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Anti-CD20 monoclonal antibody (rituximab) treatment for hepatitis C-negative therapy-resistant essential mixed cryoglobulinemia with renal and cardiac failure.
Ghijsels E, Lerut E, Vanrenterghem Y, Kuypers D.
Division of Nephrology and Renal Transplantation, Department of Medicine, University Hospital Gasthuisberg, Leuven, Belgium. Erik.Ghijsels@uz.kuleuven.ac.be
A case of hepatitis C virus (HCV)-negative essential mixed cryoglobulinemia with initial skin, joint, and liver involvement, complicated by severe renal and cardiac failure and resistant to corticosteroid therapy, plasmapheresis, chlorambucil, and cyclophosphamide is presented. Treatment with an anti-CD20 monoclonal antibody (rituximab) induced a persistent recovery of renal and cardiac function, disappearance of skin and joint lesions, and disappearance of cryoglobulins. In a 24-month follow-up period, our patient remains in remission and free of symptoms.
PMID: 15112197 [PubMed - in process]
B cells as therapeutic targets for rheumatic diseases.
Looney RJ, Anolik J, Sanz I.
Department of Medicine, University of Rochester, Box 695, 601 Elmwood Avenue, Rochester, NY 14642, USA. John_Looney@URMC.Rochester.edu
PURPOSE OF REVIEW: Trials treating human rheumatic diseases with biologic agents and drugs that selectively affect B cells will be reviewed. Rituximab, an anti-CD20 monoclonal mouse/human antibody, will be the primary focus of the review because it has been widely used in several autoimmune and rheumatic conditions, but the limited studies on other reagents such as anti-BlyS, anti-CD154, and B cell tolerogens will also be covered. RECENT FINDINGS: The single most important recent development was the completion of a randomized, double-blind, placebo-controlled trial of rituximab in methotrexate-resistant rheumatoid arthritis. In this trial, B cell depletion with rituximab led to a sustained clinical response with an impressive improvement in America College of Rheumatology 50% response (ACR 50) at both 24 and 48 weeks. Additional open studies of rituximab showing clinical benefit in systemic lupus erythematosus, cryoglobulinemia, antineutrophil cytoplasmic antibodies+ vasculitis, and dermatomyositis are noteworthy but must be interpreted with caution until randomized control trials are available. Two well-designed studies of anti-CD154 antibodies in systemic lupus erythematosus were reported. Unfortunately, one was halted because of unexpected vascular complications, and the other failed to show any beneficial clinical effect. A phase I study using anti-BlyS in SLE demonstrated a selective effect on B cells and no overt toxicity, but in this very short-term study no effect on serology or clinical activity was seen. Two B cell tolerogens have been used in human trials. The first tolerogen, directed at anti-dsDNA responses in SLE, did significantly decrease titers of high-affinity anti-dsDNA antibodies but had no clinically beneficial effect overall. A phase I trial of a tolerogen directed at anti-beta2-glycoprotein I antibodies demonstrated a decrease in antibody titers after a single injection. SUMMARY: Several therapeutic agents targeting B cells have now been tested or are being tested in human trials. The success of rituximab in a well-controlled trial confirms previous preliminary reports indicating that B cell depletion can treat established autoimmune disease.
PMID: 15103242 [PubMed - in process]
Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis.
Lamprecht P, Lerin-Lozano C, Merz H, Dennin RH, Gause A, Voswinkel J, Peters SO, Gutzeit O, Arlt AC, Solbach W, Gross WL.
Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Luebeck, and Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538 Luebeck, Germany. email@example.com
OBJECTIVES: To report the successful induction of remission with the monoclonal anti-CD20 antibody rituximab in a patient with hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis and a non-Hodgkin's lymphoma (NHL) resistant to previously advocated conventional treatments. Case report: The patient was a 45 year old woman with HCV associated cryoglobulinaemic vasculitis, with purpura, arthralgia, constitutional symptoms, and a polyneuropathy. A malignant NHL was found as underlying lymphoproliferative disease. At this stage the disease was refractory to interferon alpha2b and ribavirin and to subsequent immunosuppressive treatment with cyclophosphamide. Six rituximab infusions targeting the CD20 antigen on cells of the B cell lineage induced remission of the vasculitis. Bone marrow biopsy disclosed absence of the NHL. Remission has subsequently been maintained and HCV eliminated with the new pegylated interferon alpha2b and ribavirin for nearly one year. CONCLUSIONS: Transition of the underlying "benign" lymphoproliferative disease to a malignant lymphoma may result in difficult to treat HCV associated cryoglobulinaemic vasculitis. Rituximab offers a new possibility for inducing remission in refractory HCV associated cryoglobulinaemic vasculitis and the lymphoproliferative disorder. After remission, HCV may subsequently be eliminated with pegylated interferon alpha2b and ribavirin.
