László Váróczy

Malignant lymphoma-associated autoimmune diseases – a descriptive epidemiological study

Abstract. Lymphoproliferative disorders and autoimmune diseases have some common aspects in their clinical appearance. We reviewed 940 patient charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 421 non-Hodgkins lymphoma (NHL) patients (230 males, 191 females), 32 (7.6%) had an autoimmune disease (26 females, six males, mean age 48.3 years). The most common diagnosis was Sjögrens syndrome. The other cases were autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), other musculoskeletal disorders (2), rheumatoid arthritis (1), vasculitis (1), undifferentiated collagenosis (1), colitis ulcerosa (1), autoimmune hepatitis (1), Addisons disease (1), and autoimmune hemolytic anemia (1). Of 519 Hodgkins lymphoma patients (308 males, 211 females), an associated autoimmune disease occurred in 45 (8.6%) (25 females, 20 males, mean age 39.2 years). In 31 cases, we found autoimmune thyroid disorders, then came glomerulonephritis (3), immune thrombocytopenia (3), insulin-dependent diabetes mellitus (2), autoimmune hemolytic anemia (1), seronegative spondylarthritis (1), systemic lupus erythematosus (1), mixed connective tissue disease (1), scleroderma (1), and vasculitis (1). We also analyzed histology, choice of treatment, and sequence of appearance of the disease types. We found a difference between NHL and Hodgkins lymphoma patients, since in NHL autoimmunity – mostly from Sjögrens syndrome – preceded the lymphoma diagnosis (70%), but in Hodgkins the autoimmunity developed mainly after the treatment of malignancy. The relatively high prevalence of autoimmune diseases in malignant lymphomas has several explanations. Clinicians have to consider autoimmunity when treating lymphoproliferative disorders.

Hypothyroidism and thyroiditis after therapy for Hodgkin's disease

During the follow-up of thyroid function of 151 patients with Hodgkin’s disease in complete remission for at least 1 year, 26 cases of subclinical, 12 cases of manifest clinical hypothyroidism and 2 cases of hyperthyroidism (Graves-Basedow disease) were confirmed. Thyroid dysfunction was more frequent in patients who had undergone mantle or neck radiotherapy. Hypothyroidism was most often revealed from the 6th year on following radiotherapy. Thyroid autoantibody positivity was found to be more frequent in patients with thyroid dysfunction, and conversely, thyroid dysfunction was more frequent among the 28 patients with autoantibody positivity. Ultrasound examination and fine needle aspiration cytology of the thyroid confirmed thyroiditis in 96% of the patients with antibody positivity. No relationship was found between thyroiditis and the form of treatment for Hodgkin’s disease. We have found that both neck irradiation and thyroiditis may play a role in the increased number of thyroid dysfunction in patients treated for Hodgkin’s disease. Thyroiditis is not caused by neck radiotherapy but may be the result of immune regulation disorders in Hodgkin’s disease. For substitution or isohormone therapy, levothyroxine is suggested for use. We suggest that examination of the thyroid should be performed at least once a year during the follow-up of Hodgkin’s disease patients.

Successful Treatment of B Cell Chronic Lymphocytic Leukemia-Associated Severe Paraneoplastic Pemphigus with Cyclosporin A

Since the first description of paraneoplastic pemphigus, several cases have been described in the literature. However, curative therapy is usually a challenge to the physicians treating this disease. Several publications are available discussing the efficacy of steroids, cyclophosphamide and cyclosporin A. Recently, a report of the successful use of rituximab was also published. However, the use of cyclosporin A is controversial in the case of B cell malignancies, as there are reports showing the cytotoxic effect of this drug on B cells. However, other authors report no effect, or even unwanted effects resulting in B cell proliferation. We report the case of a 50-year-old Caucasian male. He developed a B cell lymphoma consisting of CD5/CD20-double-positive cells, and 2 months later, it was followed by a very severe paraneoplastic pemphigus affecting the mucosa and the skin. The lymphoma was well managed with CHOP and CVP polychemotherapy, followed by oral chlorambucil; however, the bullous eruptions did not disappear. Oral steroids, cyclophosphamide, plasmapheresis and IVIG therapy were only partially successful, so we decided to use oral cyclosporin A. Starting with 7 mg/kg and maintaining a steady plasma level of no less then 110 ng/l, the bullae completely disappeared within 6 weeks, and the patient has been in remission for 17 months now, taking the oral cyclosporin A continuously. The underlying B cell disorder did not relapse during the therapy.

