Pemphigus: The promises of peptide immunotherapy

Pemphigus is caused by IgG autoantibodies directed against desmogleins (Dsg), keratinocyte desmosomal glycoproteins belonging to the cadherin family. Anti-Dsg IgG antibodies interfere with adhesive of desmogleins, causing the detachment of keratinocytes (acantholysis). In our laboratory, an alternative approach to pemphigus immunotherapy has been tested. The peptidic vaccine approach is based on the identification of peptidic epitodes within the sequence of known autoantigens and the use of such peptides to evoke tolerance (as in autoimmune disease) or to boost effector immune mechanisms (as in immunotherapy of tumors). This approach shows that in silico mapping of low-similarity sequences may add to the prediction of peptide immunogenicity. Thus peptide immunotherapy for pemphigus deserve further investigations before joining the therapeutic arsenal for pemphigus and related disorders.     

Emerging targets for the treatment of scleroderma

Introduction: Scleroderma is an often-fatal autoimmune connective tissue disease. Recommendations for treating digital ulcers and pulmonary hypertension in scleroderma have recently been established by the European League Against Rheumatism. Conversely, although many valuable insights have been generated into the molecular mechanism underlying the persistent fibrotic phenotype in scleroderma, no safe, clinically proven effective treatment has been found for this aspect of the disease.

Areas covered: Recent evidence suggests that, based on genome-wide molecular profiling, scleroderma can be loosely divided into ‘fibroproliferative' and ‘inflammatory' cohorts. The latter cohort contains patients with localized and ‘limited' disease, as well as a small subset of those with ‘diffuse' disease. Drugs targeting either B cells or ILs might be useful to treat patients who possess an ‘inflammatory' gene expression signature.

Expert opinion: In the future, a ‘personalized medicine' approach might be used to treat patients with scleroderma: individuals with an ‘inflammatory' gene expression signature may be successfully treated with drugs specifically targeting the immune system. Indeed, drugs currently approved for other rheumatic disease might also be used to treat scleroderma patients bearing an ‘inflammatory' gene expression profile.     

Preliminary analysis of mortality associated with rituximab use in autoimmune diseases

Abstract

Normal antibodies and pathogenic autoantibodies are produced by B-cells and plasma cells. Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on cells that express them on their surface and kills them. Rituximab has been increasingly used to treat several autoimmune diseases. Studies on fatal outcomes associated with rituximab therapy are lacking. A comprehensive and detailed analysis in which the multiple factors that could contribute to a fatal outcome in all the autoimmune diseases in which rituximab has been used would be cumbersome, lack uniformity and would prove difficult in making certain definitive conclusions and comparisons, but more importantly it would not allow to provide specific precautions and recommendations to prevent mortality. Hence, autoimmune mucocutaneous blistering diseases (AMBD) were used as model to study fatal outcomes in patients treated with rituximab between 2000 and 2013, using uniform 13 criteria. Fatal outcomes were found in 14 patients with autoimmune blistering diseases out of 134 patients (10.4%). Patients died due to infections (75%), gastrointestinal (17%) and cardiac events (8%). Causes of death were reported in 101 patients with other autoimmune diseases out of 4320 with a mortality rate of 2.4%. Among them, 44 patients (43.6%) died from infections. A statistical analysis of the data demonstrated that a statistically significant higher mortality rate was observed in patients with AMBD compared to patients with other autoimmune diseases. Similarly, a statistically significant higher rate of death due to infections was reported in patients with AMBD compared to patients with other autoimmune diseases. Use of systemic corticosteroids and immunosuppressive agents as concomitant therapy with rituximab enhanced immunosuppression. In many patients, B-cells were depleted for prolonged periods, even after clinical recovery was observed. Although its main action is depletion of B-cells, rituximab has a significant impact on the immune and inflammatory systems, directly and indirectly and thus enhances susceptibility to infection. These preliminary data suggests that physicians using rituximab to treat autoimmune diseases should monitor their patients closely, especially their B-cell levels until they return to normal, be vigilant for possible sources of infection, and be aware of potential fatal outcomes.     

Emerging biotherapies for Sjögren's syndrome

Importance of the field: Sjögren's syndrome (SS) is an autoimmune epithelitis. This exocrinopathy is frequently associated with extraglandular complications, and the patients are at risk of developing B cell lymphoma. Given the lack of disease-modifying drugs, and the fact that SS is a quintessential B-cell mediated disease, attention has recently been focused on biotherapies.

Areas covered in this review: Despite negative grounds, TNF-α antagonists have been tested in the disease, and proven not be efficient. However, B-cell depleting therapy using anti-CD20 antibodies such as rituximab, which is a chimeric mAb, has shown promise in the field, while anti-CD22 mAb seems to be less active.

What the reader will gain: New treatments against the B-cell activating factor of the TNF family are about to be tested, or replaced by receptor immunoglobulin decay protein.

Take home message: B-cell depleting therapies seem promising in SS, but no data are, thus far, available on treatments targeting B-cell activating factor of the TNF family.     

