Prolonged Immunosuppressive Therapy Research Articles

Successful response to rituximab in two cases of acquired haemophilia refractory to standard-therapy

Acquired autoantibodies against coagulation factors (acquired haemophilia) frequently constitute a life-threatening bleeding situation requiring a prompt therapeutic intervention, including control of bleeding and secondarily an attempt of eradication of the inhibitor by prolonged immunosuppressive therapy. The combination of oral corticosteroids and cyplophosphamide seems to be effective to eradicate the autoantibody, but some patients may be resistant. Another therapeutic approach, recently described, observes treatment with the chimeric anti-CD20 monoclonal antibody rituximab. We report two consecutively treated patients whose acquired FVIII inhibitors did not respond to standard immunosuppressive regimens, and only when rituximab was added to therapy, complete response and prolonged remission were obtained.

Historical reflections on autoimmune hepatitis.

Autoimmune hepatitis (AIH), initially known as chronic active or active chronic hepatitis (and by various other names), first came under clinical notice in the late 1940s. However, quite likely, chronic active hepatitis (CAH) had been observed prior to this and was attributed to a persistently destructive virus infection of the liver. An earlier (and controversial) designation in 1956 as lupoid hepatitis was derived from associated L.E. cell test positivity and emphasized accompanying multisystem features and immunological aberrations. Young women featured prominently in early descriptions of CAH. AIH was first applied in 1965 as a descriptive term. Disease-characteristic autoantibodies were defined from the early 1960s, notably antinuclear antibody (ANA), smooth muscle antibody (SMA) and liver-kidney microsomal (LKM) antibody. These are still widely used diagnostically but their relationship to pathogenesis is still not evident. A liver and disease specific autoantigen has long been searched for but unsuccessfully. Prolonged immunosuppressive therapy with predisolone and azathioprine in the 1960s proved beneficial and remains standard therapy today. AIH like many other autoimmune diseases is associated with particular HLA alleles especially with the "ancestral" B8, DR3 haplotype, and also with DR4. Looking forwards, AIH is one of the several enigmatic autoimmune diseases that, despite being (relatively) organ specific, are marked by autoimmune reactivities with non-organ-specific autoantigens. New paradigms are needed to explain the occurrence, expressions and pathogenesis of such diseases.

Hepatitis B Reverse Seroconversion in Long Term Survivors of Allogeneic Hematopoietic Stem Cell Transplantation.

