Traditional Immunosuppressive Therapy Research Articles

Rituximab combined with conventional therapy versus conventional therapy alone for the treatment of mucous membrane pemphigoid (MMP)

The use of rituximab for refractory autoimmune blistering diseases is increasing. Data related to rituximab for the treatment of mucous membrane pemphigoid (MMP) are limited. We sought to compare the efficacy of adding rituximab with traditional immunosuppressive therapies in the treatment of MMP. The primary outcome was achievement and time to disease control. Patients with a diagnosis of MMP from August 2001 to June 2015 who had greater than 6 months of follow-up after the initiation of therapy were reviewed. In all, 24 patients were treated with rituximab and 25 were treated with conventional immunosuppression. Of patients, 100% in the rituximab group achieved disease control compared with 40% in the conventional group (P < .01), with a mean time to disease control of 10.17 months and 37.7 months (P = .02). Adverse events were seen in 33% of patients after rituximab, compared with 48% of patients in the conventional group (P = .2). Rituximab dosing was not uniform and the 2 groups were not matched in terms of disease severity, nor were they randomized. Our study indicates that the addition of rituximab to conventional therapy in patients with MMP results in more rapid and sustained disease control with potentially fewer adverse events.

Immune Profiling of Immune Thrombocytopenia (ITP) Patients: Evidence for CD8 T Cell Involvement in the Disease

Introduction: Immune thrombocytopenia (ITP) is a bleeding disorder caused by an autoimmune response against platelets. In the majority of cases, ITP is thought to be caused by the presence of autoreactive B cells that produce anti-platelet autoantibodies and target platelets for destruction by phagocytic cells. However, in about 40% of ITP patients platelet autoantibodies cannot be detected and there is some evidence that cytotoxic cells might also be responsible for platelet death. Indeed, many patients repeatedly fail to respond to current immunosuppressive therapies that target B cells and their autoantibodies. As a consequence, these patients retain very low platelet counts with increased bleeding diathesis. In this study we have immunophenotyped a group of adult chronic ITP patients that have not responded to traditional immunosuppressive therapies and we identified 2 subgroups of patients with either an increase or decrease in the frequency of CD8+ T effector memory CD45RA+ cells (CD8TEMRA) compared to healthy controls.Methods: PBMCs were isolated from blood samples of 14 ITP patients with platelet counts <100x109/L and 14 matched healthy controls. The cells were phenotyped using a variety of antibodies including: CD3, CD4, CD8, CD45RA, CCR7, CD127, CD25, CD14, CD16 and CD19. In addition, at least 5x106 PBMCs were stimulated with PMA (50ng/ml) and ionomycin (1µg/ml) for 5 hours at 37°C, 5% CO2 and stained with antibodies against CD3 and CD8, then fixed and permeabilised before staining with antibodies specific to Granzyme B and Interferon-γ.Results and discussion: In our cohort of ITP patients we were able to identify two subgroups of patients based on their frequency of CD8TEMRA cells, identified as CD45RA+ CCR7- cells, gated on CD3+ CD8+ cells. Compared to healthy controls (mean=16.33%), 6/14 patients had significantly lower frequencies of CD8TEMRA cells (mean=11.31%) and 8/14 patients showed a significant increase (mean=31.50%). Interestingly, these two groups of patients also show significant differences between them in the frequency of CD19+ B cells (gated on CD3- cells), as the group with the lowest CD8TEMRA frequency showed a significant increase in B cells compared to the high CD8TEMRA group. Considering that CD8TEMRA cells are described as highly differentiated cytotoxic T cells, these results suggest that in patients with active ITP in which the CD8TEMRA population is more prevalent and the frequency of B cells is reduced, cytotoxic T cells might play an important role in platelet destruction. Although an increase in the frequency of CD8TEMRA with age has been described we did not find a correlation between these two variables in our cohort of patients. In the low CD8TEMRA group we also observed a significant increase in the frequency of T regulatory cells (Tregs) and monocytes when compared to healthy controls, whereas the trend in the high CD8TEMRA group was for frequencies closer to controls. In addition, when analysing the production of Granzyme B and Interferon-γ after a short in vitro stimulation, we found that the trend was for the CD8+ T cells in the high CD8TEMRA group to produce higher levels of both Granzyme B and Interferon-γ when compared to the patients in the low CD8TEMRA group. This would support the hypothesis that in patients with increased frequency of CD8TEMRA there has been an expansion of cells with cytotoxic properties. Further work will be required to confirm that in this cohort of patients there is a CD8+ T cell population that can specifically target and lyse platelets, thus contributing to ITP pathogenesis. DisclosuresProvan:UCB: Consultancy; GSK: Equity Ownership, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medimmune: Consultancy.

