Immunosuppression Group Research Articles

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

ObjectivesThe rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.MethodsThis...

P439 Diagnosis and management of latent and active tuberculosis in the context of biologic therapy in inflammatory bowel disease

Background: Anti-TNF treatments have improved the outcomes for patients with inflammatory bowel disease (IBD). However, they are associated with an increase in risk of Tuberculosis (TB). The aim of this study is to determine the proportion of latent TB infections (LTBI) in our IBD cohort treated with anti-TNFs and the management of these patients. We also examined the effect of different immunosuppressive drugs on the indeterminate rate of the interferon-gamma release assays (IGRA) in LTBI screening Methods: We conducted a retrospective review of all patients treated with biologics between March 2007 and November 2015. Patient notes and electronic records were reviewed. LTBI screening was assessed using a risk assessment form, chest x-ray, and tuberculin skin test (TST) or IGRA for the screening for LTBI and the nature of the immunosuppressive treatment was documented. Results: 732 patients with IBD were screened for LTBI before starting a biological treatment during the study period. 31 of 732 (4%) IBD patients were diagnosed and treated for LTBI with no significant side effects. 596 of 732 received their biologic treatment with a median delay of 86 days in initiating biologics. 6 of 596 patients who received biologic treatment developed active TB; 5 of whom were Caucasian. 247 patients were screened with an IGRA test. 6 were positive, 162 were negative and 79 patients were indeterminate. 45% with indeterminate IGRA had a repeat; half were negative and half remained indeterminate. 73% of the patients were receiving immunosuppressive (IMM) medication(s). There was a higher indeterminate rate of the IGRA in the IMM group compared to the no-IMM group (32% compared to 9%). The combination of steroids and thiopurines gave the highest rate of an indeterminate IGRA. High and low doses of steroids were equally likely to result in an indeterminate IGRA result. Conclusions: 4% of patients screened had LTBI and 1% of patients treated with biologics developed active TB. Delays in initiating biologics due to LTBI screening may have detrimental effects on the IBD management. Almost one third of patients on immunosuppressants had an indeterminate IGRA, which supports the need for a guideline incorporating a risk stratification strategy based on factors such as country of birth and local TB prevalence. There is a need to remain vigilant for TB regardless of baseline LTBI results or epidemiological factors.

Clinical study on the role of immunosuppressant agents in prevention of postoperative recurrence of Crohn's disease

Objective To investigate the effects of different therapeutic strategies on recurrence of postoperative Crohn's disease (CD) patients. Methods From September 2009 to September 2014, 85 CD patients with intestinal resection were enrolled. The clinical features and maintenance therapeutic medication were retrospectively analyzed. The patients were divided into non-treatment group (induding continuously or cumulatively taking medicine less than three months), 5-aminosalicylic acid (5-ASA) group and immunosuppressant agents group (including azathioprine, methotrexate and thalidomide). Kaplan-Meier method was performed to compare the recurrence rate in postoperative CD with different therapeutic medication and the risk factors of postoperative recurrence were also analyzed. Results Among 85 CD patients, there were 32, 21 and 32 patients in non-treatment group, 5-ASA group and immunosuppressive agents group, respectively. After surgery, the one year accumulated clinical recurrence rate of immunosuppressant agents group was 12.5% (4/32), which was significantly lower than that of non-treatment group (56.3%, 18/32) and 5-ASA group (38.1%, 8/21), and the differences were statistically significant (χ2=12.250, P 0.05). Penetrating lesion was an risk factor of postoperative clinical recurrence in CD patients (χ2=4.963, P=0.026, odds ratio (OR)=2.221, 95%confidence interval (CI) 1.121 to 5.775). Conclusions Immunosuppressive agents rather than 5-ASA have remarkable effects in preventing postoperative clinical recurrence in CD patients. Postoperative clinical recurrence is more likely to happen in patients with penetrating lesions. Key words: Crohn disease; Postoperative recurrence; Immunosuppressive agents; Retrospective studies

Immunosuppressive treatment for myocarditis: a meta-analysis of randomized controlled trials.

