Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
Rituximab (Rituxan®, Genentech/ Biogen Idec) is a genetically engineered chimeric murine/human monoclonal antibody directed against CD20, a B lymphocyte-specific antigen. Initially approved for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL), rituximab has been increasingly used to treat a variety of immune-mediated and autoimmune diseases. While anecdotal case reports recommend its “off-label” use in dermatology, randomized clinical trials are required to firmly establish the safety and efficacy of this emerging biologic therapy.
Rituximab, Rituxan®, immune skin disease, monoclonal antibody
In 1994, Reff and colleagues developed a chimeric murine/ human anti-CD20 monoclonal antibody which induced the rapid depletion of CD20+ B lymphocytes in vivo.1 By 1997, rituximab (Rituxan®) was approved by the US FDA for the treatment of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL). Originally developed for the treatment of B cell malignancies, rituximab has since been used to treat a variety of immune-mediated and autoimmune diseases (i.e., rheumatoid arthritis, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura). Herein, we review the potential applications and limitations of rituximab use in dermatology.
Mechanism of Action/ Pharmacology
Rituximab is an immunoglobulin G1 (IgG1) kappa monoclonal antibody composed of a murine variable region (Fab portion) that is fused onto a human constant region (Fc portion). The Fab portion binds specifically to the CD20 antigen, located exclusively on the surface of pre-B and mature B lymphocytes. Once bound, the Fc portion of rituximab recruits immune effector cells to help mediate cell lysis of the CD20+ B lymphocytes via 3 possible mechanisms:
- complement-dependent cytotoxicity (CDC)
- antibody-dependent cell-mediated cytotoxicity (ADCC)
The exact contribution of each mechanism remains unclear, and different mechanisms may prevail in different diseases.2
The use of rituximab results in the rapid depletion of both normal and malignant CD20+ B lymphocytes in the peripheral blood and, to a lesser extent, the lymph nodes.1 The CD20 antigen is not expressed on the surface of hematopoietic stem cells or pro-B cells; thus, the capacity of these precursor cells to regenerate the B lymphocyte population remains intact.1 As the majority of plasma cells fail to express the CD20 antigen, plasma cells are generally spared and serum immunoglobulin levels tend not to fall dramatically.3 Here lies the selective advantage of rituximab.
In patients receiving rituximab intravenously, serum levels are dose-proportional, correlate with patient response to therapy, and increase with each successive infusion.3-5 The half-life of rituximab is also proportional to the dose, increases with each subsequent infusion, and varies greatly from patient to patient. The wide variability in elimination half-lives may reflect differences in tumor burden and changing CD20+ B cell populations with repeated administrations. Though the mechanisms involved in the metabolism and elimination of rituximab are not fully understood, it is postulated that rituximab is degraded nonspecifically in the liver and excreted in the urine.6
In adults, the standard dosing schedule for rituximab is 375mg/m2 given intravenously once per week for 4 consecutive weeks. Premedication with an antipyretic (i.e., acetaminophen) and an antihistamine (i.e., diphenhydramine) should be administered prior to and throughout each infusion to reduce the likelihood of infusion-related reactions.7
In order to minimize the risk of tumor lysis syndrome, bulky tumors require higher doses of rituximab to be staggered over several weeks. As there is a limited number of CD20+ B cells in the normal immune system, an alternate dosing regimen was developed for patients with rheumatoid arthritis (RA). In RA patients, rituximab may be given as two-1000mg intravenous infusions separated by 2 weeks.8
Recently, a few cases of primary cutaneous B-cell lymphoma have been treated successfully with intralesional injections of rituximab. The dose ranged from 1-3mL of a 10mg/mL solution and variable numbers of injections were administered.9-12
Rituximab is currently supplied at a concentration of 10mg/mL in either 100mg (10mL) or 500mg (50mL) single-use vials.7
Adverse Effects/ Drug Interactions
Rituximab is generally well tolerated, though most patients experience mild-to-moderate infusion-related reactions with their first treatment. The most common symptoms include fever (48%), chills (32%), weakness (18%), nausea (17%), headache (13%), pruritus (12%), and rash (11%).7 The symptoms are usually reversible by temporarily discontinuing the infusion and providing symptomatic relief. Infusion-related side-effects tend to diminish or disappear with subsequent infusions.