Clinical application of gancyclovir in the complex treatment of the different forms of true acantholytic pemphigus

Short summary and results of the own clinical observations on efficacy of developed complex method on the treatment of true acantholytic pemphigus composed of traditional immunosuppressive therapy and antiviral remedy - gancyclovir are presented. The etiology of herpesvirus infection had been discussed in the pathogenesis of the disease.

Vasculitides and the Complement System: a Comprehensive Review.

Systemic vasculitides are a group of rare diseases characterized by inflammation of the arterial or venous vessel wall, causing stenosis or thrombosis. Clinical symptoms may be limited to skin or to other organs or may include multiple manifestations as systemic conditions. The pathogenesis is related to the presence of leukocytes in the vessels and to the IC deposition, which implies the activation of the complement system (CS) and then the swelling and damage of vessel mural structures. The complement system (CS) is involved in the pathogenesis of several autoimmune diseases, including systemic vasculitides. This enzymatic system is a part of the innate immune system, and its function is linked to the modulation of the adaptive immunity and in bridging innate and adaptive responses. Its activation is also critical for the development of natural antibodies and T cell response and for the regulation of autoreactive B cells. Complement triggering contributes to inflammation-driven tissue injury, which occurs during the ischemia/reperfusion processes, vasculitides, nephritis, arthritis, and many others diseases. In systemic vasculitides, a group of uncommon diseases characterized by blood vessel inflammation, the contribution of CS in the development of inflammatory damage has been demonstrated. Treatment is mainly based on clinical manifestations and severity of organ involvement. Evidences on the efficacy of traditional immunosuppressive therapies have been collected as well as data from clinical trials that involve the modulation of the CS. In particular in small-medium-vessel vasculitides, the CS represents an attractive target. Herein, we reviewed the pathogenetic role of CS in these systemic vasculitides as urticarial vasculitis, ANCA-associated vasculitides, anti-glomerular basement membrane disease, cryoglobulinaemic vasculitides, Henoch-Schönlein purpura/IgA nephropathy, and Kawasaki disease and therefore its potential therapeutic use in this context.

B Cell Depletion in Systemic Vasculitis

The important role of B cells in the pathogenesis of systemic vasculitis has become increasingly clear over recent years. B cell directed therapies offer an exciting new approach to the treatment of these conditions, in which there has been little change in the options available to managing clinicians since the advent of traditional immunosuppressive therapy. The introduction of conventional immunosuppression has transformed survival in systemic vasculitis, particularly ANCA-associated vasculitis, but at the expense of significant toxicity, and with suboptimal efficacy. B cell therapies offer the possibility of targeted, individually tailored immunotherapy, which by improving efficacy, and reducing toxicity will improve clinical outcomes in systemic vasculitis. However, the heterogeneity of vasculitic syndromes suggests that one agent is unlikely to be effective in all situations. The precise indications and optimal combination of B cell directed with other therapies will need to be determined. Keywords: Vasculitis, B cell, rituximab, ANCA, Aortitis, aorta, Anti-neutrophil cytoplasm antibodies, Giant cell arteritis, Polyarteritis nodosa, Churg-Strauss Syndrome

Subclinical Interstitial Lung Abnormalities in Stable Renal Allograft Recipients in the Era of Modern Immunosuppression