PMID: 14644867 [PubMed - indexed for MEDLINE]
Treatment recommendations in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.
Gertz MA, Anagnostopoulos A, Anderson K, Branagan AR, Coleman M, Frankel SR, Giralt S, Levine T, Munshi N, Pestronk A, Rajkumar V, Treon SP.
Mayo Clinic, Rochester, MN, USA.
This presentation represents consensus recommendations for the treatment of patients with Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the second International Workshop held in Athens, Greece during September 2002. The faculty adopted the following statements for the management of patients with Waldenstrom's macroglobulinemia: (1) Alkylating agents, nucleoside analogues, and rituximab are reasonable choices for first line therapy of WM. (2) Both cladribine and fludarabine are reasonable choices for the therapy of WM. (3) Combinations of alkylating agents, nucleoside analogues, or rituximab should at this time be encouraged in the context of a clinical trial. (4) In WM, rituximab can cause a sudden rise in serum IgM and viscosity levels in certain patients, which may lead to complications, therefore close monitoring of these parameters and symptoms of hyperviscosity is recommended for WM patients undergoing rituximab therapy. (5) For relapsed disease, it is reasonable to use an alternate first line agent or re-use of the same agent; however, since autologous stem cell transplantation may have a role in treating patients with relapsed disease it is recommended that for patients in whom autologous transplantation is seriously being considered, exposure to alkylator or nucleoside analogue drugs should be limited. (6) Combination chemotherapy for patients who can tolerate myelotoxic therapy, thalidomide alone or with dexamethasone, can reasonably be considered to have relapsed. (7) Autologous stem cell transplantation may be considered for patients with refractory or relapsing disease. (8) Allogeneic transplantation should only be undertaken in the context of a clinical trial. (9) Plasmapheresis should be considered as interim therapy until definitive therapy can be initiated. (10) Rituximab should be considered for patients with IgM-related neuropathies. (11) Corticosteroids may be useful in the treatment of symptomatic mixed cryoglobulinemia. (12) Splenectomy is rarely indicated but has been used to manage painful splenomegaly and hypersplenism. Copyright 2003 Elsevier Inc. All rights reserved.
- Consensus Development Conference
PMID: 12720120 [PubMed - indexed for MEDLINE]
Efficacy and safety of rituximab in type II mixed cryoglobulinemia.
Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, Michelutti A, Baccarani M, Fanin R, Ferraccioli G.
Division of Hematology-Dipartimento di Ricerche Mediche e Morfologiche, University of Udine, Italy.
The best treatment of type II mixed cryoglobulinemia (MC) has still to be defined. Antiviral treatment for the frequent underlying infectious trigger hepatitis C virus (HCV) may be ineffective, contraindicated, or not tolerated in a fraction of cases, whereas current immunosuppressive treatments may lead to relevant complications. Selective B-cell blockade with rituximab was used in this study, based on favorable results in preliminary experience. Fifteen consecutive patients with type II MC (HCV-related in 12 of 15) were treated with rituximab, 375 mg/m(2) intravenously weekly for 4 weeks. Only medium- to low-dose steroids were allowed, if already administered at the time of recruitment. All patients had active disease, poorly controlled or difficult to manage with previous treatments, including corticosteroids in all. Efficacy and safety of rituximab therapy were evaluated in the following 6 months. The overall follow-up after rituximab treatment ranged from 9 to 31 months. Rituximab proved effective on skin vasculitis manifestations (ulcers, purpura, or urticaria), subjective symptoms of peripheral neuropathy, low-grade B-cell lymphoma, arthralgias, and fever. Nephritis of recent onset went into remission in one case. Laboratory features, that is, significantly decreased serum rheumatoid factor and cryoglobulins and increased C4, were consistent with the clinical efficacy. Treatment was well tolerated, with no infectious complications. Thrombosis of retinal artery or self-limiting panniculitis occurred in one patient each. Rituximab may represent a safe and effective alternative to standard immunosuppression in type II MC. Controlled studies are needed to better define drug indications and the cost-efficacy profile in the different systemic manifestations.