Immunosuppressive treatment for myocarditis is controversial. Several small-scale randomized controlled trials (RCTs) reported inconsistent outcomes for patients with myocarditis. We searched on the Medline, Embase, and Cochrane databases for articles in English language between January 1966 and May 2013, as well as on the China National Knowledge Internet (CNKI, 1979 to May 2012) and the Chinese Biomedical Literature Database (CBM, 1978 to May 2013) for articles in Chinese language. Statistical analysis was performed using Review Manager 5.0. Nine articles were finally selected, in which 342 patients were in immunosuppressive treatment group and 267 patients in conventional treatment group. The immunosuppressive treatment group showed a significant improvement in left ventricular ejection fraction at both short-term (≤3 months) [difference: 0.08, 95% confidence interval (CI): 0.05-0.10) and long-term (difference: 0.10, 95% CI: 0.00-0.21)] follow-up. Moreover, left ventricular end-diastolic dimension decreased significantly in the immunosuppressive treatment group after short-term follow-up (difference: -1.85 mm, 95% CI: -3.18 to -0.52 mm), but a long-term beneficial effect was not sustained (difference: -5.79 mm, 95% CI: -15.30 to 3.72 mm). There was no difference, however, between the two groups in the rate of death or heart transplantation (odds ratio: 1.33, 95% CI: 0.77, 2.31). Immunosuppressive treatment might be beneficial for improving left ventricular systolic function and remodeling in patients with myocarditis, which could be considered as a therapeutic alternative when optimal conventional therapy is not effective. More large RCTs, however, are required.

Similar outcomes for anti-tumor necrosis factor-α antibody and immunosuppressant following seton drainage in patients with Crohn's disease-related anal fistula.

Anal fistula is common in patients with Crohn's disease (CD) and leads to significant morbidity. The efficacy of seton drainage combined with anti-tumor necrosis factor-α monoclonal antibody (anti-TNF-α) or immunosuppressant in the treatment of CD-related anal fistula remains unclear. The aim of the present study was to compare the efficacy between seton drainage combined with anti-TNF-α and seton drainage combined with immunosuppressant postoperatively on the treatment of CD-related anal fistula. A total of 65 patients with CD-related anal fistula who had received seton drainage combined with postoperative medication were divided into an antibiotics only group, anti-TNF-α group and immunosuppressant group; all patients were treated with antibiotics. Fistula closure, external orifice exudation rate and recurrence rate were assessed among these patients. The duration of follow-up ranged from 3 to 84 months with an average of 25.3 months. There were 11 (16.9%) cases of recurrence after seton drainage, 9 of which underwent a second seton drainage. In the total study group, 34 (52.3%) cases achieved complete fistula closure, and 10 (15.4%) cases showed external orifice exudation. No significant difference was found among these three groups, regarding fistula closure rate, closure time of fistula and recurrence rate. The external orifice exudation rate was significantly higher in the anti-TNF-α group compared with the antibiotics only group and immunosuppressant group (P=0.004 and P=0.026, respectively). Seton drainage is an effective treatment for CD-related anal fistula. The efficacy is similar whether combined with anti-TNF-α or immunosuppressant.

Mucosal Healing in Paediatric Patients with Moderate-to-Severe Luminal Crohn's Disease Under Combined Immunosuppression: Escalation versus Early Treatment.

We aimed to compare the efficacy of combined immunosuppression in terms of mucosal healing in paediatric patients with moderate-to-severe luminal Crohn's disease receiving infliximab according to either an 'escalated combined immunosuppression' or an 'early combined immunosuppression' strategy. In this prospective observational study, the efficacy of combined immunosuppression was evaluated in terms of mucosal healing at weeks 14 and 54 from baseline infliximab infusion. Comparison was performed between the escalated combined immunosuppression group [group A] and the early combined immunosuppression group [group B]. Factors associated with mucosal healing at weeks 14 and 54 from baseline infliximab infusion were also investigated. Seventy-six patients initiated infliximab with concomitant azathioprine [group A = 28; group B = 48]. Comparison of baseline characteristics revealed a significantly longer duration from initial diagnosis to infliximab infusion in group A [median 8.1 vs. 0.7 months; p < 0.001]. Mucosal healing was achieved in 32% of patients in group A and 51% in group B at week 14 [p = 0.121], and in 42% in group A and 74% in group B at week 54 [p = 0.007]. Group B was also positively associated with mucosal healing at week 54 on multivariate logistic regression [odds ratio = 6.216, 95% confidence interval = 1.782-21.686, p = 0.004]. Mucosal healing during combined immunosuppression is more effectively achieved by treatment with an early combined immunosuppression strategy without corticosteroid induction administered within 1 month rather than escalating to receive combination therapy later during the course. The therapeutic window of opportunity in early Crohn's disease may be shorter than generally thought, especially in children.