Background Interstitial lung abnormalities have been detected in up to 24% of kidney transplant patients receiving traditional immunosuppressive therapies (eg, cyclosporine, azathioprine); they usually occur early after transplantation and tend to resolve over time. Newer immunosuppressants such as mycophenolic acid and, particularly, mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus) may cause significant lung toxicity. However, the prevalence and severity of interstitial lung lesions in long-term, stable kidney transplant patients receiving either traditional or newer immunosuppressants is not known. Methods We conducted a prospective, cross-sectional study examining high-resolution lung computed tomography (CT) scans in 63 stable kidney transplant recipients whose immunosuppressive therapy had remained unchanged for over 24 months. We compared CT findings of patients taking newer (mycophenolic acid and mTOR inhibitors) and traditional (calcineurin inhibitors and azathioprine) immunosuppressive drugs. Results Interstitial lung alterations were observed in only 3/63 patients (4.8%); the prevalence was 11.5% (3/26) versus 0% (0/37) among the newer versus traditional immunosuppressive therapy groups, respectively ( P = .065). The CT patterns were usual interstitial pneumonia and nonspecific interstitial pneumonia-like. The median time between transplant and CT was 49 months in the three patients with CT alterations and 95 months in the remaining 23 patients on newer immunosuppressants. It was 75 months for all patients on newer immunosuppressive drugs and 133 months for those on traditional therapies ( P = .0015). A follow-up CT, performed in 2/3 patients with interstitial abnormalities, showed that the lesions were stable in one, while they had disappeared in the other. Conclusions Interstitial lung abnormalities are infrequent and mild in stable kidney transplant patients treated with newer as well as traditional immunosuppressive drugs. As such abnormalities were detected in patients screened earlier after transplantation, the time since transplantation rather than the drug type is probably the major determinant.

Analysis of binding properties of VP2 protein of Human parvovirus B19 through in silico molecular docking

AbstractHuman parvovirus B19, a member of the Parvoviridae family, is a pathogen associated with a wide variety of diseases. Most commonly, it causes childhood rash erythema infectiosum, but in some cases more serious symptoms such as persistent arthropathy, critical failures of red cell production causing transient aplastic crisis, this infection in pregnancy causes hydrops fetalis and myocarditis. Traditional immunosuppressive therapy being unsuccessful, anti-viral therapy might be worthy of consideration. Functional annotation would provide role of viral proteome in its survival and pathogenic mechanisms. SVMProt functional family annotations of VP2 protein had deciphered its zinc-binding, coat protein, outer membrane, chlorophyll biosynthesis, DNA repair and calcium-binding nature. VP2 protein is having a key role in viral assembly of B19 virus and being non-homologous to human proteome, it was identified as an attractive molecular target for structure based drug discovery. The VP2 protein crystal structure was energy minimized using CHARMM. A structure based virtual screening method was applied using LigandFit to identify potential inhibitors of VP2 protein from ChemBank database and ten potential Human parvovirus B19 VP2 inhibitors were proposed.

Natural History of Paroxysmal Nocturnal Hemoglobinuria Clones In Patients Presenting as Aplastic Anemia