Immunological reconstitution after autologous stem cell transplantation in patients with refractory systemic autoimmune diseases

Objective: High-dose chemotherapy followed by autologous haematopoietic stem cell transplantation (AHSCT) can be a salvage therapy for patients with severe, refractory systemic autoimmune diseases. The function of the newly rebuilt immune system is important, but little is known about immune reconstitution after AHSCT in autoimmune disorders. Our aim was to investigate the repopulation of different lymphocyte subsets in patients with systemic autoimmune diseases after AHSCT. Methods: Twelve patients with severe refractory, autoimmune diseases were enrolled in the study: four with rheumatoid arthritis (RA), four with systemic sclerosis (SSc), three with systemic lupus erythematosus (SLE), and one with autoimmune overlap syndrome (myositis and RA). After stem-cell mobilization, CD34+ apheresis was carried out, followed by conditioning and AHSCT. After transplantation, peripheral lymphocyte subsets were regularly assessed by flow cytometry. Results: The follow-up time was 24 months. The overall transplantation-related mortality (TRM) was 16.7% and the transplant-related toxicity was 33% 2 years after AHSCT. Regarding the immune reconstitution, CD56+ natural killer (NK) cells appeared in the earliest phase after transplantation, followed by CD8+ T cells. B cells and CD4+ T cells became normal within 150 days. The ratio of naive cells was low 30 days after AHSCT; however, naive B cells regenerated within 2 months whereas the repopulation of naive T cells took longer. After a short increase, the ratio of memory cells decreased 2 months after transplantation. Regulatory T (Treg) cells did not change significantly in the peritransplant period. Altogether approximately 5–6 months were required for the reconstitution of the peripheral immune network. Conclusions: AHSCT can be a salvage therapeutic modality in autoimmune patients who are refractory to other conventional therapies.

Aspects of B-Cell Non-Hodgkin's Lymphoma Development: A Transition from Immune-Reactivity to Malignancy

The development of B‐cell lymphomas is an intricate interplay among various pathogenic factors, leading to a multi‐step process, encompassing various stages of B‐cell maturation. Besides genetic abnormalities, a variety of environmental and microbial factors, as well as disproportional immune‐regulatory processes lead to the malignant transformation. Yet, little is known about the exact chain of events, which lead from the physiological polyclonal B‐cell activation as a response to exogenous antigens through oligoclonality to a monoclonal, uncontrolled, malignant B‐cell proliferation. The aim of the present review was to summarize the potential harmful steps in the development of B‐cell lymphomas, according to conventional and novel theories, and to depict therapeutic regimens presently in use as well as to envision future drug developments, beneficial in the battle against this lymphoid malignancy.

Autologous stem cell transplantation in autoimmune and rheumatic diseases: from the molecular background to clinical applications

Autoimmune diseases have a multifactorial origin. Because of disturbances of the immune system, autoreactive T and B cells target self-antigens, leading to permanent organ damage. Despite novel therapeutic protocols, the disease course is chronic and in many instances the outcome is lethal. The efficacy of stem cell therapy has been observed in autoimmune animal models and in autoimmune diseases related to haematological abnormalities. Although the therapy is more than 30 years old, its broad spread has been delayed by the serious side-effects due to the conditioning treatments based on oncological protocols. Evaluation of the data of patients who have undergone autologous stem cell therapy reinforced the view that protocols used for conditioning treatments, mostly causing lymphoablation, and procedures carried out in specialist centres significantly reduced mortality, with an almost optimal therapeutical efficacy. New, multicentre investigations have been launched to compare the efficacy of various protocols. In this review, we summarize certain aspects of the molecular background of autologous stem cell transplantation and also depict the response to therapy in various autoimmune and rheumatic diseases.

Adolescent hodgkin lymphoma: Are treatment results more favorable with pediatric than with adult regimens?