Efficacy of ursodeoxycholic acid alone or combined with immunosuppressant in primary biliray cirrhosis-autoimmune hepatitis overlap syndrome

Objective To evaluate the efficacy of ursodeoxycholic acid (UDCA) alone or combined with immunosuppressant in primary biliary cirrhosis-autoimmune hepatitis overlap syndrome (PBC-AIH). Methods From January 2001 to December 2014, 41 patients with PBC-AIH were screened out from patients with autoimmune hepatitis (AIH) and retrospectively analyzed. According to their therapy, they were divided into UDCA alone group (n=20) and UDCA combined with immunosuppressant group (n=21). Before and after treatment, serum biochemical indicators, immune indicators and response rates of the two groups were compared. Rank sum test or t-test was performed for statistical analysis. Results After treatment for 12 months, the levels of globulin, alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) of UDCA alone group were all lower than those before treatment ((35.76±5.36) g/L vs (40.51±9.07) g/L, 32.5 U/L(12.0-149.9 U/L) vs 75.0 U/L(11.0-667.0 U/L), 34.0 U/L(8.0-77.9 U/L) vs 66.1 U/L(19.0-399.0 U/L), 134.0 U/L(63.0-389.7 U/L) vs 256.0 U/L(107.0-503.0 U/L), 78.0 U/L(12.0-444.0 U/L) vs 204.0 U/L(80.0-725.4 U/L)), and the differences were statistically significant (t=2.721, Z=-3.454, -3.421, -3.743 and -3.784; all P 0.05). Conclusions For PBC-AIH patients, in one year the remission of biochemical indicators is similar between UDCA alone and UDCA combined with immunosuppressant, however the level of IgG of UDCA combined with immunosuppressant group is lower than that of UDCA alone group. Key words: Hepatitis, autoimmune; Overlap syndrome; Ursodeoxycholic acid; Immunosuppressive agents; Efficacy

Fewer cytomegalovirus complications after kidney transplantation by de novo use of mTOR inhibitors in comparison to mycophenolic acid.

Cytomegalovirus (CMV) is a risk factor for patient and graft survival after kidney transplantation. We retrospectively analyzed risk factors for CMV infection in 348 patients who received a kidney transplant donated after brain death (n = 232) or by living donation (n = 116) between 2008 and 2013. Of the 348 patients analyzed, 91 received a mammalian target of rapamycin inhibitor (mTORi)-based immunosuppressive regimen. A total of 266 patients were treated with standard immunosuppression (Group 1) consisting of basiliximab induction, calcineurin inhibitor (CNI), and either mycophenolic acid (MPA, n = 219) or everolimus (EVE) (n = 47). We also included 82 patients who received more intense immunosuppression (Group 2) with lymphocyte depletion, CNI, plus either MPA (n = 38) or EVE (n = 44). Only patients in the high-risk constellation received CMV prophylaxis in Group 1, while all patients in Group 2 received prophylaxis for 6 month. The overall rate of CMV infections was low with 10.1% in all patients. Despite the different prophylaxis strategies applied, no difference was seen in CMV infections between Group 1 (10.9%) and Group 2 (13.6%). A multivariate analysis revealed that patients on EVE had fewer CMV complications compared with patients on MPA (P = 0.013, odds ratio [OR] 4.8, confidence interval [CI] 1.4-16.5). Donor and recipient age >65 years was an independent risk factor (P = 0.002, OR 3.2, CI 1.5-6.7) for CMV infections. Patients with CMV infections had significantly worse graft function after 2 years (P = 0.001). CMV is a significant risk factor for long-term graft outcome. Patients treated with EVE developed fewer CMV complications compared to patients on MPA. The use of mTORi is useful in patients at high risk of developing CMV infections.