AbstractAbstract 4428 Introduction:Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are closely related bone marrow failure disorders. Most AA results from an autoimmune attack directed against hematopoietic stem/progenitor cells. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a PIG-A mutation. The PIG-A gene mutation leads to glycosylphosphatidylinositol-anchor protein (GPI-AP) biosynthesis deficiency and subsequent hemolysis secondary to the absence of complement regulatory proteins (CD55 and CD59). Both PNH and AA can be cured by allogeneic bone marrow transplantation (alloBMT), but only a minority of patients is offered this approach due to the potential morbidity and mortality. AA can be treated with immunosuppressive therapy (IST) and PNH can be controlled by eculizumab. It has been estimated that more than 50% of AA patients harbor small, but expandable PNH populations at diagnosis. The natural history of PNH clones in AA patients following non-transplant therapy is not well studied. The purpose of this study is to determine the fate and clinical relevance of these PNH clones in patients with AA who did not receive an alloBMT. Patients and Method:Twenty-seven patients with AA and a detectable PNH clone were monitored for a median of 5.3 years (range,1.5 to 11.5 years). The PNH granulocyte clone sizes were measured using flow cytometry and analyzed via CellQuest software. PE-conjugated anti-CD15 and fluoresceinated aerolysin variant (FLAER) staining were used to define granulocytes and GPI-AP deficient cells respectively. Serum lactate dehydrogenase (LDH) value was used as a surrogate for monitoring hemolysis and 1.5× the upper limit of normal LDH value (330mg/dL) as a cut-off point to define clinically apparent hemolysis. A PNH size change <2.5% was considered as stable. Patients were treated with IST, HiCy, or both. Result:We found a linear relationship between PNH granulocyte clone size and LDH values (Pearson correlation coefficient=0.73; P<0.0001). A PNH clone size above 23% was the threshold to identify hemolysis as measured by LDH (ROC analysis with AUC=0.88). Higher LDH values over the period of follow-up were associated with larger PNH granulocyte clone size at diagnosis (P=0.03). Patients with small (≤15%) initial PNH granulocytes had lower LDH levels at 5 years after diagnosis (mean±SD: 236.9±109.9 vs 423.1±248.8; P=0.02), and were less likely to develop hemolysis (13.3% vs 55.6%, P=0.06) comparing to those with larger (>15%) initial PNH granulocytes.Of 9 patients who initially were treated with traditional IST (ATG, CsA, and prednisone), 7 did not respond to treatment and eventually received high-dose cyclophosphamide (HiCy) salvage therapy, 2 achieved a remission and did not require further treatment though one demonstrated PNH clone size expansion to 50% after 37 months. After HiCy salvage, all 7 patients became transfusion independent and 4 of them had no further PNH clone expansion. PNH clone expansion was observed in 7 of 9 patients at a median time of 3 (range: 2 to 87) months after treatment.Of 15 patients who received HiCy as initial therapy, 14 achieved remissions. Later expansion of PNH size was observed in 7 patients, of which 5 eventually required intermittent blood transfusion but only 1 developed symptomatic hemolysis necessitating eculizumab therapy. The median time to PNH granulocyte clone expansion after HiCy was 52 (range: 18 to 106) months. In 5 patients who received HiCy and then relapsed, their PNH clone size only increased (1±0.7)% in (71±31) months observation during post treatment remission; however, their PNH clone size increase accelerated to (38±14)% in (34±21) months after AA relapse (P=0.04).Two nSAA patients with an initial PNH clone size ≤15% spontaneously recovered hematopoiesis at 84 and 56 months respectively, neither had PNH clone size expansion.In this study, 25.9% patients kept a stable PNH size, 48.1% patients increased the size, and 26% patients decreased the size. The group with small initial PNH clone sizes (≤15%) was the most stable over time. Conclusion:The risk of developing clinically significant PNH over 10 years appears to be low in AA patients with PNH clones, especially for those with small initial PNH granulocyte clones (≤15%) and for those who maintain remission following therapy. Disclosures:No relevant conflicts of interest to declare.

Functional annotation of human parvovirus b19 proteome and Molecular docking of VP1 protein with Teniposide

AbstractParvovirus B19 is a common source of infection with a seroprevalence of 60-70% in the adult population. Human parvovirus causes several distinct clinical syndromes such as erythema, polyarthritis resembling rheumatoid arthritis, vasculitis, hydrops fetalis, myocarditis etc. Recent years have witnessed manifest increase in clinical knowledge of parvovirus B19-associated complications, diagnosis and treatment. Traditional immunosuppressive therapy being unsuccessful, anti-viral therapy might be worthy of consideration. Functional annotation of human parvoviral proteome may provide insights into role of viral proteome in its survival and pathogenic mechanisms. Availability of whole proteome in the open source aided functional annotation of protein using SVMprot. Protein functions common to both structural and non-structural proteins are metal -binding, lipid-binding, copper-binding, calcium-binding, zinc-binding, magnesium-binding, DNA-binding, RNA-binding, transmembrane and outer membrane group of proteins. VP1 protein of human parvovirus b19 being quiet important for its structural integrity and being non homologous to human proteome, was identified as an attractive molecular target for structure based drug discovery. 3D structure of target protein VP1protein is predicted based on VP2 protein from human parvovirus b19 using MODELLER9V6. The modeled structure is validated using PROCHECK. Binding sites were predicted in Discovery studio 2.0 and Teniposide was found to be best docked lead molecule among selected ligands those docked to the functionally important site 1 using LigandFit protocol. The docking complex shows teniposide forming strong hydrogen bond with serine 580 of modeled VP1 protein. The strong hydrogen bonding, hydrophobic interaction, Vander wall interaction marked by teniposide would affect the structural integrity of parvovirus B19 significantly. The detailed insight of structural, functional and interactive aspect of the protein is being studied would enable us delineate it as potential drug target. Also different docking poses generated through docking studies may be considered as a model for identifying drug candidate against parvovirus.