Reverse seroconversion (RS) known as reactivation of resolved hepatitis B virus (HBV) infection is a complication after allogeneic hematopoietic stem cell transplantation (SCT) in patients exposed to hepatitis B virus. Four hundred thirty six (436) patients with hematological disorder received SCT from an HLA identical sibling in our institute between September 1993 and June 2004. Of these, 103 patients who are 3 or more years post-transplantation have been enrolled in a long-term evaluation protocol. Sixteen had pre-transplant resolved HBV infection (negative HBsAg, positive anti-HBs and anti-HBc antibodies). We investigated the serologic markers of HBV infection in this cohort (median follow-up 59.5 months, range 40–113). Diagnoses included chronic or acute myelogenous leukemia and myelodysplastic syndrome (14), acute lymphoblastic leukemia (1), and severe aplastic anemia (1). Median age at SCT was 32 years (range 10–56). Thirteen patients were positive for anti-HBc and anti-HBs. One had anti-HBc, one had anti-HBs alone, and 1 had no antibodies to hepatitis B. None had detectible HBsAg (HBV surface antigen) at transplant. Twelve patients (median age 39.5 years) received a 12–13.6 Gy total body irradiation (TBI)-based myeloablative SCT followed by a T-cell depleted peripheral blood stem cell transplantation (PBSCT). Four patients (median age 31 years) received a reduced-intensity regimen of fludarabine 125 mg/m2 and cyclophosphamide 60 mg/kg, followed by a PBSCT. All received cyclosporine as graft-verse-host disease (GVHD) prophylaxis. Nine developed acute GVHD, and 13 developed chronic GVHD. Nine (56%) patients received immunosuppressive therapy (IST) for chronic GVHD beyond 3 years from SCT. Fifteen (94%) patients were alive with a median follow-up of 59.5 months. One patient with RS of HBV died at 59 months after SCT. Six (38%) patients developed RS of hepatitis B with reappearance of HBsAg, 21–101 (median 29.5) months after SCT. Four (67%) of the 6 developed clinical hepatitis and received Lamivudine treatment with a decrease of HBV viral load. There was no significant difference in median age of 6 patients with, and 10 patients without RS (38 vs 32 years). RS of hepatitis B was associated with prolonged immunosuppressive therapy for cGVHD. Theses results show that RS of HBV post SCT is a significant long-term complication of patients with pre-transplant resolved HBV infection. This emphasizes the importance of long-term hepatitis B serologic monitoring, post-transplant prophylaxis with Lamivudine, HBV vaccine, and prompt initiation of Lamivudine treatment if RS of HBV occurs.VariableWith RS of HBVWithout RS of HBVCases6 (38%)10 (62%)Age in years (median, range)38 (10–46)32(13–56)Myeloablative48Reduced intensity22aGVHD2/6 (33%)7/10 (70%)cGVHD5/6 (83%)8/10 (80%)IST for cGVHD >3 years4/6 (67%)5/10 (50%)Lamivudine Treatment4/6 (67%)Lamivudine Prophylaxis5/10 (50%)HBV Vaccine after HSCT5/10 (50%)RS of HBV in months (median, range)29.5 (21–101)Follow-up in months (median, range)71(55–107)57.5 (40–113)

Authors' Response to Letter

Reply: We thank Drs Basude and Dhawan for their comments. We agree that, had liver enzymes been measured before minocycline treatment was started, our patient's clinical picture would be clearer. One purpose of our report (1) was to alert clinicians to the possible clinical consequences of minocycline therapy and the importance of monitoring liver enzymes in patients receiving minocycline. Our patient's clinical course, including his positive anti-histone antibodies, is most typical of drug-induced liver disease. Other investigators have described patients with minocycline-induced liver disease who have required prolonged immunosuppressive therapy (2), similar to our patient. Although minocycline may cause autoimmune hepatitis, it may only do so in susceptible individuals. Differentiating between spontaneous autoimmune hepatitis and minocycline-induced autoimmune hepatitis in a child who has received minocycline may not be possible.

A Retrospective Study and Gene Analysis of Canine Sterile Panniculitis

In this study, a retrospective analysis was conducted to assess the current aspects and predisposing factors of canine sterile panniculitis. Miniature dachshund, neutered, and younger dogs appeared to be predisposed. In addition, histories of previous surgery and injection were associated in 46.5% of the cases, with several types of surgical suture materials used. About 88% of the dogs had multifocal lesions, frequently with signs of systemic illnesses. Whereas systemic immunosuppressive therapy was effective in most dogs, surgical excision of lesions was rarely curative. In order to prevent recurrences, over 65% of the cases required prolonged immunosuppressive therapy. Polymorphism of canine alpha(1)AT gene was investigated as a candidate gene for sterile panniculitis. Eight polymorphisms were discovered in seven Miniature dachshunds by direct nucleotide sequencing, which included a 12-bp deletion, three non-synonymous single nucleotide polymorphisms, and four silent substitutions. Genotyping of the two polymorphisms, c.109_120del12 and c.483A>C, which identified at high incidence in the dachshunds, was conducted in 83 dogs of 6 popular breeds. The frequencies of neither polymorphism differed between Miniature dachshunds and other breeds, suggesting that neither is responsible for developing panniculitis.