Effects of Lactobacillus plantarum NCU116 on Intestine Mucosal Immunity in Immunosuppressed Mice.

The effects of Lactobacillus plantarum (L. plantarum) NCU116 isolated from pickled vegetables on intestine mucosal immunity in cyclophosphamide treated mice were investigated. Animals were divided into six groups: normal group (NIM), immunosuppression group (IM), immunosuppression plus L. plantarum NCU116 groups with three different doses (NCU-H, NCU-M, and NCU-L), and plus Bifidobacterium BB12 as positive control group (BB12). Results showed that the thymus indexes of the four treatment groups were significantly higher than that of the IM group (2.02 ± 0.16) (p < 0.05) and close to the index of the NIM group (2.61 ± 0.37) at 10 days. The level of immune factor IL-2 notably increased (IM, 121 ± 9.0) (p < 0.05) and was close to 65% of NIM group's level (230 ± 10.7). The levels of other immune factors (IFN-γ, IL-10, IL-12p70, and sIgA), the gene expression levels of IL-2 and IFN-γ, and the number of IgA-secreting cells showed similar patterns (p < 0.05). However, the level of immune factor IL-4 remarkably decreased (IM, 128 ± 10.2) (p < 0.05) and was only approximately 50% of the NIM group (154 ± 18.2). The levels of other immune factors (IL-6 and IgE) and the gene expression level of IL-6 at 10 days exhibited similar changes (p < 0.05) but showed a slight recovery at 20 days, accompanied by the altered protein expression levels of T-bet and GATA-3 in the small intestine. These findings suggest that L. plantarum NCU116 enhanced the immunity of the small intestine in the immunosuppressed mice.

The significance of pre-therapeutic F-18-FDG PET-CT in lymphoma-associated hemophagocytic lymphohistiocytosis when pathological evidence is unavailable.

Purpose The significance of positron emission tomography/computed tomography (PET–CT) in identifying patients with lymphoma-associated hemophagocytic lymphohistiocytosis (LAHLH) when pathological evidence is unavailable remains uncertain.MethodsIn this retrospective study, 44 HLH patients who underwent PET–CT before clinical treatment were enrolled, and 18 of them were highly suspected as LAHLH by PET–CT. We compared the PET–CT parameters between confirmed LAHLH and non-LAHLH patients. The efficacy of initial therapies for highly suspected LAHLH patients was analyzed as well.Results We found that the SUVSp, SUVBM, SUVLN, SUVmax, SUVLN/Li, and SUVmax/Li in LAHLH group were significantly higher than those in non-LAHLH group (p = 0.003, p = 0.034, p = 0.003, p < 0.001, p = 0.039, and p = 0.035, respectively). HLH patients with an SUVmax value >5.5, an SUVLN value >3.3, and an SUVSp value >4.8 were more likely to be LAHLH (p < 0.001, p = 0.003, and p = 0.003, respectively). And the incidence of multiple lymphadenopathy with increased FDG uptake or the incidence of multiple bone lesions in LAHLH patients was significantly higher than those in non-LAHLH group (92.9 vs. 35.7 %, p = 0.004; 42.9 vs. 0 %, p = 0.016, respectively). Furthermore, by comparing the efficacy of initial therapies for highly suspected LAHLH patients (n = 18), we indicated that the CR rate was significantly higher in lymphoma-chemotherapy group than in immunosuppressive therapy group (90 and 25 %, respectively; p = 0.013). OS analysis revealed that highly suspected LAHLH patients treated with lymphoma-chemotherapy had better prognosis (264 days) than those treated with immunosuppressive therapy (15 days) (p < 0.0001).ConclusionsWhen pathological evidence is absent, PET–CT may play an important role in identifying HLH patients underlying lymphoma. Once highly suspected as LAHLH by PET–CT, lymphoma-chemotherapies that directly treat the underling lymphoma may have a relatively favorable effect and better clinical outcomes than immunosuppressive therapy.

Intensive Supportive Care plus Immunosuppression in IgA Nephropathy

BackgroundThe outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain.MethodsWe conducted a multicenter, open-label, randomized, controlled trial with a two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin–angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio <0.2 [with both protein and creatinine measured in grams] and a decrease in the estimated glomerular filtration rate [eGFR] of <5 ml per minute per 1.73 m2 of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m2 at the end of the trial. The primary end points were analyzed with the use of logistic-regression models.ResultsThe run-in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m2 (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis.ConclusionsThe addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.)

