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Gabriella Moroni, Beniamina Gallelli, Silvana Quaglini, Giovanni Banfi, Emilio Rivolta, Piergiorgio Messa, Claudio Ponticelli, Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up, Nephrology Dialysis Transplantation, Volume 21, Issue 6, June 2006, Pages 1541–1548, https://doi.org/10.1093/ndt/gfk073
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Abstract
Background. Whether corticosteroid and immunosuppressive therapy may be safely withdrawn in patients with proliferative lupus nephritis is still unclear.
Methods. In 32 patients with biopsy-proven proliferative lupus nephritis previously put into remission, therapy was gradually tapered off.
Results. When immunosuppressive therapy was stopped (median: 38 months; 25th–75th percentile: 24–81 months, after biopsy), 24 patients were in complete remission and eight had a median proteinuria of 1.05 g/24 h (25th–75th percentile: 0.91–1.1 g/24 h) with normal renal function. After stopping therapy, patients were followed for a median of 203 months (25th–75th percentile: 116–230 months). Fifteen patients (Group 1) never developed lupus activity. The other 17 patients (Group 2) developed lupus exacerbations in a median of 34 months (25th–75th percentile: 29–52 months) after stopping therapy and were re-treated. The only significant differences between the two groups were the longer median durations of treatment, 57 months (25th–75th percentile: 41.5–113.5 months) vs 30 months (25th–75th percentile: 18–41 months; P<0.009), and remission, 24 months (25th–75th percentile: 18–41) vs 12 months (25th–75th percentile: 7–20 months; P<0.02), before stopping therapy in Group 1 than in Group 2. At last follow-up, 12 patients of Group 1 were in complete remission, two had mild proteinuria and one had died. In Group 2, one patient died, 14 were in complete remission, one had mild proteinuria and in another patient serum creatinine doubled.
Conclusions. Some patients with severe lupus nephritis who enter stable remission can be maintained without any specific treatment for many years. Those patients who have new flares can again go into remission with an appropriate treatment. The longer the treatment and remission before withdrawal, the lower the risk of relapse.
Introduction
There is agreement that early diagnosis and aggressive treatments of lupus exacerbations are of paramount importance in order to prevent the development of irreversible lesions. In fact, it has become clear that renal flares represent a strong predictor of renal insufficiency, particularly when they are associated with an acute renal dysfunction [1,2]. Nephritic flares are common even in patients with complete response to therapy, but they do not necessarily result in loss of kidney function if treated with additional immunosuppressive agents [1,3].
Instead, there is less agreement about the optimal maintenance treatment. Many units use intravenous cyclophosphamide pulses or a combination of corticosteroids and purine synthesis inhibitors in order to quench the activity of systemic lupus erythematosus (SLE). However, the prolonged exposure to corticosteroids and/or immunosuppressive drugs can cause invalidating or even life-threatening complications in the long-term. Premature atherosclerosis is frequent in SLE patients [4,5]. The incidence of myocardial infarction is about five times higher in patients with lupus than in the general population and in young women the age-specific incidence is increased by a factor of 50 [6]. With only a few exceptions [7], the majority of studies have found that the development of cardiovascular complications is associated with the doses and the duration of corticosteroid therapy [8,9]. Diabetes, myopathy, ocular complications and osteoporosis are also frequently found complications of long-term steroid therapy [10]. Aesthetic disfiguration and obesity are often the reason for poor compliance in young women. Cyclophosphamide can induce ovarian failure, precluding the possibility of a pregnancy [11]. Moreover, cyclophosphamide and azathioprine may favour the development of infection, bone marrow toxicity and malignancy.
In 1988, we reported that the complete withdrawal of these agents after a long period of inactive disease was well tolerated in 14 patients with lupus nephritis as only one patient developed a renal exacerbation 2 years after discontinuation of therapy [12]. However, conflicting results have been reported in the few attempts of discontinuing therapy [13–17], so that it is still uncertain whether and when treatment can be actually stopped in patients with proliferative lupus nephritis.
In this retrospective study, we report the long-term clinical outcome of 32 patients with type III–IV lupus nephritis in whom corticosteroids and cytotoxic agents were progressively tapered off after stable remission of renal disease. In this series, seven patients are included who were already reported in our previous report, in whom the follow-up was updated in 2005. We compared the outcome of these patients to that of 12 patients who developed a renal or an extra-renal flare when therapy was progressively reduced to very low dosage and to that of 50 patients who were not selected for interrupting treatment.
Subjects and methods
Participants
We selected from 102 Italian patients with SLE and histological diagnosis of proliferative nephritis admitted, to our unit between 1973 and 2004 for this retrospective study 32 patients who had corticosteroids and cytotoxic agents completely discontinued for ≥6 months, 12 patients in whom an attempt to discontinue treatment failed and 50 patients who never interrupted therapy. Eight patients with a creatinine clearance <20 ml/min at presentation were excluded from the study. At presentation, all patients fit the diagnosis of SLE according to the American College of Rheumatology criteria [18]. Lupus nephritis was classified according to WHO classification [19]. Activity and chronicity indices were calculated according to Austin et al. [20].
Interventions
In patients with stable, complete or partial remission (see definitions), corticosteroid and/or immunosuppressive agents were progressively reduced. Those patients who did not show any sign of renal or extra-renal activity continued to have therapy reduced. An attempt to stop therapy was begun when lupus nephritis remained inactive (normal serum creatinine, proteinuria <1 g/day, inactive urine sediment, no extra-renal signs of active SLE) for ≥6 months. After that period, prednisone was reduced to 5 mg/day and azathioprine to ≤50 mg/day. After therapy was stopped, patients were seen and biological parameters were checked every 7–10 days for the first 2 months, every fortnight for 4 months, every month for another 6 months and then every 2–3 months.
Patients who could stop therapy were subdivided into two groups. Group 1 included patients who never showed any signs of systemic or renal activity during the follow-up and Group 2 included those patients who showed SLE flares at some time during the follow-up. In a third group of patients who were unable to discontinue treatment, the main outcome measures of renal disease were also reported.
Definitions
Renal insufficiency was taken as creatinine clearance <60 ml/min and nephrotic syndrome as proteinuria >3.5 g/24 h with plasma albumin <3 g/dl. In non-nephrotic proteinuria, proteinuria was between 0.21 and 3.5 g/24 h. A patient was considered to have arterial hypertension when supine diastolic blood pressure was >90 mmHg and/or systolic blood pressure was >140 mmHg in three consecutive measurements.
Nephritic flare was taken as a sudden increase in plasma creatinine of ≥30% over the last value, associated with nephritic urinary sediment and increased proteinuria. Proteinuric flare was an increase in proteinuria without modification of plasma creatinine. Proteinuria had to increase by ≥2 g/day if the basal proteinuria was <3.5 g/day or had to double if the patient already had nephrotic proteinuria.
Renal failure was defined as a doubling of plasma creatinine lasting for ≥6 months, with plasma creatinine ≥2 mg/dl and without any improvement over time. Complete renal remission was recorded when plasma creatinine ≤1.2 mg/dl, proteinuria <0.2 g/24 h and urinary red blood cells <5 per high power field (HPF). Partial remission was noted when plasma creatinine <1.2 mg/dl, proteinuria 0.21–2 g/day and urinary red blood cells <5 per HPF.
Statistical methods
Since the distribution of the variables showed high non-normality, the distribution median and 25th–75th interquartile ranges (IQR) were used for descriptive analysis. For the same reasons, t-test and the non-parametric Wilcoxon test were used to investigate differences between patients of Groups 1 and 2 and between patients who stopped and those who never stopped therapy. Cross-tabulated data were analysed by chi-square test or by Fisher's test when the expected cell count was less than five.
Results
Among 102 patients with proliferative lupus nephritis followed in our unit, an attempt to completely withdraw therapy was made in 44 patients with prolonged, complete or partial remission. However, 12 patients in whom therapy was progressively reduced developed a renal (eight patients) or an extra-renal flare (four patients). At the onset of lupus nephritis these patients had received an induction treatment of three methylprednisolone pulses followed by oral prednisone associated in four patients with oral cyclophosphamide (1.5–2 mg/kg/day) for 2 months, and then azathioprine and low-dose prednisone. All these patients were in complete remission when therapy was progressively reduced. Renal flares that occurred 1–5 months after prednisone reduction to very low dosage (2.5 or 5 mg/day) were treated as follows: three patients were treated with reinforcement of prednisone to 0.5 mg/kg/day; the other nine patients were treated with three intravenous methylprednisolone pulses (0.5 g each) followed by oral prednisone 0.5 mg/kg/day in all patients; cyclophosphamide (1.5 mg/kg/day) was added in two patients, azathioprine (2 mg/kg/day) in two patients and cyclosporin (2 mg/kg/day) in two patients. At the last observation (median: 174.4 months; IQR: 139.2–201.2 months, after the diagnosis of lupus nephritis) all patients were alive, 11 were in complete remission and one patient had non-nephrotic proteinuria. One patient had a non-fatal myocardial infarction.