Severe and potentially fatal adverse events, though rare, have been associated with rituximab therapy. These include severe infusion-related reactions, tumor lysis syndrome, mucocutaneous reactions such as Stevens-Johnson Syndrome (SJS), anaphylaxis, serious pulmonary events, cardiac arrythmias, renal failure, hematological abnormalities, bowel obstruction/perforation, and significant infections, such as bacterial sepsis, reactivation of hepatitis B with fulminant hepatitis, and progressive multifocal leukoencephalopathy (PML).7 With regard to PML, a recent safety warning was issued by the US FDA regarding the development of this potentially fatal viral infection in the central nervous system (CNS) in 2 patients with systemic lupus erythematosus (SLE) who were being treated with rituximab.13 Patients should be urged to seek prompt medical attention if they develop any new neurological symptoms (i.e., changes in vision, balance, or cognition).
The use of rituximab in children and in patients with renal or hepatic failure has not been studied extensively. Rituximab should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (Pregnancy Risk Category C). As human IgG is excreted in breast milk, lactating mothers should be advised to discontinue nursing until circulating blood levels are no longer detectable. Though there have been no formal drug interaction studies performed with rituximab, the concomitant use of rituximab and cisplatin should be avoided as this combination has been associated with renal failure.7
Although approved for the treatment of relapsed or refractory low-grade or follicular NHL, the list of “off-label” indications for rituximab continues to grow. Case reports and small case series document its use in the dermatologic literature. Potential indications are listed in Table 1, and select dermatologic diseases are reviewed.
Primary Cutaneous B-Cell Lymphoma (PCBCL)
In a recent review, more than 40 individual cases of PCBCL were treated with rituximab intravenously.2 In the two largest case series, 10 patients were enrolled in each study. The overall response rate was 70% (20% complete response, 50% partial response) in the first study and 90% (70% complete response, 20% partial response) in the second study.14,15
Nineteen cases of PCBCL treated with intralesional rituximab were found in the literature.9-12,16 A complete response was seen in 84% of patients, while a variable response was seen in the remaining 16%. Relapse rates were found to be higher with intralesional therapy when compared with standard systemic therapy.
- Primary cutaneous B-cell lymphoma
- Immunobullous disease
- Pemphigus vulgaris
- Pemphigus foliaceus
- Paraneoplastic pemphigus
- Bullous pemphigoid
- Mucous membrane pemphigoid
- Epidermolysis bullosa acquisita
- Chronic graft versus host disease
- Systemic lupus erythematosus
- Small vessel vasculitis
- Hypocomplementemic urticarial vasculitis Antineutrophil cytoplasmic antibody-vasculitis
- Schnitzler syndrome
- Waldenstrom’s macroglobulinemia
Table 1: Potential dermatological uses of rituximab
Pemphigus Vulgaris (PV)
Multiple case reports suggest that rituximab is an effective treatment option for PV. In a recent review of 18 patients with refractory PV, 3 patients (17%) experienced complete remission (no further therapy required), 4 patients (22%) experienced clinical remission (healing of all lesions but further therapy required), and 11 patients (61%) experienced partial remission.17 The standard course of rituximab was administered in all but 2 patients who received additional infusions. Serious infections occurred in 4 of the 18 patients, of which 1 was fatal. Notably, patients were allowed to remain on concomitant immunosuppressive therapy.
In 11 patients with extensive, recalcitrant PV, efficacy was noted using a combination of rituximab and intravenous immunoglobulin (IVIG).18 Rituximab (375mg/m2) was administered once weekly for 3 weeks and followed by an infusion of IVIG (2g/kg) in the fourth week. The cycle was repeated once and, upon completion of the induction therapy, monthly rituximab and IVIG infusions were given for 4 consecutive months. Of the 11 patients, 9 patients had a clinical remission lasting between 22–27 months; no serious adverse events were noted. Taken together, the data suggest that rituximab may be effective for patients with severe, refractory PV.