Sepsis in Patients Receiving Immunosuppressive Drugs in Korea: Analysis of the National Insurance Database from 2009 to 2013

Background: The aim of this study is to evaluate the influence of immunosuppressants on in-hospital mortality from sepsis. Methods: Using data of the Health Insurance Review & Assessment Service, we collected data from patients who were admitted to the hospital due to sepsis from 2009 to 2013. Based on drugs commonly used for immunosuppression caused by various diseases, patients were divided into three groups; immunosuppressant group, steroid-only group, and control group. Patients with no history of immunosuppressants or steroids were assigned to the control group. To identify risk factors of in-hospital mortality in sepsis, we compared differences in patient characteristics, comorbidities, intensive care unit (ICU) care requirements, and immunodeficiency profiles. Subgroup analysis according to age was also performed. Results: Of the 185,671 included patients, 13,935 (7.5%) were in the steroid-only group and 2,771 patients (1.5%) were in the immunosuppressant group. The overall in-hospital mortality was 38.9% and showed an increasing trend with age. The steroid-only group showed the lowest in-hospital mortality among the three groups except the patients younger than 30 years. The steroid-only group and immunosuppressant group received ICU treatment more frequently (p < 0.001), stayed longer in the hospital (p < 0.001), and showed higher medical expenditure (p < 0.001) compared to the normal group. Univariate and multivariate analyses revealed that age, male gender, comorbidities (especially malignancy), and ICU treatment had a significant effect on in-hospital mortality. Conclusions: Despite longer hospital length of stay and more frequent need for ICU care, the in-hospital mortality was lower in patients taking immunosuppressive drugs than in patients not taking immunosuppressive drugs.

Low Adherence to Immunosuppressants Is Associated With Symptom Experience Among Kidney Transplant Recipients

PurposeThe purpose of this study was to investigate the relationship between immunosuppressant-related symptom experience (SE) and adherence to immunosuppressant regimens among kidney transplant (KT) recipients. MethodsA total of 239 KT recipients on an immunosuppressant regimen who were followed up after transplantation participated in this study. Data was collected through a self-reported questionnaire survey (medication adherence, SE, and quality of life) and medical record review. ResultsLow adherence in the immunosuppressant group was associated with longer time since KT, less comorbidity (<3), and a higher rehospitalization rate. Low adherence among KT recipients showed significantly greater overall symptom occurrence (P = .001) and symptom distress (P = .002) levels than patients with high or medium adherence after adjusting for a number of covariates. The most common symptom both in terms of occurrence (96.4%) and distress (91.1%) among poorly adherent KT recipients was tiredness. ConclusionLow adherence to an immunosuppressant regimen was significantly associated with high SE among KT recipients. Strategies to decrease immunosuppressant-related SE are needed to improve adherence to immunosuppressants.

Rat-to-Chinese tree shrew heart transplantation is a novel small animal model to study non-Gal-mediated discordant xenograft humoral rejection.

Since α-1,3-galactosyltransferase knockout (GalT-KO) pigs became available, there has been an increasing interest in non-Gal natural antibody (nAb)-mediated xenograft rejection. To better understand mechanisms of non-Gal nAb-mediated rejection, a simple small animal model without gene manipulation would be extremely valuable. Here, we tested whether the Chinese tree shrew (CTS), which is a small-sized mammal that is phylogenetically close to primates, could serve as a model for discordant xenograft rejection. Study 1: Expression of α-Gal antigens in hearts and kidneys of CTSs and rats was assessed by IB4 lectin binding. Presence of anti-Gal and anti-non-Gal IgM and IgG nAb in CTS sera was tested by FACS using Gal+ and GalTKO PBMC as well as BSA-ELISA. Study 2: Rat hearts were transplanted into CTS recipients (group 1, n = 7), and CTS hearts were transplanted in rats [n = 10; seven received no immunosuppression (group 2) and three received FK506 + leflunomide (group 3)]. Study 1: Both CTSs and rats had α-Gal expression in hearts and kidneys. ELISA showed CTSs do not have anti-Gal nAb, and flow cytometry indicated CTSs have anti-non-Gal IgM and IgG nAb in serum. Study 2: Rat hearts in CTSs were uniformly rejected within 35 mins, while CTS hearts in rats continued beating until day 5 without immunosuppression, and up to day 8 with immunosuppression. Rat-to-CTS heart transplantation is a discordant xenotransplant model, CTS-to-Rat heart transplantation is a concordant xenotransplant model. CTSs are valuable small animals to study mechanisms and strategies to avoid non-Gal nAb-mediated xenograft rejection.

