A review of rituximab in cutaneous medicine
Department of Dermatology St. Lukes Roosevelt Hospital Center, New York, NY. Scheinfeld@earthlink.net
The rituximab antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Rituximab is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma. Rituximab is also commonly used to treat chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and immune or idiopathic thrombocytopenic purpura (ITP). Rituximab is an effective treatment for primary cutaneous B-cell lymphoma and other cutaneous lymphomas. Rituximab is an effective treatment for mixed cryoglobulinemia. Rituximab is a promising treatment for systemic lupus erythematosus, dermatomyositis, pemphigus, vasculitis, and a variety of hematologic diseases. Black-box warnings on rituximab include fatal infusion reactions, tumor lysis syndrome, and severe mucocutaneous reactions. A variety of cardiac, pulmonary, renal, and hematologic side effects can occur. It commonly causes mild cutaneous side effect and rarely has caused paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.
Rituximab is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin lymphoma . Rituximab is also commonly used to treat chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and immune or idiopathic thrombocytopenic purpura (ITP). It is a promising agent for the treatment on any disease called by B-Cells and the pathogenic antibodies that they produce .
The rituximab antibody is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1-κ immunoglobulin containing murine light-chain and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM .
Rituximab binds specifically to the antigen CD20 (human B lymphocyte restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre- and mature-B lymphocytes. The antigen is also expressed on > 90 percent of B-cell non Hodgkin lymphomas (NHL), but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. CD20 regulates early steps in the activation process for cell-cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation .
The Fab domain of Rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line. Rituximab binding has been observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the nonlymphoid tissues examined .
Rituximab is usually given in a dose of 375 mg intravenously once a week for 4-8 weeks, often with other types of chemotherapy. Therapy using rituximab often utilizes combinations such as CHOP or fludarabine and cyclophosphamide. Rituximab is sometimes administered with ibritumomab tiuxetan.
Uses of rituximab to treat diseases with cutaneous manifestations
Treatment of cutaneous B cell lymphoma
Rituximab is an effective treatment for primary cutaneous B-cell lymphomas [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]. This is even true in cases of primary cutaneous B-cell lymphoma that have relapsed or failed other therapies .
Rituximab is an effective therapy of atypical B-cell-lymphoma variants. Primary cutaneous large B-cell lymphoma mimicking pyoderma gangrenosum of the leg has been effectively treated with rituximab [14, 15, 16, 17]. Cutaneous large B-cell lymphoma of the leg masquerading as a chronic venous ulcer can be treated with rituximab . Systemic therapy of primary cutaneous B-cell lymphoma, marginal-zone type, with rituximab, has been successful . Regression of cutaneous intravascular lymphoma with rituximab has been noted .
Intralesional therapy with anti-CD20 monoclonal antibody rituximab has been found to be an effective treatment of primary cutaneous B-cell lymphoma [21, 22, 23]. In comparison to intravenous administration, intralesional application of the drug allows the use of lower dosages.
With rituximab therapy lymphomas can lose CD20 expression and, with that, susceptibility to rituximab. Cutaneous B-cell lymphoma with loss of CD20 immunoreactivity after rituximab therapy has occurred [24, 25]. Relapse of diffuse large B cell lymphoma to CD20-negative multiple cutaneous tumors immediately after anti-CD20 monoclonal antibody (rituximab) therapy has been reported .
Treatment of other lymphomas and lymphoma with unique presentations
Some types of lymphoma of the skin can be effectively treated with rituximab. Successful treatment of isolated cutaneous relapse of follicular lymphoma with rituximab has been noted . Cutaneous immunocytoma (which most commonly manifests as extremity based clustered erythematous brown papules) can be treated with rituximab . Intravascular lymphoma commonly presents with skin findings of tender indurated plaques and nodules, but has a rare variant manifesting as telangectatic plaques that can be treated by rituximab . Retreatment with rituximab alone can induce sustained remission in patients with follicular lymphoma with multiple extranodal sites of involvement, relapsing soon after primary treatment with fludarabine-rituximab .
Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis responded to treatment with rituximab . EBV-associated cutaneous plasmocytoma in a renal transplant patient has been treated effectively with rituximab , .
Rituximab has been found to be effective therapy of mixed cryoglobulinemia, with decreases in cryoglobulin values and improvement in complement values [34, 35, 36]. In a study of 15 people, Rituximab proved an effective treatment of cryoglobulinemia with skin vasculitis manifestations (ulcers, purpura, and 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 with rituximab is well tolerated, with few 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 cryoglobulinemia . Initial increase in the cryoglobulin level after rituximab therapy for type-II cryoglobulinemia secondary to Waldenstrom macroglobulinemia does not indicate failure of response .