Sexual Dimorphism on Cytokines Expression in the Temporomandibular Joint: The Role of Gonadal Steroid Hormones

Temporomandibular joint pain-related conditions are generally characterized by local inflammation; however, little studies have focused on the role of gonadal hormones in the expression of inflammatory mediators, such as cytokines. Therefore, we asked whether gonadal steroid hormones affect formalin-induced cytokines expression in the rat temporomcandibular joint. The expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and cytokine-induced neutrophil chemoattractant (CINC)-1 was significantly higher in males than in diestrus and proestrus females and was decreased by orchiectomy and restored by testosterone replacement. The expression of IL-6 was significantly higher in diestrus and proestrus females than in males, and was decreased by ovariectomy and restored by estradiol or progesterone administration. We conclude that testosterone increases the expression of TNF-α, IL-1β and CINC-1, and estradiol and progesterone increase the expression of IL-6. New clinical approaches based on inhibition of pro-inflammatory mediators are starting to supplant traditional immunosuppressive therapies and gonadal hormones may influence their effectiveness or clinical dosage.

Rituximab therapy for myopathy associated with anti–signal recognition particle antibodies: A case series

The myopathy associated with anti-signal recognition particle (anti-SRP) is a severe necrotizing immune-mediated disease characterized by rapidly progressive proximal muscle weakness, markedly elevated serum creatine kinase (CK) levels, and poor responsiveness to traditional immunosuppressive therapies. Reports on the efficacy of B cell depletion therapy for anti-SRP-associated myopathy are mixed. We describe 8 patients with anti-SRP-associated myopathy and their response to treatment with the anti-CD20 monoclonal antibody rituximab. We identified 8 patients with myopathy who tested positive for anti-SRP antibodies by immunoprecipitation and were treated with rituximab as part of clinical care. We reviewed their medical records to assess clinical, serologic, and histologic characteristics and response to therapy. In 5 patients, serum was collected before and after rituximab therapy. Autoantibodies were detected by immunoprecipitation and quantitated by densitometry, and the percent decreases in anti-SRP autoantibody levels were calculated. Six of 8 patients who had been refractory to standard immunosuppressive therapy demonstrated improved manual muscle strength and/or decline in CK levels as early as 2 months after rituximab treatment. Three patients sustained the response for 12-18 months after initial dosing. All of the patients were continued on adjunctive corticosteroids, but doses were substantially reduced after rituximab. Quantitative levels of serum anti-SRP antibodies also decreased after rituximab treatment. B cell depletion therapy with rituximab is effective for patients with myopathy associated with anti-SRP. The substantial decrease in anti-SRP antibody levels after rituximab treatment also suggests that B cells and anti-SRP antibodies may play a role in the pathogenesis of this myopathy.

High‐dose cyclophosphamide treatment for refractory severe aplastic anemia in children

To determine if high-dose cyclophosphamide is an effective therapy for children with refractory severe aplastic anemia (SAA). SAA is an illness characterized by the depletion of hematopoietic precursors associated with life-threatening complications. Hematopoietic stem cell transplant (HSCT) is the treatment of choice if a human leukocyte antigen (HLA)-related donor is available. Immunosuppression with anti-thymocyte globulin (ATG) and cyclosporine A (CSA) is an option for patients who are not HSCT candidates. Unrelated donor HSCT has been used with limited success. High-dose cyclophosphamide has been used successfully in the treatment of adults with SAA, but experience in children is limited. Five pediatric patients who had failed previous immunosuppressive therapy for SAA were treated with high-dose cyclophosphamide (45 mg/kg/day x 4 days). After 12 months of treatment, two of five patients experienced a complete response with high-dose cyclophosphamide therapy. The two complete responders achieved red cell recovery with a hematocrit of >36% at days 212 and 112 and platelet recovery with a platelet count of >100 x 10(9)/L at days 126 and 324. Of the remaining patients, one patient failed to respond, and two patients expired from infectious complications. High-dose cyclophosphamide can lead to complete responses in children with SAA who have failed to respond to traditional immunosuppressive therapy.