Peritoneal Fluid Penetration of Tigecycline

To describe the peritoneal fluid penetration of tigecycline. A 33-year-old critically ill man who had undergone orthotopic liver and cadaveric renal transplant presented with sepsis. The patient required empiric antimicrobial coverage, continuous veno-venous hemofiltration, prolonged mechanical ventilation, tracheostomy placement, and maintenance immunosuppressive therapy. After multiple infections with multi-drug resistant pathogens, the patient developed vancomycin-resistant Enterococcus faecium peritonitis. Tigecycline 50 mg was administered every 12 hours, and ascites fluid drug concentrations were obtained. Drug concentrations in the peritoneal fluid were determined by high-performance liquid chromatography and revealed a tigecycline concentration of 0.074 microg/mL. Despite aggressive measures, the patient's condition continued to decline; he died 2 weeks after tigecycline initiation. As of October 3, 2006, these are the first data to describe tigecycline peritoneal fluid penetration. Tigecycline was aggressively administered at twice the recommended dosage for overt liver failure in light of the severity of this patient's condition. A tigecycline peritoneal fluid concentration of 44-54% of serum concentration was calculated based on the patient's peritoneal fluid drug concentration and previously published serum concentrations from a similar population. Peritoneal penetration of tigecycline was approximately 50% in this critically ill patient. Establishment of site-specific breakpoints for tigecycline may be necessary. Future studies will need to evaluate the penetration of tigecycline into peritoneal fluid and other tissues.

A case of destructive Wegener's granulomatosis complicated by cytomegalovirus infection

A 63-year-old man with a 4-year history of Wegener's granulomatosis presented with hemoptysis, palatal ulceration and sensorimotor polyneuropathy. Physical examination, serologic testing, proteinase 3 enzyme-linked immunosorbent assay, IgG and IgM specific to Epstein-Barr virus enzyme-linked immunosorbent assay, MRI of the middle face, an ear, nose and throat consultation, immunohistochemical staining of an esophageal sample obtained from esophagogastroduodenoscopy, polymerase chain reaction of cytomegalovirus (CMV) DNA from esophageal and blood samples, and measurement of pp65 early antigen. Wegener's granulomatosis with progressive palatal ulceration and osseous destruction complicated by CMV-related esophagitis during induction treatment. Induction treatment with cyclophosphamide pulse therapy was discontinued and antiviral therapy with ganciclovir was started. Cyclophosphamide pulse therapy was later reintroduced, but there was subsequent CMV reactivation, and, therefore, cyclophosphamide pulse therapy was suspended again and ganciclovir and intravenous immunoglobulin were started. After control of CMV, cyclophosphamide pulse therapy was reinitiated. Prolonged immunosuppressive therapy controlled disease activity, without CMV reactivation.

Modified Desensitization Protocol Using Two Formulations of L-Asparaginase in a Pediatric Patient with Recurrent Acute Lymphoblastic Leukemia (ALL)

RATIONALE: L-asparaginase (LA), a chemotherapeutic agent for treatment of ALL, often causes hypersensitivity reactions (HSR). Commercially available forms include the E.coli derivative and PEG- L-asparaginase (PLA). We modified a previously published intravenous (IV) desensitization protocol (Bonno, et al.), added intramuscular (IM) PLA injections, and successfully desensitized a 7 year old male with relapsed ALL and a previous HSR to IM PLA. METHODS: Skin testing was not performed due to prolonged antihistamine and immunosuppressive therapy. After pre-treatment with antihistamines and steroids, the patient was desensitized in an intensive care setting, with continuous cardiopulmonary monitoring, 1:1 nursing, and hourly vital signs. Pre- and post-desensitization laboratory studies were obtained to monitor for drug toxicity. Four 250 ml bags with increasing concentrations of LA (5, 50, 500, and 5000 units per bag) were infused over a total of 12.5 hours. He subsequently received 5 doses of IM PLA over 5 hours. The IM doses started at 15 Units, increasing to a final dose of 1500 Units, for a total IM dose of 2790 Units. RESULTS: Desensitization to both forms was completed over 18 hours. The patient tolerated the IV and IM doses without adverse reaction or evidence of toxicity. After desensitization, the patient tolerated daunorubicin and vincristine administration. One month later, his ALL was in remission. CONCLUSIONS: HSR to LA are common, yet there are few published desensitization protocols for use when alternative therapy fails. This protocol safely and effectively desensitized a patient using the two formulations, providing a therapeutic option for patients with HSR and recurrent disease.

