1 and high beta-hidroxybutyricacid (BHB) and low levels of glucose were observed at day 30 after calving in Herd A. A marked poor condition in Herd A during the peripaturient period was clearly expressed by low WCR in this experiment. WCR can express body condition of herds and is suggested to be a useful parameter in the determination of herd performance in field experiments.

Serum free amino acid concentration in hepatic lipidosis of dairy cows in the periparturient period.

Blood samples were taken from eight multiparous cows at a dairy farm on eight occasions between the prepartum period and peak lactation to study the serum concentrations of amino acids and biochemical constituents. The cows were classified as having either severe hepatic lipidosis (HL) or non-hepatic lipidosis (non-HL) according to their clinical condition after calving and changes in serum biochemical parameters. The serum concentrations of beta-hydroxybutyric acid were higher in the HL group than in the non-HL group (ANOVA: p<0.01). The serum concentrations of methionine (Met), phenylalanine, and arginine were significantly different between the two groups (ANOVA: p<0.05). In particular, the Met levels were significantly low for 14 days after calving in the HL group (p<0.05), although Met levels in the HL group tended to be lower than the values in the non-HL group until 30 days after calving, starting 14 days before calving. The results suggest that an insufficiency of Met during the periparturient period is related to the development of hepatic lipidosis.

Relationship between leukocyte population and nutritive conditions in dairy herds with frequently appearing mastitis.

To clarify the relationship between cellular immune status and nutritive condition, feeding program, blood profiles, and leukocyte populations were analyzed in two dairy herds experiencing frequent mastitis. Fourteen of the 35 lactating cows in herd A, and 18 of the 50 lactating cows in herd B scored positive on the California Mastitis Test (CMT), and 3 of the 73 lactating cows were CMT positive in herd C, which was the control. All herds were evaluated during five different milking stages, and blood was collected from five cows at each stage. With regard to feed content, the percentages of total digestible nutrients (TDN) and crude protein (CP) were found to be lower in herds A and B than in herd C. Levels of serum total cholesterol and blood urea nitrogen were lower in herds A and B than those in herd C. Neutrophil counts in herds A and B were increased compared to the neutrophil counts in herd C. On the other hand, the numbers of CD3(+) T cells and CD14-MHC class(+) cells were lower in herd A and B than in herd C. A decrease in peripheral lymphocytes and undernourishment were observed in the herds with frequent occurring mastitis.

Changes in leukocyte population after ozonated autohemoadministration in cows with inflammatory diseases.

In this study, we investigated whether ozonated autohemoadministration (OAHA) influences leukocyte populations in cows with clinical inflammatory disease. Eleven cows with inflammatory disease (Inflammatory Group) and three healthy cows (Control Group) were used for this study. The CD4(+)/CD8(+) ratio in the Inflammatory Group increased significantly compared to that in the Control Group 3 to 4 days after OAHA treatment. In the Inflammatory Group, the number of CD14(+) cells decreased gradually after OAHA, but CD14(+) levels remained stable in the Control Group. The number of MHC class-II(+) cells decreased gradually in the Inflammatory Group, but increased gradually in the Control Group, and the difference between the groups was significant on day 14 after OAHA. These findings suggest a possible difference in the activation of immune response after OAHA in infected cows compared to healthy cows.

Effect of dietary administration of bananas on immunocytes in F1 hybrid calves.

The effect of dietary administration of bananas on immunocytes in calves was investigated. Twenty Fl hybrid calves were used in this study (treated group n=10, control group n=10). Banana (2 g/kg BW) was administered to the calves for 5 days. Leukocyte subsets were examined on days 0, 5, 10, and 15. The numbers CD3+, (CD3+)CD45R-, and (CD3+)TcR+ cells significantly increased between day 0 and day 5 in the treated group (P<0.01), and were significantly higher on day 5 in the treated group relative to the control group (P<0.05). These data showed that feeding banana to calves increased T-lymphocytes, suggesting it might be possible to enhance protective functions against infections.

Carrier rate of Factor XI deficiency in stunted Japanese black cattle.

Blood examinations and genotyping of Factor XI (F11) were performed in growth retardation Japanese Black cattle and their dams. Genotyping of F11 revealed that the recessive homozygous and heterozygous genotype frequencies were 5.2% and 50.0% in the Claudin-16 (CL-16) deficiency group (n=58), 0% and 14.2% in the renal dysplasia group (n=7), 0% and 26.1% in the non-CL-16 deficiency nephritis group (n=23), 8.9% and 46.7% in the hypogenesis syndrome group (n=45), 6.2% and 25.0% in the neonatal weak calf syndrome group (n=32), 9.1% and 38.6% in the respective dams group (n=44), 0% and 23.1% in the normal cattle group (n=13), and 5.9% and 38.2% in total (n=222), respectively. These results showed that the carrier rate of F11 deficiency was high in Japanese Black cattle, and that the CL-16 deficiency, hypogenesis syndrome, neonatal weak calf syndrome, and dams groups had a large amount of recessive homozygous genotype than the other groups. No abnormal bleeding was observed clinically in the present study, and 4 of the recessive homozygous dams showed normal growth and parturition.

Effect of nutritional conditions on changes in leukocyte populations in Japanese black calves.

To clarify the effect of nutritive conditions on changes in immune cells in Japanese Black (JB) calves during the growth period, leukocyte populations were analyzed in ten healthy JB calves managed in one herd. The calves were divided into two groups: five calves in Group 1 were given insufficient nutrition, and the other five calves in Group 2 received adequate nutrition. The levels of serum total cholesterol and glucose were significantly lower in Group 1 than in Group 2 at 1 month. The numbers of CD3+, CD4+ and CD8+ cells tended to be lower in Group 1 than in Group 2 at months 1 and 2, and the difference in CD4+ was significant at month 2. The number of MHC class-II(+high) cells was significantly lower in Group 1 than in Group 2 at months 1 and 2. These results suggest that adequate nutrition might stimulate an increase in immune cells in calves during the growth period.

The relationship between changes in serum glycine and alanine concentrations in non-essential amino acid and milk production in the transition period in dairy cows.

The serum concentration of non-essential amino acid (NEAA) was measured in ten Holstein dairy cows grouped as low production (n=5) and high production (n=5) from one month pre-partum through four months post-partum and the relationship between production and amino acid concentrations was studied. The glycine (Gly)/NEAA ratio and the glycine/alanine ratio of the high production group were significantly higher than the low production group (p<0.01). The observed decrease of the alanine (Ala)/NEAA ratio was more remarkable in the high production group than in the low production group. Measurement of Gly/Ala ratio in serum may be useful for evaluating the nutritional status of peri-parturient dairy cow.

Changes in peripheral leukocyte subsets in dairy cows with inflammatory diseases after calving.

To clarify the cellular immune system in dairy cows with inflammatory diseases after calving, the leukocyte subsets were examined in Holstein dairy cows. Twenty Holstein cows reared in one herd, were used in this study. Nine cows (Group 1) experienced onset of mastitis or puerperal fever within 2 weeks after calving, and the other eleven cows remained healthy (Group 2) after calving. The numbers of CD3(+), CD4(+) and CD8(+) cells tended to be lower in Group 1 than in Group 2 from the day of calving through week 1. These results suggested that the cows with inflammatory diseases might have experienced a decline in T cells by the day of calving, before the onset of disease.