Immunosuppression in inflammatory bowel disease: traditional, biological or both?

To focus on the emerging clinical evidence for the use of traditional immunosuppressives and biologicals in the treatment of inflammatory bowel disease. Evidence published this year indicates that in Crohn's disease the early use of combined infliximab and purine analogues before the introduction of steroid therapy induces faster steroid-free remission and improves mucosal healing. We have also learned that, in patients with Crohn's disease who are naïve to traditional immunosuppressive therapy, combined infliximab and azathioprine improves clinical and mucosal healing outcomes at 6 months. On the contrary, in patients already exposed to traditional immunosuppressives prior to starting infliximab, withdrawal of azathioprine or methotrexate after 6 months of combined scheduled infliximab maintenance with these agents does not affect outcomes after 2 years of continued infliximab therapy. Finally, several important studies on the safety of immunosuppressives including anti-tumour necrosis factor agents have been published. The cumulative body of evidence suggests that combined immunosuppressive therapy in patients with inflammatory bowel disease increases toxicity. Treatment paradigms for traditional immunosuppressives and biologicals in inflammatory bowel disease are evolving, and the choice of therapy becomes highly dependent on the drugs previously used and disease severity.

Telomerase Gene Mutation Screening and Telomere Length Detection in Chinese Patients with Bone Marrow Failure Syndrome.

Background Acquired bone marrow failure syndrome (BMF) is a group of diseases include aplastic anemia(AA), melodysplastic syndrome (MDS) and paraoxymal nocturnal hemoglobinuria (PNH). Some BMF patients have short telomeres in their peripheral nucleated cells. The length of telomere is maintained by a group of enzymes called telomerase complex. The core components of this complex are a RNA template and a reverse transcriptase, called TERC and TERT, respectively. Recently several studies in the west and Japan have disclosed the presence of telomerase complex gene mutation in a small group of patients with acquired bone marrow failure. They speculated that this small group of patients might represent a subset of cryptogenic Dyskeratosis Congenita (DKC), in which the premature exhaustion of hematopoietic reservoir is caused by mutations in the telomerase gene. This group of patients, though very small in number, would benefit from early bone marrow transplantation instead of traditional immunosuppressive therapy. The incidence of aplastic anemia in Chinese people is relatively high compared with that in the western country. But there has so far been no study in China about the incidence of telomerase gene mutation in acquired bone marrow failure and its relationship with telomere length.Objectives To study the incidence of telomerase gene (namely TERC and TERT ) mutation in Chinese patients with acquired bone marrow failure and explore its relationship with telomere shortening.Methods Blood samples from 90 patients with AA, MDS, and PNH in northern China were collected and performed TERC and TERT mutation analysis. Telomere length was measured by Southern blotting and compared with their normal counterparts.Results 2 TERC mutations (n37 A→G, reported previously ; n66G→C) and 2 TERT mutations (n1870G→T (E/*); n1780G→T (S/I) ) were identified in 90 BMF patients. Among them, 3 mutations are reported first time. 1 patient with TERT mutation, however, was finally diagnosed as DKC instead of acquired AA, making the incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure 3.4%, similar to that of the western people. Southern Blot analysis showed the small group of patients carrying TERC and TERT mutations has very short telomeres, compared with normal controls and with their aplastic counterparts.Conclusions The incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure is 3.4%, similar to that of the western people. This small group of patients has very short telomeres, it is thus clinically important to screen for this small group of patients.

Obesity following kidney transplantation and steroid avoidance immunosuppression

Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 +/- 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population.

Treatment of inflammatory diseases with a monoclonal antibody to intercellular adhesion molecule 1.