Fungal infections in bone marrow transplant recipients

Invasive fungal infections (IFIs) can cause significant morbidity and mortality in patients after haematopoietic stem cell transplantation. The two most notorious pathogenic fungal species in this group of patients are Candida and Aspergillus. Risk factors for IFIs include: prolonged neutropaenia; fungal overgrowth and conditioning regiment-related mucositis; graft versus host disease; and steroid therapy. Clinical manifestations can be protean, and radiological changes are frequently nonspecific. Diagnostic methods include culture- and nonculture-based techniques. Some experts recommend IFI prophylaxis in the high-risk groups, such as patients with severe graft versus host disease who require prolonged immunosuppressive therapy or patients with a previous history of aspergillosis. Treatment options include therapy with azoles, including the newer agent voriconazole, amphotericin and caspofungin.

A Case of Autoimmune Hemolytic Anemia Treated with Rituximab in a Child

Autoimmune hemolytic anemia (AIHA) in children usually responds well to short-term steroid therapy. However, in some cases, AIHA requires prolonged immunosuppressive therapy, with the subsequent development of severe side effects. Compared with previous conventional immunosuppressive therapy, rituximab, an anti-CD20 chimeric monoclonal antibody, shows good therapeutic efficacy and safety in the treatment of autoimmune disorders. Herein, the case of a 13-year-old male patient, who showed a remarkable and durable response to rituximab, at a dose of 375mg/m2 , is reported. Before this trial, he had been a hepatitis B carrier and steroid dependent AIHA for 4 years, with a cushingoid facial appearance and growth retardation. After 10 months, he experienced a recurrence of hemolysis, which was successfully retreated, and was then taken off the steroid ther apy. The therapy was well tolerated, without serious complications. It is suggested that rituximab could be a new option in the treatment of steroid-dependent AIHA. Therefore, long-term follow-up and studies of the risk factors of a relapse are

TREMORS AND CHOREA INDUCED BY TRIMETHOPRIM-SULFAMETHOXAZOLE IN A CHILD WITH PNEUMOCYSTIS PNEUMONIA

A 1.5-year-old girl developed high frequency tremors and chorea after receiving a dose of 120 mg/kg/d trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of Pneumocystis pneumonia. The child was human immunodeficiency virus-negative but immunocompromised because of prolonged immunosuppressive therapy. These symptoms disappeared 3 days after TMP-SMX was discontinued. Pediatricians should be aware of tremors and chorea among the potential adverse effects of high doses of TMP-SMX.

Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study

AbstractPrevious studies of recipients of hematopoietic stem-cell transplants suggest that graft-versus-host disease (GVHD) and its therapy may increase the risk for solid cancers, particularly squamous-cell carcinomas (SCCs) of the buccal cavity and skin. However, the importance and magnitude of these associations are not well characterized. We conducted a case–control study of 183 patients with posttransplantation solid cancers (58 SCCs, 125 non-SCCs) and 501 matched control patients within a cohort of 24 011 patients who underwent hematopoietic stem-cell transplantation (HSCT) at 215 centers worldwide. Our results showed that chronic GVHD and its therapy were strongly related to the risk for SCC, whereas no increase in risk was found for non-SCCs. Major risk factors for the development of SCC were long duration of chronic GVHD therapy (P < .001); use of azathioprine, particularly when combined with cyclosporine and steroids (P < .001); and severe chronic GVHD (P = .004). Given that most patients who received prolonged immunosuppressive therapy and those with severe chronic GVHD were also treated with azathioprine, the independent effects of these factors could not be evaluated. Additional analyses determined that prolonged immunosuppressive therapy and azathioprine use were also significant risk factors for SCC of the skin and of the oral mucosa. These data provide further encouragement for strategies to prevent chronic GVHD and for the development of more effective and less carcinogenic treatment regimens for patients with moderate or severe chronic GVHD. Our results also suggest that clinical screening for SCC is appropriate among patients exposed to persistent chronic GVHD, prolonged immunosuppressive therapy, or both.