- Clinical Trial
- Multicenter Study
PMID: 12560225 [PubMed - indexed for MEDLINE]
Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20.
Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F.
Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
A controlled study has been carried out to assess the efficacy of rituximab, a chimeric antibody that binds to the B-cell surface antigen CD20, in 20 patients with mixed cryoglobulinemia (MC) and hepatitis C virus (HCV)-positive chronic active liver disease, resistant to interferon alpha (IFN-alpha) therapy. They received an intravenous infusion of 375 mg/m(2) rituximab once a week for 4 consecutive weeks. Infusion of rituximab had a good safety profile and no severe side effects were reported. Sixteen patients (80%) showed a complete response (CR), characterized by rapid improvement of clinical signs (disappearance of purpura and weakness arthralgia and improvement of peripheral neuropathy), and decline of cryocrit. CR was associated with a significant reduction of rheumatoid factor (RF) activity and anti-HCV antibody titers. Decline of IgG anti-HCV titers in the cryoprecipitates was usually associated with a favorable response (r = 0.81; P <.005). No differences in the dynamics of B-cell depletion and recovery were found between responders and nonresponders. Molecular monitoring of the B-cell response revealed disappearance/deletion of peripheral clones in the responders and great stability in the nonresponders. Rituximab had a deep impact on hepatitis C viremia; HCV RNA increased approximately twice the baseline levels in the responders, whereas it remained much the same in the nonresponders. Twelve (75%) of 16 responders remained in remission throughout the follow-up. The results indicate that rituximab has clinical and biologic activity in patients with HCV(+) MC. However, in view of the increased viremia in the responders, additional modes of application and combination of rituximab with other agents need to be investigated.
PMID: 12506023 [PubMed - indexed for MEDLINE]
[Hepatitis-C-virus-associated cryoglobulinemia. Pathogenesis, diagnosis and treatment]
[Article in German]
Staak JO, Glossmann JP, Diehl V, Josting A.
Klinik fur Innere Medizin. Universitat zu Koln, Germany. Oliver.Staak@uni-koeln.de
BACKGROUND: Chronic hepatitis C-virus (HCV) infection is frequently associated with a variety of autoimmune phenomenons. Mixed cryoglobulins appear in up to 50% of chronic HCV-infected patients, mostly asymptomatic. PATHOGENESIS: Cryoprecipitates present IgM with rheumatoid factor activity and development of immunocomplexes deposited in small vessels responsible for resulting vasculitis. MANIFESTATIONS: Characteristic clinical findings are weakness, arthralgia and purpura with further complications including glomerulonephritis and neuropathic lesions. Several mechanisms for HCV-induced clinical lymphoproliferation are discussed, such as chronic B-cell stimulation and activation of the antiapoptotic oncogene bcl-2 leading to immunoglobulin synthesis and eventually evolving into B-cell non-Hodgkin's lymphoma (NHL). TREATMENT: Conventional treatment of HCV-associated mixed cryoglobulinemia aimes at reducing circulating immunocomplexes and causal therapy with interferon (IFN) and ribavirin. New approaches using the anti-CD20 antibody rituximab have been described recently.
PMID: 12386793 [PubMed - indexed for MEDLINE]
Treatment of refractory antibody mediated autoimmune disorders with an anti-CD20 monoclonal antibody (rituximab).
Arzoo K, Sadeghi S, Liebman HA.
Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
BACKGROUND: Rituximab, a chimeric monoclonal anti-CD20 antibody, has recently been used for the treatment of refractory antibody mediated autoimmune diseases such as immune mediated thrombocytopenia and haemolytic anaemia. PATIENTS: Because of its novel mechanism of action, rituximab was used to treat three patients with refractory systemic antibody mediated autoimmune disorders. The first patient, a 71 year old woman with idiopathic type II mixed essential cryoglobulinaemia, had both dermatological and neurological manifestations with marked renal disease attributed to her cryoglobulinaemia. Patient 2, a 73 year old woman with Goodpasture's syndrome, was refractory to conventional treatment (cyclophosphamide, prednisone, plasmapheresis). She had persistent haemoptysis and haematuria and positive antiglomerular basement membrane antibodies. The third patient, a 75 year old man with primary biliary cirrhosis, myelodysplasia, and systemic immune complex vasculitis, had progressive renal insufficiency, a macular erythematous rash, and severe thrombocytopenia. RESULTS: Treatment with rituximab resolved all clinical and laboratory manifestations in the three patients. CONCLUSIONS: Rituximab may be an important therapeutic agent for the treatment of patients refractory or intolerant to corticosteroid or cytotoxic treatment, or both.