A mouse monoclonal antibody to intercellular adhesion molecule 1 (ICAM-1) has been evaluated in multiple animal models of inflammation as well as in the clinic. Anti-ICAM-1 has been found to protect against allograft rejection and ischaemia/reperfusion injury in non-human primates and rabbits. In open-label phase I-II studies, anti-ICAM-1 appears to have prolonged kidney allograft survival when used as induction therapy in conjunction with traditional triple immunosuppressive therapy. Anti-ICAM-1 has shown beneficial effects in the treatment of rheumatoid arthritis when given for five days. Most patients receiving anti-ICAM-1 made antibodies to the mouse immunoglobulin.

Maintenance infliximab therapy in patients with crohn’s disease: how long, how much, how frequent?

Maintenance infliximab therapy in patients with crohn’s disease: how long, how much, how frequent?

Corticosteroid-Sparing Effect of Etanercept in Idiopathic Panuveitis Resistant to Immunosuppressive Therapy

Uveitis, an inflammatory eye disease with varying immunopathogenic mechanisms, may be associated with autoimmune disorders, may be secondary to infection, or may be idiopathic. Response to treatment of uveitis is inconsistent. In this report we describe an adult with idiopathic panuveitis who attempted to lower his oral corticosteroid dose from intolerable levels but was unable to do so because of the reappearance of symptoms. His 8-year course was managed with ocular and systemic corticosteroids, methotrexate, and cyclosporine, which allowed only partially successful control of his ocular inflammation. Complete control was not achieved until the addition of etanercept. With this case report we are the first to describe the complete response of idiopathic panuveitis to etanercept. Our success with this patient strongly supports the critical role of tumor necrosis factor in the immunopathogenesis of some cases of idiopathic panuveitis. Furthermore, etanercept offers a relatively nontoxic, safe option in cases of panuveitis that are unresponsive to traditional immunosuppressive therapy.

Polyarteritis Nodosa and Extrahepatic Manifestations of HBV Infection: The Case Against Autoimmune Intervention in Pathogenesis

Numerous extrahepatic manifestations have been reported in patients with both acute and chronic hepatitis B (arthralgias or arthritis, skin rashes, glomerulonephritis and neuritis), all of which are present in polyarteritis nodosa (PAN) which is the most unique and spectacular extrahepatic manifestation. In the 1970s, the frequency of PAN due to the hepatitis B (HBV) reached 30%. Immunization programs explain the decrease and it is now down to 7%. PAN usually occurs within 6 months of infection. Clinical manifestations reflect this most classic form of PAN, Hepatic manifestations including, ALT/AST elevations are mild and usually overlooked. Besides HBV, other viruses may be responsible for cases of vasculitides including PAN, HIV, Parvovirus B19, and EBV. Different pathogenic mechanisms have been identified but immune complexes are mainly thought to be responsible. In glomerulonephritis, detailed immunostaining and ultrastructural findings indicate that HBe antigen (Ag) is more likely to be the responsible antigen. In PAN, fewer reports are available and early studies with poorly defined antibodies need to be revisited. Interestingly almost all cases of HBV/PAN are associated with wild-type HBV infection, characterised by HBe antigenemia and high HBV replication, supporting the concept that lesions could result from the deposit of viral Ag/Ab complexes soluble in Ag excess, possibly involving HBe Ag. The recent observation of PAN cases associated with precore mutation which abrogates the formation of HBe Ag challenges this view. It may suggest that other, still undefined, circulating HBV-related Ag(s) distinct from HBe Ag could be involved. Remarkably, none of the HBV/PAN cases or glomerulonephritis exhibit antineutrophil cycoplasmic antibodies (ANCA) reactivity. Viral PAN can now be completely separated from other form of vasculitis mostly autoimmune in nature. Based on the efficacy of antiviral agents in chronic hepatitis B and of plasma exchanges in PAN we combined both therapies to treat HBV PAN. This was associated with swift recovery, even in the most severe forms. The perfect time correlation between inhibition of virus replication and resolution of all bioclinical signs suggest a direct pathogenic role of the virus possibly via immune complexes. Traditional immunosuppressive and steroid therapy should no longer be used for HBV PAN cases.