Using Genetic Variation to Predict and Extend Long-term Kidney Transplant Function.

Renal transplantation has transformed the life of patients with end-stage renal disease and other chronic kidney disorders by returning endogenous kidney function and enabling patients to cease dialysis. Several clinical indicators of graft outcome and long-term function have been established. Although rising creatinine levels and graft biopsy can be used to determine graft loss, identifying early predictors of graft function will not only improve our ability to predict long-term graft outcome but importantly provide a window of opportunity to therapeutically intervene to preserve graft function before graft failure has occurred. Since understanding the importance of matching genetic variation at the HLA region between donors and recipients and translating this into clinical practise to improve transplant outcome, much focus has been placed on trying to identify additional genetic predictors of transplant outcome/function. This review will focus on how candidate gene studies have identified variants within immunosuppression, immune response, fibrotic pathways, and specific ethnic groups, which correlate with graft outcome. We will also discuss the challenges faced by candidate gene studies, such as differences in donor and recipient selection criteria and use of small data sets, which have led to many genes failing to be consistently associated with transplant outcome. This review will also look at how recent advances in our understanding of and ability to screen the genome are starting to provide new insights into the mechanisms behind long-term graft loss and with it the opportunity to target these pathways therapeutically to ultimately increase graft lifespan and the associated benefits to patients.

High-dose immunosuppressant alters the immunological status of New Zealand white rabbits following skin transplantation.

The aim of this study was to investigate the effect of an immunosuppressant on the immunological status of New Zealand white rabbits after skin grafting, and to evaluate a method for monitoring the immunological status of subjects with skin transplants. The rabbits were randomly divided into allograft rejection, autograft tolerance, nontransplant, allograft low-dose immunosuppressant and allograft high-dose immunosuppressant groups. The rabbits in the low- and high-dose immunosuppressant groups were treated with cyclosporine A intravenously 8 h prior to skin transplantation and once daily following transplantation at doses of 2 and 25 mg/kg, respectively. At 12 days after skin transplantation, the spleens of donor (female) rabbits and recipient (male) rabbits were harvested for the preparation of single-cell suspensions. The splenocytes from recipient and donor rabbits were labeled with 0.3 or 6 µM carboxy fluorescein diacetate succinimidyl ester, respectively, and a mixed cell suspension was prepared. The final preparation was intravenously injected into recipient New Zealand white rabbits. The ratio of the two fluorescently labeled cell populations in the peripheral blood was measured using flow cytometry at 1, 2, 4 and 8 h after the injection, and the cell death rate was calculated. Histological analysis was also performed on samples collected at the time of splenectomy. The cell death rates of the allograft rejection and low-dose immunosuppressant groups reached their highest levels 8 h after the injection of spleen cell suspension. Allogeneic spleen cells from donor male rabbits were almost completely removed within 8 h of injection. The cell death rate increased slowly in the nontransplant, autograft and high-dose immunosuppressant groups without specificity. This study provides a specific method for the in vivo monitoring of the immunological status of patients after skin grafting. This method can quickly and accurately detect the immunological status of recipients following the injection of a mixed splenocyte suspension, thereby indicating the strength of immune rejection by the immune systems of the recipients.