Other Immunobullous Diseases
Case reports document the successful use of rituximab in other immunobullous diseases, including: pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita.19-24 In most cases, complete remission was achieved with the standard therapeutic regimen. However, several cases of PNP have shown resistance to rituximab therapy.
Chronic Graft Versus Host Disease (CGVHD)
The use of rituximab in the treatment of refractory CGVHD has been documented in multiple case series with mixed results. In one case series, 8 patients with extensive CGVHD were treated with the standard course of rituximab.25 Four of these patients (50%) responded to rituximab therapy whereas the other 4 patients (50%) were nonresponders. In the largest series of 21 patients with steroid-refractory CGHVD, the overall response was 70% and included 2 patients who experienced a complete remission.26 In these patients, rituximab facilitated a statistically significant reduction in the median dose of steroid use from 40mg/day to 10mg/day (p<0.001). A steroid-sparing effect was therefore demonstrated in patients with CGVHD.
In an open-label pilot study of 6 patients with longstanding refractory DM, patients received four weekly intravenous infusions of rituximab at a dose of 100mg/m2 (three patients) or 375mg/m2 (three patients).27 All patients experienced marked clinical improvement in both cutaneous and muscle disease. Overall, rituximab was well tolerated in this patient group and no major adverse events were reported.
In another study, three patients with refractory DM experienced marked clinical improvement of their cutaneous disease.28 In this small cohort, the heliotrope rash and the violaceous poikiloderma were most responsive to therapy.
Other Dermatologic Disease
Rituximab has been shown to benefit other dermatologic conditions including systemic lupus erythematosus (SLE), cryoglobulinemia, Waldenstrom’s macroglobulinemia, Schnitzler syndrome, vitiligo, angioedema as well as cutaneous vasculitides such as small vessel vasculitis, hypocomplementemic urticarial vasculitis and antineutrophil cytoplasmic antibody-associated vasculitis.21,29-31
Though approved for the treatment of low-grade or follicular NHL, rituximab has demonstrated therapeutic efficacy in a variety of recalcitrant immune-mediated and autoimmune skin disorders. Few therapeutic failures have been described, possibly resulting from long-lived CD20- plasma cells capable of producing pathogenic autoantibodies. In most patients, rituximab is safe and tolerable with infusion-related reactions and infectious complications dominating the adverse-event profile. Clinical trials with long-term follow-ups are warranted to firmly establish the efficacy, tolerability and dosing of rituximab in the treatment of dermatologic disease.
- Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83(2):435-45 (1994 Jan).
- Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol 56(1):e55-79 (2007 Jan).
- Maloney DG, Liles TM, Czerwinski DK, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84(8):2457-66 (1994 Oct).
- McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16(8): 2825-33 (1998 Aug).
- Berinstein NL, Grillo-López AJ, White CA, et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 9(9):995-1001 (1998 Sep).
- Cartron G, Blasco H, Paintaud G, Watier H, Le Guellec C. Pharmacokinetics of rituximab and its clinical use: thought for the best use? Crit Rev Oncol Hematol 62(1):43-52 (2007 Apr).
- Canadian Pharmacists Association. Compendium of pharmaceuticals and specialties: the Canadian drug reference for health professionals. Toronto: Canadian Pharmacists Association (2006).
- Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum 54(9):2793-806 (2006 Sep).
- Heinzerling L, Dummer R, Kempf W, Schmid MH, Burg G. Intralesional therapy with anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell lymphoma. Arch Dermatol 136(3):374-78 (2000 Mar).
- Paul T, Radny P, Krober SM, Paul A, Blaheta HJ, Garbe C. Intralesional rituximab for cutaneous B-cell lymphoma. Br J Dermatol 144(6):1239-43 (2001 Jun).