Background The aim of our work was to compare the treatment modalities and the survival rates in adolescents (14 to 21 y) with Hodgkin lymphoma (HL) treated with adult (A) or with pediatric (P) regimens. Procedure From January 1990 to December 2004, 134 (A) and 111 (P) adolescents with HL were treated. Male:female ratio was 1:1.48 (A) and 1:1.36 (P), the mean-age 18.6 (A) and 15.8 years (P), respectively. Results The patients were treated either with doxorubicin, bleomycin, vinblastine and dacarbazine (A) or with OPPA/OEPA±COPP regimens (P). About 82% (A) and 89% (P) of the patients received radiotherapy. Relapse rates were 13% (A) and 14% (P). Fourteen patients died in group (A) and 9 in group (P). There were no significant differences in the overall survival and event-free survival rates at 5 and 10 years between the 2 patients groups. For children under age of 18 years old overall survival was 92.8±3% at 5 and 89.6±3% at 10 years in group (P) and 89.4±4% at 5 years and 83.1±6% at 10 years (P=0.2822) in group (A). For children under the age of 18 years event-free survival was 82.4±4% at 5 and 10 years in group (P) and 69.6±7% at 5 years and 59.1±8% at 10 years (P=0.0192) in group (A). Conclusion In case of the patients younger than 18 years, the survival rates are more favorable by using pediatric regimens, so these patients might have a benefit if they are treated in pediatric institutes.

Intracellular IL-4/IFN-gamma producing peripheral T lymphocyte subsets in B cell non-Hodgkin's lymphoma patients.

Aim:  The availability of several biological therapy options is rapidly growing in the field of malignant lymphomas. This emphasizes the need to understand the precise interaction of the host immune system with the malignant disease. We measured the intracellular cytokine responses in lymphoma patients’ lymphocytes, to characterize the polarization changes in their immune system.

Diagnostics and treatment of pulmonary BALT lymphoma: a report on four cases

Bronchus-associated lymphoid tissue (BALT) is a lymphoid aggregate located in the submucosal area of bronchioles and plays a central role in airway mucosal immunity by inducing the accumulation of secretory IgA-producing cells. Long-lasting antigen stimuli promote the hyperplasia of BALT, which may develop into pulmonary mucosa-associated lymphoma (baltoma). Most pulmonary lymphomas are low-grade B-cell lymphomas. We have recently treated four patients with BALT lymphoma and this is our first report on their diagnostics and treatment. Based on these cases we wanted to demonstrate the difficulties of differential diagnosis during bronchoscopic and computed tomography (CT) examinations as well as the pitfalls of thoracosurgical vs hemato-oncological treatments.

Successful administration of rituximab–bendamustine regimen in the relapse of Hodgkin lymphoma after autologous hemopoietic stem cell transplantation

Objectives. Treatment options for relapsing Hodgkin lymphoma (HL) are controversial after autologous hemopoietic stem cell transplantation (HSCT). Nevertheless, allogeneic HSCT may be curative if it is performed in complete remission. Case report. In 2007, a 22‐year‐old female patient was diagnosed with nodular sclerosis subtype of classical HL. Her clinical stage was IIAX with unfavorable prognosis. Eight courses of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy and involved field irradiation were applied, but after 3 months of complete remission, disseminated relapse was recognised by 18FDG‐PET/CT. After two cycles of salvage dexamethasone, cisplatinum, and cytosine arabinoside therapy, further progression was noticed, so the treatment was modified to ifosfamide, gemcitabine, vinorelbine, and prednisone (IGEV) regimen. After two cycles of IGEV regimen, she achieved a complete metabolic remission, which was confirmed by a 18FDG‐PET/CT scan again. She was referred for autologous‐HSCT, and a successful stem cell collection was performed in August 2008. However, a rapid progression was detected again, so total body irradiation was applied before the conditioning therapy with R‐mini‐BEAM regimen. The 18FDG‐PET/CT scan performed 100 days after the autologous‐HSCT was still positive. In December 2009, multiple nodal and extranodal progression was detected, so ifosfamide, carboplatine, etoposide, mesna protection rescue treatment was started, but it was ineffective. Based on sporadic data of the literature, rituximab–bendamustine therapy was started in March 2010. After four cycles, she achieved complete metabolic remission, which was verified by 18FDG‐PET/CT. The patient has been referred for an allogeneic HSCT with reduced intensity conditioning. Conclusions. Based on our experience, bendamustine–rituximab salvage therapy can be a suitable option for the treatment of post‐transplant progression or relapse of HL. Copyright