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Rituximab: A New Treatment for Recalcitrant PV?

Rituximab (RTX) is anti-CD20 chimeric antibody that selectively targets B cells.  CD20 is a molecule that functions as an antigen for it.  CD20 is expressed on mature antibody producing B cells, but not on plasma cells.(1) The FDA has approved the use of Rituximab for the treatment of B cell lymphomas.(2) Since the pathogenic and clinical manifestations of PV appear to be antibody related, it could be hypothesized that eliminating the pathogenic antibody and the cells that produce it, might be more effective than general nonspecific immune suppression.  This is the rationale for using Rituximab in treating pemphigus vulgaris.  Indeed, success with the Rituximab has been observed in many autoimmune diseases which are mediated by antibodies such as systemic lupus erythematosus and immune thrombocytopenic purpura.(3)

In a recent review of the available published literature in the English language on Rituximab was done. (4)  There were 17 patients presented in ten different studies.  These patients had been treated with RTX using the lymphoma protocol.  In this protocol, patients are given four weekly infusions.  The dose is 375 mg/m2 for each infusion.  The results were variable, but overall it appeared that 88% of the patients were free of lesions, for at least a six months follow-up period.  Unfortunately, many of the patients were treated simultaneously with conventional immunosuppressive therapy (CIST).  In many of them, the use of RTX allowed for lowering the dose of Prednisone.  One of the major problems associated with RTX in these patients was infection.  Four patients had serious infections and in addition one patient died from it.  None of these patients got intravenous immunoglobulin (IVIg).

Since the cumulative literature supported the use of RTX in producing a positive clinical outcome, we decided to study the use of RTX in recalcitrant pemphigus vulgaris.  Our major concerns were (i) can the use of RTX eliminate conventional immunosuppressive therapy, and (ii) could RTX therapy produce prolonged and sustained clinical remissions.  Recently we have published data on 11 patients in the October 26, 2006 issue of the New England Journal of Medicine.(5)  To the readers of the Quarterly, it would be important to identify the group of patients we studied by providing some key characteristics.  The important features of this group were that they all had been treated initially with Prednisone and other immunosuppressive agents.  The mean daily dose of Prednisone was 125 mg.  All had been treated with mycophenolate morfetil, 10 with azathioprine, 9 with methotrexate and 6 with cyclophosphamide. 

Since the patients did not respond to conventional immunosuppressive therapy, they were subsequently treated with IVIg.  The IVIg was not totally effective.  To augment the effect of IVIg, Dapsone with methotrexate was added to the IVIg.  The mean duration of all previous systemic therapy, prior to the use of Rituximab, was 68.8 months, indicating that the disease had been present for 6 – 7 years and had not responded to all of the known therapies for PV.  These patients also had extensive disease involving the skin and multiple mucous membranes.  The patients were treated with RTX in a newly designed protocol never published before or used to treat any other disease.  The patients were given the same dose of RTX as in previous studies (375 mg/m2).  The protocol was as follows:

Prior to the initiation of RTX, the patient’s got one cycle of IVIg.  Then during the first month of therapy, for the first three weeks, they received weekly infusions of RTX.  In the fourth week, they received one cycle of IVIg.  This same procedure was repeated in the second month. In the 3rd, 4th, 5th, and 6th month, the patients received only one infusion of RTX followed by one cycle of IVIg.  Hence, the patients got a total of 10 infusions of RTX in this particular protocol.
Shortly after the initiation of RTX, the patient’s B cell counts were reduced to zero.  Hence, the IVIg was given primarily to assist preventing infection.  In addition, it was also used as an immunomodulatory agent.  It was hypothesized that if the pathogenic antibody and the cells producing it were no longer present, this would provide the immune system an opportunity to regulate itself to the predisease state.

Indeed all of the 11 patients have stayed in remission.  The mean duration of remission has been 31.1 months.  Two patients had recurrences.  In both patients, the recurrences were treated with only RTX and the patients went into a prolonged clinical remission.

It is critical to be aware of the fact that RTX warrants the very rigorous prescreening procedure.  Prior to initiation of RTX therapy, we have always obtained clearance from the primary care physician of the patient.  In addition, an oncologist has evaluated the patients requiring a CT scan of the neck, chest, abdomen and pelvis to exclude any existing lymphomas.  Evaluation of liver and kidney functions and the serological tests for various infections was done.  During the RTX therapy, CBC’s, chemistries, but most importantly, peripheral blood T & B cells were monitored on a very regular basis.  Until the B cells have returned to normal, monthly infusions of IVIg were given.  Once the B cells returned to normal, the IVIg protocol was completed in which the patients received infusions at 6, 8, 10, 12, 14, and 16 week intervals.(6)  We believed this was essential to help restore the immune system to its normal balance.  Recurrences have not been seen to date in all of those patients in whom this protocol was completed.   Hence the ability to complete the IVIg protocol is an integral component of this therapy and needs to be emphasized when initiating the therapy.

Hence, this study of a limited number of patients clearly indicated that RTX used with IVIg, according to this protocol, produces long-term clinical remission.  None of the patients had any serious side effects and none of them developed any infections.  Therefore, there is optimism to indicate that RTX would be a valuable form of therapy in treating patients who have recurrent disease who are non-responsive to conventional immunosuppressive therapy and only partially responsive or non-responsive to IVIg therapy.  This protocol is certainly not the only protocol that could be effective. Indeed studies in the future might provide valuable information on the use of RTX using different protocols. 

In closing it is important to emphasize two issues to the readership.  First, that RTX is not for every PV patient.  Second, RTX is not a benign harmless drug.  Its use can have serious consequences.  Experience with the drug is limited and additional studies that must include long- term follow-up are critical.  If you think you are an appropriate candidate for RTX, please speak to your dermatologist.

Dr. Ahmed can be reached at [email protected]

References
1. Maloney DG, Smith B, Rose A.  Rituximab: mechanism of action and resistance.  Semin Oncol 2002;29(Suppl 2):2-9.
2. Rastetter W, Molina A, White CA.  Rituximab: expanding role in therapy for lymphomas and autoimmune diseases.  Annul Rev. Med. 2004;55:477-503.
3. Chambers SA, Isenberg D.  Anti-B cell therapy (Rituximab) in the treatment of autoimmune diseases.  Lupus 2005;14:210-4.
4. Abdul Kader El Tal, MD, Marshall R. Posner, MD, Zachary Spigelman, MD, and A. Razzaque Ahmed, MD.  Rituximab:  A monoclonal antibody to CD 20 used in the treatment of pemphigus vulgaris.  JAAD September 2006;55(3):449-466.
5. A. Razzaque Ahmed, M.D., Zachary Spigelman, M.D., Lisa A. Cavacini, Ph.D., and Marshall R. Posner, M.D.  Treatment of Pemphigus Vulgaris with Rituximab and Intravenous Immune Globulin.  N Engl J Med. 2006;355:1772-9
6. A. Razzaque Ahmed, MD, DSc; Mark V. Dahl, MD; for the Consensus Development Group.  Consensus Statement on the Use of Intravenous Immunoglobulin Therapy in the Treatment of Autoimmune Mucocutaneous Blistering Diseases.  Arch Dermatol. 2003, Aug;139:1051-1059.
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