A decision model for the watch-and-wait strategy in systemic sclerosis–associated interstitial lung disease

To develop a decision model to identify SSc-associated interstitial lung disease (ILD) patients who are eligible for watchful waiting at ILD diagnosis. One hundred and fifty-one SSc-ILD patients who received medical care at Seoul National University Hospital from 1986 to 2013 were enrolled in this retrospective cohort study. ILD was diagnosed by chest CT. Patients with and without immunosuppressive treatment were compared in terms of characteristics at ILD diagnosis to identify distinguishing variables. After multivariate analysis, a decision model for watchful waiting was formulated. Its validity was assessed by comparing the survival of patients whose management in real practice did and did not accord with the management recommended by the model. The untreated group had better survival than the immunosuppressive treatment group (P = 0.0316, by log-rank test). The untreated group was less likely to have gastrointestinal involvement (P = 0.008) and pulmonary arterial hypertension (PAH), as determined by echocardiography) (P = 0.015) and more likely to have favourable initial forced vital capacity (P = 0.0004), favourable initial lung diffusion capacity for carbon monoxide (P = 0.0002) and a low CT grade (P < 0.001). The final watchful waiting decision model included lack of PAH and limited ILD extent on CT. Application of the model to the cohort revealed that patients who were eligible for watchful waiting (as determined by the model) and underwent this management strategy had better survival than eligible patients who underwent immunosuppressive treatment (P = 0.048, by log-rank test). Watchful waiting may be effective for SSc-ILD patients who have minimal pulmonary involvement on CT and lack PAH on echocardiography at baseline.

Prognosis of Ocular Myasthenia Gravis: Retrospective Multicenter Analysis

To calculate the rate and timing of conversion from ocular myasthenia gravis to generalized myasthenia gravis. Retrospective multicenter analysis. Patients included in the study were diagnosed with ocular myasthenia gravis without the presence of generalized disease at onset. We conducted a retrospective multicenter analysis. We reviewed charts of 158 patients who met diagnostic criteria for ocular myasthenia gravis. Patients were divided into 2 subgroups: an immunosuppressant treatment group and a nonimmunosuppressant treatment group. Timing of conversion to generalized disease and duration of follow-up also was evaluated. Additional data such as clinical symptoms at presentation, laboratory test results, and chest imaging results also were recorded. Conversion rates to generalized myasthenia at 2 years, effect of immunosuppression on conversion, and timing of conversion. The 158-patient cohort included 76 patients who received immunosuppressant therapy; the remaining 82 patients did not. The overall conversion rate to generalized disease was 20.9%. At 2 years, generalized myasthenia developed in 8 of 76 patients in the treated group and in 15 of 82 patients in the nonimmunotherapy group (odds ratio, 0.52; 95% confidence interval, 0.20-1.32). Median time for conversion to generalized disease was 20 months in the nonimmunosuppressant group and 24 months in the immunosuppressant group. Conversion occurred after 2 years of symptom onset in 30% of patients. Conversion rates from ocular to generalized myasthenia gravis may be lower than previously reported both in immunosuppressed and nonimmunosuppressed patients. A subset of patients may continue to convert to generalized disease beyond 2 years from onset of symptoms, and close monitoring should be continued.

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil (group 3). Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors.

Are antimicrobial peptides related to cyclosporine A-induced gingival overgrowth?

ObjectiveThe aim of the present study was to investigate the effect of cyclosporine-A (CsA) medication on gingival crevicular fluid (GCF) LL-37, human neutrophil peptide (HNP)1-3 and adrenomedullin (ADM) levels. DesignCsA-treated renal transplant recipients with GO (CsA GO+) and without GO (CsA GO−), tacrolimus-medicated renal transplant recipients (n=20/group), systemically healthy subjects with gingivitis (n=21) and individuals free of periodontal and systemic diseases (n=20) were included in the present study. Periodontal parameters were recorded and GCF samples were obtained from the study participants. GCF LL-37, HNP1-3 and ADM levels were analyzed by enzyme-linked immunosorbent assay. ResultsGCF LL-37 total amount was higher at GO+ sites than the other study sites (p<0.05). Total amount of GCF HNP1-3 was higher in immunosuppressive treatment groups than healthy and gingivitis groups, regardless of GO presence (p<0.05). GCF ADM total amount was similar in all study groups. GCF volume, papillary bleeding index and hyperplastic index (p<0.05) were significantly correlated with GCF LL-37 total amounts (p<0.05), but not with GCF HNP1-3 and ADM total amount at GO+ sites (p>0.05). ConclusionNeutrophil infiltration due to extended inflammation might have increased GCF LL-37 levels at GO+ sites and contributed to the pathogenesis of CsA-induced GO.