Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party

To specify the incidence and risk factors for secondary autoimmune diseases (ADs) after HSCT for a primary AD, we retrospectively analyzed AD patients treated by HSCT reported to EBMT from 1995 to 2009 with at least 1 secondary AD (cases) and those without (controls). After autologous HSCT, 29 of 347 patients developed at least 1 secondary AD within 21.9 (0.6-49) months and after allogeneic HSCT, 3 of 16 patients. The observed secondary ADs included: autoimmune hemolytic anemia (n = 3), acquired hemophilia (n = 3), autoimmune thrombocytopenia (n = 3), antiphospholipid syndrome (n = 2), thyroiditis (n = 12), blocking thyroid-stimulating hormone receptor antibody (n = 1), Graves disease (n = 2), myasthenia gravis (n = 1), rheumatoid arthritis (n = 2), sarcoidosis (n = 2), vasculitis (n = 1), psoriasis (n = 1), and psoriatic arthritis (n = 1). After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8% ± 2% at 5 years. Lupus erythematosus as primary AD, and antithymocyte globulin use plus CD34(+) graft selection were important risk factors for secondary AD by multivariate analysis. With a median follow-up of 6.2 (0.54-11) years after autologous HSCT, 26 of 29 patients with secondary AD were alive, 2 died during their secondary AD (antiphospholipid syndrome, hemophilia), and 1 death was HSCT-related. This European multicenter study underlines the need for careful management and follow-up for secondary AD after HSCT.     

The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial: rationale and design of a multicenter, randomized, placebo-controlled, clinical trial of metoprolol for patients with diabetes mellitus who are undergoing major noncardiac surgery

Background

Recent trials suggest that perioperative β-blockade reduces the risk of cardiac events in patients with a risk of myocardial ischemia who are undergoing noncardiac surgery. Patients with diabetes mellitus are at a high-risk for postoperative cardiac morbidity and mortality. They may, therefore, benefit from perioperative β-blockade.

Methods

The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial is an investigator-initiated and -controlled, centrally randomized, double-blind, placebo-controlled, multicenter trial. We compared the effect of metoprolol with placebo on mortality and cardiovascular morbidity rates in patients with diabetes mellitus who were β-blocker naive, ≥40 years old, and undergoing noncardiac surgery. The study drug was given during hospitalization for a maximum of 7 days beginning the evening before surgery. The primary outcome measure is the composite of all-cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure leading to hospitalization or discovered or aggravated during hospitalization. Follow-up involves re-examination of patients at 6 months and collection of mortality and morbidity data via linkage to public databases. The study was powered on the basis of an estimated 30% 1-year event rate in the placebo arm and a 33% relative risk reduction in the metoprolol arm. The median follow-up period was 18 months.

Results

Enrollment started in July 2000 and ended in June 2002. A total of 921 patients were randomized, and 54% of these patients had known cardiac disease, hypertension, or both.

Conclusion

The results of this study may have implications for reduction of perioperative and postoperative risk in patients with diabetes mellitus who are undergoing major noncardiac surgery.     

A gene in the telomeric HLA complex distinct from HLA-A is involved in predisposition to juvenile idiopathic arthritis

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is associated with particular alleles at 3 different HLA loci: HLA-A, HLA-DR/DQ, and HLA-DP. These associations are independent of each other (i.e., they cannot be explained by the known linkage disequilibrium between alleles at these loci). The purpose of this study was to look for additional JIA susceptibility genes in the HLA complex. METHODS: One hundred two Norwegian JIA patients and 270 healthy individuals, all carrying the DQ4;DR8 haplotype, were investigated by scanning approximately 10 megabases of DNA covering the HLA complex with microsatellite polymorphisms. An expectation-maximization algorithm was used to estimate haplotype frequencies, and the distribution of microsatellite alleles on the high-risk DQ4;DR8 haplotype was compared between patients and controls, to exclude effects secondary to linkage disequilibrium with these susceptibility genes. RESULTS: Allele 5 at the microsatellite locus D6S265 (D6S265* 5), 100 kb centromeric of HLA-A, showed a strong positive association with the disease (odds ratio 4.7, corrected P < 10(-6)). Haplotype analysis demonstrated that the D6S265*5 association was not caused by linkage disequilibrium to the gene encoding HLA-A*02, which has previously been reported to be associated with JIA. Instead, our data suggested that a gene in linkage disequilibrium with D6S265*5, but distinct from HLA-A*02, is involved in the predisposition to JIA. CONCLUSION: We found that D6S265*5 could be a marker for an additional susceptibility gene in JIA which is distinct from A*02, adding to the risk conferred by DQ4;DR8.     

Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.     

Lack of association between the chemokine receptor 5 polymorphism CCR5delta32 in rheumatoid arthritis and juvenile idiopathic arthritis

Background  

The chemokine receptor CCR5 has been detected at elevated levels on synovial T cells, and a 32 bp deletion in the CCR5 gene leads to a non-functional receptor. A negative association between the CCR5Δ32 and rheumatoid arthritis (RA) has been reported, although with conflicting results. In juvenile idiopathic arthritis (JIA), an association with CCR5 was recently reported. The purpose of this study was to investigate if the CCR5Δ32 polymorphism is associated with RA or JIA in Norwegian cohorts.     

Existence of a differentiation blockage at the stage of a megakaryocyte precursor in the thrombocytopenia and absent radii (TAR) syndrome

The thrombocytopenia and absent radii (TAR) syndrome is a rare disease associating bilateral radial agenesis and congenital thrombocytopenia. Here, we investigated in vitro megakaryocyte (MK) differentiation and expression of c-mpl in 6 patients. Using blood or marrow CD34(+) cells, the colony-forming unit (CFU)-MK number was markedly reduced. CD34(+) cells were also cultured in liquid medium in the presence of a combination of 3 cytokines (stem cell factor, interleukin-3, and interleukin-6) or megakaryocyte growth and development factor (PEG-rHuMGDF) with or without SCF. In the presence of PEG-rHuMGDF, the majority of mature megakaryocytes (CD41 high, CD42 high) underwent apoptosis. This phenomenon was also observed in cultures stimulated by three cytokines. However, this last combination of cytokines allowed a more complete terminal MK differentiation. Surprisingly, a homogeneous population of CD34(-)CD41(+)CD42(-) cells accumulated during the cultures. This population was unable to differentiate along the myeloid pathways. This result suggests that a fraction of MK cells is unable to differentiate in the TAR syndrome. We subsequently investigated whether this could be related to an abnormality in c-mpl. No mutation or rearrangement in the c-mpl gene was found by Southern blots or by sequencing of the c-mpl coding region and its promoter in any of the patients. Using Western blot analysis, a decreased level of Mpl was found in patient platelets. A decreased level of c-mpl messenger RNA in TAR platelets was also detected with a lower c-mpl-P to c-mpl-K ratio in comparison to adult platelets. Altogether, these results demonstrate that the thrombocytopenia of the TAR syndrome is associated with a dysmegakaryocytopoiesis characterized by cells blocked at an early stage of differentiation. (Blood. 2000;95:1633-1641)     

Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure,increases intraperitoneal chemotherapy drug penetration,and impedes tumor growth in a mouse colorectal carcinomatosis model

Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible.