The regimen of systematically administered cyclophosphamide and rituximab described here minimized the need for daily corticosteroid therapy over a sustained five years of follow up. While compliance with the admissions for rituximab and cyclophosphamide was easily monitored and assured, only routine efforts were made to encourage compliance with the daily dosage of corticosteroids and hydroxychloroquine [After six years one patient developed recurrent hematuria and a decreased C3 level which resolved following one additional set (two doses two weeks apart) of rituximab and cyclophosphamide infusions and has not recurred in eighteen months of further follow-up. A second patient, who had become ANA negative became ANA positive and progressively developed additional antibodies including antibodies to Sm during the sixth year. This patient elected to be retreated with one set of rituximab and cyclophosphamide infusions following which she no longer has antibodies to Sm, but remains ANA positive].
Intravenous cyclophosphamide is a well established alkylating agent which has long been utilized for the treatment of childhood onset SLE [8–11]. Although it is recognized as a potent antimetabolite the precise mechanism of its efficacy in SLE is unknown . While previous studies have demonstrated that the systematic administration of intravenous cyclophosphamide provides significant relief for patients with SLE, significant concern remains regarding the long term toxicity of cyclophosphamide [12, 13].
Although there are many prior case reports of improvement following a single treatment with cyclophosphamide and rituximab , there is only one prior report of the risks and benefits of systematically administering this therapy which utilized a different regimen and has shorter follow-up . Rituximab has been demonstrated to efficiently eliminate the circulating pool of CD20 positive B cells, but does not eliminate the entire CD20 positive population in the body . While B cells likely play an important role in the manifestations of SLE, the failure of controlled trials utilizing rituximab alone indicates that CD20 positive B cells do not act alone in the pathogenesis of SLE .
There was a sustained improvement with the combination of rituximab and cyclosphosphamide despite a reduction in the total cyclophosphamide dosage from 17 gms/M2 in the protocol previously utilized [10, 11] to 6.75 gms/M2 or less (a reduction of over 60%). All of our patients were stable on a low daily dose of prednisone which was not associated with cushingoid faces or other clinically evident adversity within one year of starting therapy.
Mycophenolate mofetil has been shown to be effective for lupus nephritis in a number of controlled trials . This regimen has not been compared to mycophenolate mofetil. It is simply noted that satisfactory results with mycophenolate mofetil are dependent on compliance which is inhibited by gastrointestinal side effects . The package insert notes that mycophenolate mofetil is to be administered twice daily despite digestive side effects reported in more than twenty percent of patients .
This remains only a small number of patients. Nonetheless, none of the twelve patients reported have developed significant corticosteroid related complications and none manifest a "cushingoid" appearance. All report feeling, "like I don't have lupus anymore." The maximum current dose of prednisone is 10 mgs/day. In contrast to patients receiving seventeen doses of cyclophosphamide at 1 gm/M2 and hence a total dose of 17 gms/M2 over three years, these patients received at most 6.75 gms/M2 of cyclophosphamide over eighteen months. Similar results have been obtained for the patients subsequently receiving this regimen, but the emphasis of this manuscript is the sustained response.
Although we have Black patients receiving this regimen, none have yet completed five years of follow-up. There is concern that disease severity and medication efficacy may vary between races in patients with SLE .
The major advantage of this regimen was the ability to rapidly reduce the dosage of corticosteroids without disease flare and prevent (or rapidly resolve) the development of Cushingoid faces and other complications of corticosteroid therapy. All patients were compliant with the need for hospital admissions at the specified intervals and any noncompliance would have been immediately evident. While patients admit to occasionally forgetting their current dosage of prednisone (in most cases 5 mg daily) they do not report any resistance to this low dosage. It is uncertain whether it in fact remains necessary .