Autoimmune phenomena in untreated and treated marginal zone lymphoma

Introduction: Current literature suggests an association between various autoimmune conditions and marginal zone lymphoma (MZL). However, these autoimmune conditions have not been comprehensively systematized to date. As a result, their clinical implications remain largely unknown.

Areas covered: The authors provide a comprehensive review of the existing literature on various autoimmune abnormalities documented in the course of MZL, as well as on autoimmune alterations induced by certain MZL therapies.

Expert opinion: The course of MZL is accompanied by a variety of hematologic and non-hematologic autoimmune disorders. Whereas some of them could be secondary and related to the course of the MZL, others may be primary and might even favor the development of MZL itself. In addition, authentic autoimmune conditions have been documented with the use of rituximab as a single agent and the nucleoside analogs. Therefore, we believe caution should be exerted with the use of these agents in MZL patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of the MZL subtypes represents an inherent limitation, integration of emerging information from immunology research laboratories and clinical practice could translate into improved outcomes of this disease spectrum.     

Comparing the Cost-Effectiveness of Rituximab Maintenance and Radioimmunotherapy Consolidation versus Observation Following First-Line Therapy in Patients with Follicular Lymphoma

BackgroundPhase 3 randomized trials have shown that maintenance rituximab (MR) therapy or radioimmunotherapy (RIT) consolidation following frontline therapy can improve progression-free survival for patients with follicular lymphoma (FL), but the cost-effectiveness of these approaches with respect to observation has not been examined using a common modeling framework.ObjectivesTo evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL.MethodsWe developed Markov models to estimate patients’ lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer’s perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses.ResultsCompared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or $37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias.ConclusionsMR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives.     

Disseminated ulcerating lupus panniculitis emerging under interferon therapy of hairy cell leukemia: Treatment‐ or disease‐related?

We report a 43‐year‐old woman, who underwent therapy with interferon‐α for hairy cell leukemia. During interferon‐α therapy she developed multiple subcutaneous swellings, accompanied by fever and fatigue. A skin biopsy revealed lobular, T‐cell lymphocytic panniculitis. In conjunction with the clinical and immunological findings, the diagnosis of lupus panniculitis was made and interferon‐α therapy stopped. Initially, she responded well to oral prednisone and hydroxychloroquine, but after several months she became resistant to it. Her condition worsened, she developed skin ulcers in the inflamed regions. Only with the leukemia‐targeted therapy using cladribine and rituximab her skin condition could be controlled, suggesting hairy cell leukemia as an additional trigger of the lupus panniculitis. Our report is the first one to show induction of lupus panniculitis under interferon therapy of hairy cell leukemia and its presumable sustentation by the latter.     

Hairy cell leukemia: short review,today's recommendations and outlook

Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately 2% of all leukemias. Treatment with splenectomy and interferon-α historically belonged to the first steps of therapeutic options, achieving partial responses/remissions (PR) in most cases with a median survival between 4 and 6 years in the 1980s. The introduction of the purine analogs (PA) pentostatin and cladribine made HCL a well-treatable disease: overall complete response rates (CRR) range from 76 to 98%, with a median disease-free survival (DFS) of 16 years a normal lifespan can be reached and HCL-related deaths are rare. However, insufficient response to PA with poorer prognosis and relapse rates of 30–40% after 5–10 years of follow-up may require alternative strategies. Minimal residual disease can be detected by additional examinations of bone marrow specimens after treatment with PA. The use of immunotherapeutic monoclonal antibodies (mAB) like rituximab as a single agent or in combination with a PA or more recently clinical trials with recombinant immunotoxins (RIT) show promising results to restrict these problems. Recently, the identification of the possible disease-defining BRAF V600E mutation may allow the development of new therapeutic targets.     

Fatigue in children and adolescents with immune thrombocytopenia

Immune thrombocytopenia (ITP), an acquired autoimmune disorder of low platelets and risk of bleeding, has a substantial impact on health-related quality of life (HRQoL). Patients with ITP often report significant fatigue, although the pathophysiology of this is poorly understood. In this observational cohort of 120 children receiving second-line therapies for ITP, we assessed reports of fatigue using the Hockenberry Fatigue Scale. Children and adolescents with ITP reported a similarly high level of fatigue with 54% (29/54) of children and 62% (26/42) of adolescents reporting moderate-to-severe fatigue. There was no correlation between fatigue and age or gender. Adolescents with newly diagnosed and persistent ITP had higher mean fatigue scores than those with chronic ITP (P = 0·03). Fatigue significantly improved in children and adolescents by 1 month after starting second-line treatments, and this improvement continued to be present at 12 months after starting treatment. Fatigue scores at all time-points correlated with general HRQoL using the Kids ITP Tool, but did not correlate with bleeding symptoms, platelet count, or platelet response to treatment. Fatigue is common in children and adolescents with ITP and may benefit from ITP-directed treatment even in the absence of bleeding symptoms.