Collagen Vascular Disease
Rituximab is a promising treatment for systemic lupus erythematosus (SLE) [39, 40]. and dermatomyositis . It can be used for long term therapy of SLE  It also might have utility in the treatment of the cutaneous manifestations of lupus  This is even true in treatment resistant cases [44, 45]. Treatment complications exist and include extremely high titers of anti-human chimeric antibody following re-treatment with rituximab in a patient with active systemic lupus erythematosus . Rituximab has been used in childhood systemic lupus erythematosus refractory to conventional immunosuppression .
Complex cases of SLE have abated with rituximab treatment. Catastrophic systemic lupus erythematosus with Rosai-Dorfman sinus histiocytosis has been treated successfully with rituximab . Saigal reported a case of hypocomplementemic urticarial vasculitis and recurrent angioedema in a patient with systemic lupus erythematosus unresponsive to mycophenolate mofetil, high-dose methylprednisolone, and intravenous immunoglobulin; that patient responded rapidly to rituximab . In summary, systemic autoimmune diseases can respond to rituximab .
Many hematological diseases are related to pathologic B-cells and the antibodies that they produce. Unsurprisingly, rituximab, which blocks the function of such B-cells, ameliorates a variety of hematologic diseases. Long-term remission from life-threatening hypercoagulable state associated with lupus anticoagulant (LA) following rituximab therapy has been reported . Rituximab is a useful treatment for adult refractory idiopathic thrombocytopenic purpura . Lian noted a 43-year-old patient who developed factor-V inhibitor 6 months after liver transplantation for primary biliary cirrhosis in association with Sjogren syndrome/systemic lupus erythematosus who suffered from ecchymoses in the lower extremities; rituximab dissipated the factor-V inhibitor after 10 weekly doses of 375-500 mg . B-cell depletion may lead to normalization of anti-platelet, anti-erythrocyte, and antiphospholipid antibodies in systemic lupus erythematosus . Sustained response to rituximab of autoimmune hemolytic anemia associated with antiphospholipid syndrome has been noted . Rituximab was an effective treatment for refractory autoimmune thrombocytopenia in a girl with systemic lupus erythematosus .
Waldenstrom's macroglobulinemia (WM) is a cancer of mature plasma cells, B lymphocytes, that causes overproduction of monoclonal macroglobulin (IgM antibody). It is sometimes referred to as a lymphoplasmacytic disorder. WM often results in the overproduction of IgM, which causes the blood to become too thick. This hyperviscosity interferes with blood flow through small vessels and leads to many of the symptoms of the disease. Some 35-50 percent of WM patients respond to single rituximab therapy, with limited toxicity . Extended rituximab therapy may lead to more major responses than standard dose rituximab in WM .
Rituximab is a useful treatment for pemphigus vulgaris [59, 60, 61]. This in not surprising because pemphigus is an antibody driven disease and rituximab blocks the function of B-cells and the production of antibodies. Rituximab is even effective treatment for recalcitrant, life-threatening pemphigus vulgaris [62, 63, 64, 65, 66, 67]. This is also true in juvenile pemphigus vulgaris . Treatment-resistant pemphigus foliaceus rapidly responds to rituximab .
The use of rituximab can result in the remission of paraneoplastic pemphigus because of its effects on the underlying neoplasm [70, 71, 72, 73]. It is effective treatment for refractory erosive stomatitis secondary to CD20(+) follicular lymphoma-associated paraneoplastic pemphigus [74, 75].
Autoimmune varieties of vasculitis can be effectively treated with rituximab. Rituximab has been found to be a useful adjunct in the treatment of giant-cell arteritis . Eriksson noted nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab . It has been found to be a useful treatment for refractory Wegener granulomatosis , [79, 80, 81]. Keogh noted induction of remission by B-lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis . As vasculitis is a type-III hypersensitivity reaction, which involves antibody immune complex, the decrease of antibody production that rituximab engenders is a useful therapy.
Cutaneous Side effects
The cutaneous side effects of rituximab are frequent but usually not serious. In a study of 356 patients treated in nonrandomized, single-arm studies of rituximab administered as a single agent 44 percent of patient suffered some side effect involving the skin and appendages. Specifically, 15 percent of patients suffered night sweats, 15 percent of patients suffered "skin rash," 14 percent of patients suffered pruritus, and 8 percent suffered urticaria . Observed side-effects in a systemic eight-cycle rituximab therapy in primary cutaneous B-cell lymphomas were two bacterial infections, two patients with shivering during infusion, one patient with sweating for months and one patient with persistent pruritus .
