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Rituxan and IVIG Resolve Treatment-Resistant Pemphigus


BOSTON -- For patients with the potentially fatal mucocutaneous blistering disease pemphigus vulgaris, a combination of Rituxan (rituximab) and intravenous immune globulin may succeed where other therapies have failed.

BOSTON, Oct. 25 -- For patients with the potentially fatal mucocutaneous blistering disease pemphigus vulgaris, a combination of Rituxan (rituximab) and intravenous immune globulin may succeed where other therapies have failed.

Nine of 11 patients with severe pemphigus vulgaris refractory to conventional therapy had remissions lasting up to three years when they were treated with a combination of Rituxan and IVIG, reported A. Razzaque Ahmed, M.D, of the Center for Blistering Diseases at New England Baptist Hospital here, and colleagues.

Two additional patients had complete resolution of lesions after additional infusions of Rituxan alone, and remained in remission. Rituxan is approved for indolent non-Hodgkin's lymphomas and rheumatoid arthritis. It is an anti-CD20 monoclonal antibody that depletes pathogenic B cells.

"No observable side effects were associated with the use of rituximab and intravenous immune globulin, and therapy with these two agents resulted in sustained and complete remission in nine of 11 patients and eventually in complete control of the disease in all 11 patients," the authors wrote in the Oct. 26 issue of the New England Journal of Medicine.

All patients were ultimately able to discontinue all treatment, the investigators reported.

Pemphigus vulgaris is an autoimmune disease affecting skin, the oral cavity, and other mucosal surfaces. Patients with the disease have been shown to have serum antibodies to desmoglein 3 (keratinocyte cell-surface antigen), a cellular adhesion molecule in skin, and these antibodies have been shown to be pathogenic, the authors noted.

Standard therapy for pemphigus vulgaris includes high-dose corticosteroids and immunosuppressants, and/or IVIG.

"This combination frequently causes long-term immuno-suppression, the consequences of which are now the most common cause of death in patients with pemphigus vulgaris," the authors wrote. "Patients who do not have a response to corticosteroids plus immunosuppressive agents or who have severe side effects from this therapy have been successfully treated with intravenous immune globulin, which can be used as monotherapy and can produce long-term remissions."

But some patients, like the 11 included in their study, do not respond to IVIG either, prompting the investigators to explore whether Rituxan alone or in combination with IVIG could provide a clinical benefit.

The investigators enrolled patients with refractory pemphigus vulgaris involving 30% or more of their body-surface area, three or more mucosal sites, or both, who had either no response or poor response to both conventional therapy and intravenous immune globulin.

Patients first received induction therapy with two cycles of intravenous Rituxan at 375 mg/m2 once weekly for three weeks, and intravenous immune globulin at 2 g/kg in the fourth week.

The patients then received once-monthly infusions of rituximab and intravenous immune globulin for four consecutive months. The investigators monitored titers of serum antibodies against keratinocytes, and numbers of peripheral-blood B cells.

They found that nine of the 11 patients had rapid resolution of lesions, with clinical remissions ranging from 22 to 37 months (mean 31.1 months).

"These patients discontinued all conventional immunosuppressive therapy and were free of pemphigus lesions during the period of remission," the authors wrote.

One patient had a recurrence six months after the 10th infusion of Rituxan and was given an additional infusion of Rituxan alone for three consecutive weeks. This patient had a complete resolution of lesions within six weeks of starting on the extra infusion, and remained disease free with no systemic therapy at 24 months.

The 11th patient also had a recurrence of disease six months after the 10th infusion of Rituxan, and this patient, too, received three additional weekly infusions of Rituxan.

This patient had another widespread recurrence eight months later and was treated with three more week Rituxan infusion, following which there was a complete clinical resolution of disease. The patient remained free of disease with no systemic therapy for 15 months.

The treatment also allowed five patients who had been unable to work because of the disease to resume full employment, the investigators noted.

When they looked at serum markers, they found that titers of pathogenic IgG4 anti-keratinocyte antibodies decreased rapidly in the nine patients with rapid resolution of disease, and showed an up-and-down course in the two patients who required additional infusions.

They also found that while peripheral-blood B cells became undetectable shortly after patients were started on Rituxan, they returned to normal values eight to 12 months after the end of therapy.

There were no clinically significant side effects of Rituxan therapy in the study, including infections, the investigators noted.

"Intravenous immune globulin alone can produce long-term clinical and serologic remissions in patients with pemphigus vulgaris, " Dr. Ahmed and colleagues wrote. "However, it did not do so in our patients. For this reason, we believe that the dramatic and rapid clinical responses we observed can be attributed to rituximab and possibly to synergistic effects of intravenous immune globulin. The long-term remissions in these patients could be due in part to the transient elimination of B cells by rituximab in combination with the regulatory effects of intravenous immune globulin."

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