Aplastic Anemia: Management of Adult Patients

The primary therapeutic approach to acquired aplastic anemia (AA) in older adults differs from the primary approach used in children and younger adults because in the former group, the results of allogeneic bone marrow transplantation (BMT) are less favorable. With increasing age of the patients, immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine (CsA) constitutes the primary treatment option and may be better than BMT. There are very few clinical clues as to the selection of patients likely to respond to immunosuppression. Repeated ATG/CsA cycles are often used as salvage regimens, but in refractory patients BMT may be the best treatment option, as the prognosis for non-responders is poor without definitive treatment. Conservative therapy such as intense immunosuppression is associated with a high relapse rate but does not impact the survival and overall prognosis. The inability to eliminate autoimmune T cell clones using current therapeutic strategies suggests that prolonged immunosuppressive maintenance therapy may be needed for a substantial proportion of patients. Late clonal complications of conservatively treated patients include evolution to myelodysplasia and paroxysmal nocturnal hemoglobinuria and may develop in 20% of the patients. However, BMT also has several sequelae including an increased frequency of solid tumors. Novel immunosuppressive and immunomodulatory agents and constantly improving results of allogeneic BMT will further improve the survival rate of adult patients with AA.

Pancreas after kidney transplantation.

After three decades of controversy surrounding the therapeutic validity of pancreas transplantation, the procedure has become accepted as the preferred treatment for patients with insulin-dependent diabetes mellitus (IDDM) and advanced diabetic nephropathy with end-stage renal disease (ESRD) and for

Novel immunosuppressive therapies for intestinal and hepatic diseases.

Recent advances in the understanding of the pathogenesis of immune-mediated hepatic and intestinal diseases have led to major therapeutic advances. The introduction of genetically engineered biologic agents specifically designed to target inflammatory mediators responsible for the perpetuation of chronic inflammatory processes is a novel example. Although corticosteroids remain important as a first-line therapeutic option for active inflammatory bowel disease, approximately one third and one fifth of patients develop steroid dependence and resistance, respectively. From a pediatric perspective, a major advance has thus been the advocation of prolonged immunosuppressive therapy with 6-mercaptopurine or azathioprine for children with inflammatory bowel disease. The introduction of effective steroid-sparing agents for the induction and maintenance of remission is a key management issue. The past year has also witnessed the increased utilization of powerful immunosuppressive agents with rapid onset of action, such as cyclosporine and tacrolimus, in patients resistant to conventional therapies. This review will afford pediatricians a sense of what to expect for the management of hepatic and intestinal disorders with immunosuppression as we advance into the new millenium.

Non-Hodgkin's lymphoma as an unexpected diagnosis in a shoulder arthroplasty

Shoulder arthroplasty (SA) is commonly performed in patients with rheumatoid arthritis (RA) who have been treated with long-term immunosuppressive medication. RA is associated with an increased risk of neoplasms of the immune system. A case of non-Hodgkin's lymphoma as an unexpected diagnosis after the routine pathologic examination of the soft tissues after SA was detected in a 54-year-old woman with long-standing RA and prolonged immunosuppressive therapy. Although this case does not support the cost-effectiveness of routine specimen evaluation during SA, we suggest that histological analysis of the surgical tissues is appropriate and should be performed in all patients who have been treated with prolonged immunosuppressive medication, especially RA patients as well as patients who have suspicious surgical findings.

