Outcome of low dose cyclophosphamide for induction phase treatment of lupus nephritis, a single center study

Approximately 35 to 50 % patients of systemic lupus erythematosus (SLE) have clinically evident kidney disease at presentation; during follow-up, lupus nephritis (LN) develops in >60 % patients [1‐4]. Overall survival in SLE is 92 % at 10 years after diagnosis; presence of LN reduces survival to approximately 88 % at 10 years [2]. LN affects the clinical outcomes both directly by target organ damage and indirectly through complications of therapy [1]. It is a major cause of end stage renal disease (ESRD) and is associated with a greater than four-fold increase in mortality [1, 5].

Use of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification can serve as a guide to initial therapy of LN [2, 6, 7]. The management of active class III, IV or V nephritis consists of an initial or induction phase of aggressive immunosuppression followed by a prolonged phase of less intense therapy [1, 2, 4, 7‐9]. The current standard for the initial phase treatment consists of steroid and intravenous cyclophosphamide (IVC) or mycophenolate mofetil (MMF) [1‐4, 7, 9‐20]. The NIH trials used IVC at 0.5–1 g/m² monthly for 6 months while the Euro-Lupus Nephritis trial used IVC 500 mg every 2 weeks for 3 months, lowering the dose and duration of IVC without sacrificing the efficacy [11, 13].

In our center, lupus nephritis is routinely treated with steroid and IVC at 500 mg monthly pulse for six months. However, no systematic analysis of the outcome has been carried out so far. In this report, we present our experience with 41 Nepalese patients with lupus nephritis and demonstrate that this dosing is clinically effective in our population. We also analyzed the clinical and pathological data, and related these findings to the outcome.

With the availability of effective treatment options to control aggressive disease in lupus nephritis, the medical community is seeking measures to decrease the toxicity of therapy without compromising efficacy [1, 8, 9, 27]. An ideal therapy for LN would be non-toxic, easy to administer, affordable, would achieve early complete remission, would not require prolonged use, would prevent relapse and essentially cure the disease instead of controlling it. Newer therapeutic options are being explored [5, 28, 29]. Our hospital uses a modified protocol of IVC, discussed before, that is based on local experience, considers the relatively smaller body surface area of our patients and aims to decrease the gonadal toxicity of IVC in young females.

The demographic parameters, symptoms, signs and baseline investigation findings of our cohort in general match with that reported by other workers [3, 6, 25, 26, 30‐36]; anemia was more common in our patients, and hypothyroidism was seen in 12 patients (29.3 %). The baseline eGFR and degree of proteinuria is comparable with the renal findings in other studies, but the mean serum albumin was lower than that observed elsewhere [3, 25, 26, 31]. We had class IV nephritis in 53.7 % of our patients, that is comparable with other studies [3, 25, 26, 36]. Our AI and CI indices also match the findings of mean AI score 8.03 ± 5.12 and mean CI score of 2.84 ± 2.2.17 in a study by Yang et al. [37]. These indices were higher than those reported by Chen et al. [26].

In our study, class IV nephritis patients presented earlier than other classes (p = 0.02) and tended to have higher systolic blood pressure and lower platelet count (p > 0.05); otherwise there was no significant difference between class IV and other classes on any of the other baseline parameters. These findings support the ACR recommendation that all patients with clinical LN, previously untreated, should undergo renal biopsy (unless strongly contraindicated) [2].