PMID: 12228164 [PubMed - indexed for MEDLINE]
Rituximab for the treatment of type II mixed cryoglobulinemia.
Zaja F, De Vita S, Russo D, Michelutti A, Fanin R, Ferraccioli G, Baccarani M.
PMID: 12209536 [PubMed - indexed for MEDLINE]
Inefficacy of rituximab in a case of low grade non-Hodgkin's lymphoma with cryoglobulinemia.
Baronciani D, Angelucci E, Gaziev J, Visani G.
PMID: 12091148 [PubMed - indexed for MEDLINE]
Wicklund MP, Kissel JT.
Department of Neurology, Division of Neuromuscular Disease, The Ohio State University, 1654 Upham Drive, Columbus, OH 43210, USA. Kissel@osu.edu
Few prospective, randomized, placebo-controlled trials have been performed to guide clinicians in the management of neuropathies seen in the setting of monoclonal gammopathies (paraproteins). Recommendations must be made on the basis of clinical experience and information gleaned from various uncontrolled and open-label trials. In every instance, decisions concerning therapy must be based on the clinical setting in which the paraprotein occurs. Treatment of paraproteinemic neuropathies associated with multiple myeloma, amyloidosis, and Waldenstrom's macroglobulinemia should be directed at the treatment of the underlying disease. These neuropathies often remain recalcitrant to therapy. If the paraprotein results from cryoglobulinemia due to hepatitis C virus infection, interferon-alpha (with or without ribavirin) provides optimal subjective and objective relief from symptoms. For neuropathy associated with osteosclerotic myeloma (POEMS syndrome) and solitary bone lesions, radiation therapy is the most effective and least toxic initial therapy. In those patients with monoclonal gammopathies of undetermined significance (MGUS), consideration of the clinical syndrome may be very helpful in selecting appropriate treatment. Patients who fulfill diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are best treated in a manner similar to that used for idiopathic CIDP (ie, with intravenous immunoglobulin, plasma exchange, and corticosteroids). Class I evidence documents plasma exchange to be effective in peripheral neuropathies associated with MGUS of the IgG and IgA, but not IgM, types. The most difficult cases to treat are those with peripheral neuropathies associated with IgM monoclonal gammopathies, with or without reactivity to myelin-associated glycoprotein (MAG). A number of published case series propose therapeutic regimens for these conditions, yet optimal treatment remains to be established. In many cases, mildly symptomatic patients should not be subjected to the morbidity associated with current treatment regimens. In those patients requiring treatment, this author initially tries plasma exchange, followed by a course of chlorambucil if the symptoms and signs are predominantly sensory. For cases with rapid progression or significant disability, a regimen of monthly pulses with prednisone and cyclophosphamide is recommended. If improvement does not ensue, a trial of a newer agent, such as rituximab, is recommended. Supportive treatment with physical therapy, orthotics, and ambulatory aids enhances patient independence at a relatively low cost.
PMID: 11180752 [PubMed - as supplied by publisher]
Waldenstrom's macroglobulinaemia: laboratory diagnosis and treatment.
Owen RG, Johnson SA, Morgan GJ.
Department of Haematology, The General Infirmary at Leeds, UK. firstname.lastname@example.org
PMID: 10960874 [PubMed - indexed for MEDLINE]
Paraproteinemia and neuropathy.
Division of Neurology, Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey 17033, USA. email@example.com
Paraprotein-associated neuropathies are a diverse group of disorders. The pathogenesis of many of them is poorly understood. Treatments have usually consisted of plasma exchange, corticosteroids, intravenous immunoglobulin, and other immunosuppressive therapies. Response to treatment has varied from good to very poor. Most recent work in this field has had two goals: achieving a better understanding of pathogenesis and developing better treatments. Such diverse entities as hepatitis C virus, vascular endothelial growth factor, and cytokines now appear to play a role in pathogenesis. More aggressive therapies such a bone marrow transplantation, interferon-alpha, and Rituximab have shown some promise.
PMID: 10590896 [PubMed - indexed for MEDLINE]
Rituximab for the treatment of type II mixed cryoglobulinemia.
Zaja F, Russo D, Fuga G, Patriarca F, Ermacora A, Baccarani M.
PMID: 10586221 [PubMed - indexed for MEDLINE]