In the trial of 356 patients, 2 percent suffered serious cutaneous side effects. The package insert notes a spectrum of serious side effects that include paraneoplastic pemphigus (an uncommon disorder that is a manifestation of the patient's underlying malignancy), Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis . The onset of the reaction in the reported cases has varied from 1 to 13 weeks following rituximab exposure.
Since rituximab's approval, a variety of serious side effects involving the skin have been reported. Several reports note that rituximab can cause serum sickness . Rituximab-induced vasculitis has been reported . Lowndes reported a case of Stevens-Johnson syndrome after treatment with rituximab; it occurred in a 36-year-old man with relapsed follicular lymphoma. The patient developed mucositis and fevers after the first two injections, followed by a florid maculopapular rash with severe orogenital ulceration after the third infusion. Over several weeks his symptoms progressed with severe cutaneous, orogenital and conjunctival ulceration, leading to visual problems and malnutrition. No improvement occurred with steroids and immunosuppressant therapy .
Buda-Okreglak described a novel, delayed, proinflammatory syndrome that occurred at or near completion of a 4-week dose-intense course with rituximab in a 58-year-old man with Waldenstrom macroglobulinemia; this syndrome mimicked acute rheumatoid arthritis affecting the hands and the knees .
To treat B-cell lymphomas, rituximab (at a dose of 250 mg QW) is sometimes administered with ibritumomab tiuxetan, an immunoconjugate in which the monoclonal antibody ibritumomab is covalently bound to tiuxetan, a high-affinity, linker-chelator for the radioisotopes yttrium-90 (Y-90) or indium-111 (In-111). The antibody moiety of ibritumomab tiuxetan is ibritumomab, a murine IgG1-κ monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes. The tiuxetan chelator provides a stable linkage between the antibody and the radioisotope, permitting radiation to be directed against antigen-positive cells. The β emission from Y-90 induces cell damage by the formation of free radicals in the target and neighboring cells. Severe mucocutaneous reactions, some with fatal outcome, have been reported in association with the ibritumomab tiuxetan therapeutic regimen, which includes rituximab, In-111 ibritumomab tiuxetan, and Y-90.
It is possible that, as an immunosuppressant, rituximab may increase the likelihood for development of cancer. There is one report of Merkel cell carcinoma (MCC) occurring in CLL patients soon after treatment with 2-CdA and/or rituximab, suggesting that this complication rarely observed in CLL patients may have a link with strongly immunosuppressive therapy with 2-CdA and rituximab .
Non cutaneous side effects
Although an extensive discussion of noncutaneous side effects in beyond the scope of this paper, a brief survey is useful for physicians contemplating the use of rituximab. Black box warnings include the following :
Other side effects listed in the package insert include the following:
Certain precautions should be taken when using rituximab . Because rituximab targets all CD20-positive B lymphocytes, malignant and nonmalignant, complete blood counts (CBC) and platelet counts should be obtained at regular intervals during rituximab therapy and more frequently in patients who develop cytopenias. The duration of cytopenias caused by rituximab can extend well beyond the treatment period. Renal toxicity was seen with this drug in combination with cisplatin in clinical trials. Human antichimeric antibody (HACA) was detected in 4 of 356 patients and 3 had an objective clinical response.
Rituximab can increase the risk of infection . In trials, infectious events occurred in 31 percent of patients: 19 percent of patients had bacterial infections, 10 percent had viral infections, 1 percent had fungal infections, and 6 percent were unknown infections. Serious infectious events including sepsis, occurred in 2 percent of patients. Immune/autoimmune events have been reported, including uveitis, optic neuritis in a patient with systemic vasculitis, pleuritis in a patient with a lupus-like syndrome,
Rixuximab has a variety of hematologic side effects. In clinical trials, series cytopenias were reported in 48 percent of patients treated with rituximab; these include: lymphopenia (40 %), neutropenia (6 %), leukopenia (4 %), anemia (3 percent ), and thrombocytopenia (2 %). The median duration of lymphopenia was 14 days (range 1-588 days) and of neutropenia was 13 days (range, 2 to 116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following rituximab therapy were reported.
The most common respiratory system adverse events experienced were increased cough, rhinitis, bronchospasm, dyspnea, and sinusitis. In both clinical studies and post-marketing surveillance, there have been a limited number of reports of bronchiolitis obliterans presenting up to 6 months post-rituximab infusion and a limited number of reports of pneumonitis (including interstitial pneumonitis) presenting up to 3 months post-rituximab infusion, some of which resulted in fatal outcomes.
Rituximab is a promising agent for the treatment of B-Cell related diseases. It has many side effects, some common and some not common. It has transformed the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, and immune or idiopathic thrombocytopenic purpura. As future research defines the role of the B-cell in disease, the uses of rituximab will likely increase.
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