- Roguedas AM, Watier H, Paintaud G, de Muret A, Vaillant L, Machet L. Intralesional therapy with anti-CD20 monoclonal antibody rituximab: local and systemic efficacy in primary cutaneous B-cell lymphoma. Br J Dermatol 152(3):541–4 (2005 Mar).
- Kerl K, Prins C, Saurat JH, French LE. Intralesional and intravenous treatment of cutaneous B-cell lymphomas with the monoclonal anti-CD20 antibody rituximab: report and follow-up of eight cases. Br J Dermatol 155(6):1197-200 (2006 Dec).
- FDA warns of safety concern regarding rituxan in new patient
- population. Retrieved January 30, 2007, from http://www.fda.gov/bbs/topics/NEWS/2006/NEW01532.html.
- Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden and stabilization of disease by systemic therapy with anti-CD20 monoclonal antibody (rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer 89(8):1835-44 (2000 Oct).
- Gellrich S, Muche JM, Wilks A, et al. Systemic eight-cycle anti-CD20 monoclonal antibody (rituximab) therapy in primary cutaneous B-cell lymphomas–an applicational observation. Br J Dermatol 153(1):167-73 (2005 Jul).
- Fink-Puches R, Wolf IH, Zalaudek I, Kerl H, Cerroni L. Treatment of primary cutaneous B-cell lymphoma with rituximab. J Am Acad Dermatol 52(5):847-53 (2005 May).
- Schmidt E, Hunzelmann N, Zillikens D, Brocker EB, Goebeler M. Rituximab in refractory autoimmune bullous diseases. Clin Exp Dermatol 31(4):503-8 (2006 Jul).
- Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355(17):1772-9 (2006 Oct).
- Goebeler M, Herzog S, Bröcker EB, Zillikens D. Rapid response of treatment-resistant pemphigus foliaceus to the anti-CD20 antibody rituximab. Br J Dermatol 149(4):899–901 (2003 Oct).
- Arin MJ, Engert A, Krieg T, Hunzelmann N. Anti-CD20 monoclonal antibody (rituximab) in the treatment of pemphigus. Br J Dermatol 153(3):620-5 (2005 Sep).
- Fatourechi MM, el-Azhary RA, Gibson LE. Rituximab: applications in dermatology. Int J Dermatol 45(10):1143-55 (2006 Oct).
- Schmidt E, Benoit S, Bröcker EB, Zillikens D, Goebeler M. Successful adjuvant treatment of recalcitrant epidermolysis bullosa acquisita with anti-CD20 antibody rituximab. Arch Dermatol 142(2):147–50 (2006 Feb).
- Crichlow SM, Mortimer NJ, Harman KE. A successful therapeutic trial of rituximab in the treatment of a patient with recalcitrant, high-titre epidermolysis bullosa acquisita. Br J Dermatol 156(1):194-6 (2007 Jan).
- Schmidt E, Seitz CS, Benoit S, Bröcker EB, Goebeler M. Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Br J Dermatol 156(2):352-6 (2007 Feb).
- Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 9(8):505-11 (2003 Aug).
- Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108(2):756-62 (2006 Jul).
- Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum 52(2):601-7 (2005 Feb).
- Dinh HV, McCormack C, Hall S, Prince HM. Rituximab for the treatment of the skin manifestations of dermatomyositis: a report of 3 cases. J Am Acad Dermatol 56(1):148-53 (2007 Jan).
- Risselada AP, Kallenberg CGM. Therapy-resistant lupus skin disease successfully treated with rituximab. Rheumatology 45(7):915-16 (2006 Jul).
- Chung L, Funke AA, Chakravarty EF, Callen JP, Fiorentino DF. Successful use of rituximab for cutaneous vasculitis. Arch Dermatol 142(11):1407-10 (2006 Nov).
- Saigal K, Valencia IC, Cohen J, Kerdel FA. Hypocomplementemic urticarial vasculitis with angioedema, a rare presentation of systemic lupus erythematosus: rapid response to rituximab. J Am Acad Dermatol 49(5 Suppl):S283-5 (2003 Nov).