Complete remission was achieved in 43.9 % patients in our study; 39.0 % achieved partial remission, 9.6 % died and 7.3 % were lost to follow up. The response rate was 82.9 %. Our response rate was higher than that observed in the ALMS multicenter study, where the response rates were 56.2 % in the MMF group and 53.0 % in the IVC group [3]. In an NIH trial [11], the methylprednisolone and IVC group attained a remission rate of 85 %; in a multicenter Chinese study the CR and response rates to IVC as per NIH protocol were 38.5 % and 82.1 % respectively [26]; these results were very similar to ours. In the Euro-Lupus trial, renal remission was achieved in 71 % of the low-dose group and 54 % of the high-dose group [13]. In the American study by Ginzler et al. [19], response rate to MMF was 52.1 % and in CYC was 30.4 %, rates far lower than what we achieved. In the trial by Chan et al. in 42 Chinese patients, 81 % of the patients in MMF group achieved CR compared with 76 % in the CYC; the response rates were more than 90 % in each [17]. There is one important difference between our study and the other studies. Our patients received a total of 3 grams IVC over six months, while the other studies have used either IVC as per NIH protocol or Euro lupus trial protocol with total of 3 grams of IVC in three months) [11, 13]. The mean dose of prednisolone at last follow up in our study was 11.7 ± 4.2 mg/day, comparable with the mean dose of prednisone on 24^th week in the Ginzler study [19]; however, we appreciate that this is still a high dose which could potentially be associated with significant side effects. These findings suggest that our induction regime could be used in Nepalese lupus nephritis patients. This IVC regime exposes the patients of LN to lower cumulative dose of CYC given over longer duration so that the side effects, especially infections and leukopenia will be decreased without sacrificing efficacy.

Our study had good follow up; only three patients (7.3 %) were lost to follow up. In the ALMS induction trial, only 82.7 % patients remained in the study at 24^th week [3]. In the Ginzler’s study 17.14 % had to be withdrawn from the study, though only 1.43 % were lost to follow up [19].

Infection and leukopenia have always been major limiting factor in lupus therapy. We had four deaths in our study (9.8 %). All of them were class IV, had significant anemia, hypoalbuminemia and markedly reduced eGFR; they died early in the course due to infection complicating severe disease. This corroborates the observation of other workers that severe disease and infection are two important causes of early deaths in lupus [1, 8, 9]. Chan et al. also reported death rate of 10 %, similar to ours [17]. A lower death rate of 3.78 %, was seen in the ALMS induction study [3]; only three deaths out of 140 patients occurred in Ginzler study [19]. This relatively higher death rate in our study compared to those from the West could be because of a relatively poorer support system and higher ambient infection in Nepal. This was observed in the relatively higher infection rates (29.3 %) without higher rates of leukopenia in our patients. The ALMS study reported an infection rate of 10 % in the IVC group and 12 % in the MMF group [3]. Our infection rate is comparable with that encountered by Chan et al. in their study over a decade ago (19 % in MMF group and 33 % in the IVC group) [17]. Pneumonia was the most common infection observed by us (in 10 out of 12 patients). We feel that balancing immunosuppression in aggressive disease against the risk of potentially fatal infection is the art in the management of lupus nephritis. Other adverse events observed in our study were the need for dialysis (in 9.8 %), readmission (in 19.5 %) and leukopenia, AKI and others in 4.87 % each. We did not observe gastrointestinal side effects, significant alopecia or new onset menstrual irregularities; this is likely because of the lower dose of IVC used.

Multiple factors are known to predict outcome in LN [1, 8, 25, 38, 39]. We found that nephrotic range proteinuria and hypoalbuminemia significantly affected the attainment of remission (p < 0.05). Those patients who did not enter remission had higher BP (p > 0.05) and none of the dialyzed patients entered CR (p > 0.05); age and baseline eGFR did not affect remission rates. These differences could simply reflect the relatively small size of our study population. We could not evaluate the influence of gender, race, anti ds-DNA and complements in outcome. Ayodele et al. showed class IV LN was histological predictor of poor renal outcome [25]. We did not see difference in remission rates when class IV was compared to other classes (p = 0.29), however, class IV lupus negatively affected survival in the short term (p = 0.03). We could not find the significant influence of activity and chronicity indices in outcomes (p > 0.05), unlike the findings of other workers [6, 40]. When all the adverse outcomes were combined, the difference between lupus class IV and other classes was not significant (p = 0.25).

The limitations of the present study are that it was an observational single center study with no control group. There was no fixed tapering schedule for prednisolone, some information during follow-up was collected telephonically, and it was a short term study, without long-term follow-up. There are, however, several strengths as well. It is the first prospective study in patients with lupus nephritis in Nepal, with a reasonable sample size and a follow up rate of 92.7 %.

The response rate of 82.9 %, with complete remission in 43.9 %, suggests that the low-dose protocol used in the study may be useful for initial phase treatment of lupus nephritis without compromising efficacy. However, larger, multicenter, multiethnic, randomised, controlled study is required to provide stronger evidence.