Accelerated appearance of neoplasms in female nzb/nzw mice treated with high‐dose cyclophosphamide

Prolonged immunosuppressive therapy with cyclophosphamide increases the prevalence of neoplasms in NZB/NZW mice, an animal model of systemic lupus erythematosus. The current study was designed to compare the oncogenic properties of high dose cyclophosphamide with a low dose therapeutic regimen. Female NZB/NZW mice received life-long therapy with "high dose" cyclophosphamide, 16 mg/kg/day, or "low-dose" cyclophosphamide, 5.7 mg/kg/day; control mice received saline. High dose therapy clearly accelerated appearance of neoplasms. Seventeen of 19 mice treated with high-dose cyclophosphamide developed neoplasms at the mean age of 61 weeks. Fifty-seven percent of these tumors were mammary carcinomas. Neoplasms appeared in all mice treated with low dose; mean longevity in this treatment group was 80 weeks (compared to high dose treated mice, P less than 0.001). Carcinomas, pulmonary adenomas, and lymphomas were the most common tumors in mice receiving low dose therapy. Positive tests for ANA were suppressed in high dose treated mice. AntiDNA antibody levels and glomerulonephritis were decreased significantly in both groups of cyclophosphamide-treated mice compared to controls. It was concluded that the high daily dose of immunosuppressive drug was related to early oncogenesis in autoimmune NZB/NZW mice.

Remission of pure red cell aplasia associated with nonthymic malignancy

Two patients with acquired pure red cell aplasia associated with malignancy are presented. One patient has breast cancer and the other had poorly differentiated nodular lymphoma; neither patient had evidence of a serum inhibitor of hemoglobin synthesis and both achieved complete hematologic remission following prolonged immunosuppressive therapy. The literature describing the association of pure red cell aplasia and nonthymic malignancy is reviewed and potential for responsiveness discussed.

Chronic granulocytic leukemia following successful renal transplantation

The use of immunosuppressive therapy has markedly increased over the past several years, and concomitant with its use has been an increased frequency of associated neoplasia. The patient presented is a 22-year-old white male who, following two renal transplants and prolonged immunosuppressive therapy with azathioprine and methylprednisolone, developed chronic granulocytic leukemia. Chromosome karyotyping demonstrated the somewhat unusual development of a Philadelphia chromosome with translocation to the No. 7 of the C group. A review of transplantation centers revealed that five cases of chronic granulocytic leukemia have occurred in a population of 25,000 renal transplant patients, a 5-fold increased incidence over the general population. Possible etiologies that may be responsible for the development of chronic granulocytic leukemia in patients on immunosuppressive therapy are discussed. It is our hope that by the introduction of these reports of chronic granulocytic leukemia into the medical literature, the need for caution in the use of immunosuppressive drugs in nonmalignant disease will again be emphasized.

THYMIC DYSPLASIA IN A CHILD WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic Lupus Erythematosus (SLE) is associated with abnormal antibody production. Recent evidence also suggests T cell dysfunction in this disorder. The patient described had ante- and post-mortem evidence of thymic dysplasia.A diagnosis of SLE was made in a 2 year old girl with clinical evidence of skin and joint involvement. Laboratory evidence included positive LE cells, high ANA titer, hypergammaglobulinemia and proteinuria. History of a severe reaction to smallpox vaccine suggested pre-existing T cell deficiency.Excellent control of the disease was achieved with prednisone and cyclophosphamide for 7 months when progressive central nervous involvement began. Death occurred 1 year after diagnosis.At autopsy the thymus was composed almost entirely of thymic epithelial cells. While depletion of lymphocytes and plasma cells may be explained by prolonged immunosuppressive therapy, the total absence of Hassall's corpuscles suggests thymic dysplasia. In this patient, there may be an abnormity of T cell modulation of B cell function resulting in formation of antibodies to non-foreign antigens.