The remaining 32 patients in whom therapy was successfully withdrawn were divided into two groups, according to the absence (Group 1) or the development of flares (Group 2) during the subsequent follow-up. The only significant differences between the two groups were the length of the previous treatment and of remission, which were significantly longer in Group 1 than in Group 2 (Table 1).
. | Group 1 . | Group 2 . | P-value . |
---|---|---|---|
Gender (female/male) | 14/1 | 16/1 | NS |
Age (years) | 26 (21.5–30.5) | 31 (23–35) | NS |
WHO class IV–IV + V | 12/1 | 14/0 | NS |
WHO class III–III + V | 1/1 | 3/2 | NS |
Activity index | 10 (8.2–13.5) | 8 (5–9) | NS |
Chronicity index | 2 (2–3) | 2 (0–2) | NS |
Plasma creatinine (mg/dl) | 1.06 (0.85–1.5) | 1.2 (1–1.8) | NS |
Proteinuria (g/24 h) | 2.6 (1.3–4.7) | 4.9 (3–7) | NS |
Arterial hypertension | 53% | 70% | NS |
Fever | 53% | 70% | NS |
Arthralgia | 87% | 53% | NS |
Malar rash | 60% | 59% | NS |
Serositis | 13% | 18% | NS |
Cerebritis | 13% | 12% | NS |
Lymphadenopathy | 20% | 29% | NS |
MP pulse therapy | 80% | 82% | NS |
Oral prednisone | 20% | 18% | NS |
Immunosuppressive therapy | 93% | 59% | NS |
Time of first remission after renal biopsy | 14 (9–27) | 11 (5–19) | NS |
Time from last remission to stop therapy | 24 (18–41) | 12 (7–20) | 0.02 |
Months of therapy before stopping | 57 (41.5–113.5) | 30 (18–41) | 0.009 |
. | Group 1 . | Group 2 . | P-value . |
---|---|---|---|
Gender (female/male) | 14/1 | 16/1 | NS |
Age (years) | 26 (21.5–30.5) | 31 (23–35) | NS |
WHO class IV–IV + V | 12/1 | 14/0 | NS |
WHO class III–III + V | 1/1 | 3/2 | NS |
Activity index | 10 (8.2–13.5) | 8 (5–9) | NS |
Chronicity index | 2 (2–3) | 2 (0–2) | NS |
Plasma creatinine (mg/dl) | 1.06 (0.85–1.5) | 1.2 (1–1.8) | NS |
Proteinuria (g/24 h) | 2.6 (1.3–4.7) | 4.9 (3–7) | NS |
Arterial hypertension | 53% | 70% | NS |
Fever | 53% | 70% | NS |
Arthralgia | 87% | 53% | NS |
Malar rash | 60% | 59% | NS |
Serositis | 13% | 18% | NS |
Cerebritis | 13% | 12% | NS |
Lymphadenopathy | 20% | 29% | NS |
MP pulse therapy | 80% | 82% | NS |
Oral prednisone | 20% | 18% | NS |
Immunosuppressive therapy | 93% | 59% | NS |
Time of first remission after renal biopsy | 14 (9–27) | 11 (5–19) | NS |
Time from last remission to stop therapy | 24 (18–41) | 12 (7–20) | 0.02 |
Months of therapy before stopping | 57 (41.5–113.5) | 30 (18–41) | 0.009 |
Data are presented as number, percentage or median (25th–75th IQR).
MP, methylprednisolone.
. | Group 1 . | Group 2 . | P-value . |
---|---|---|---|
Gender (female/male) | 14/1 | 16/1 | NS |
Age (years) | 26 (21.5–30.5) | 31 (23–35) | NS |
WHO class IV–IV + V | 12/1 | 14/0 | NS |
WHO class III–III + V | 1/1 | 3/2 | NS |
Activity index | 10 (8.2–13.5) | 8 (5–9) | NS |
Chronicity index | 2 (2–3) | 2 (0–2) | NS |
Plasma creatinine (mg/dl) | 1.06 (0.85–1.5) | 1.2 (1–1.8) | NS |
Proteinuria (g/24 h) | 2.6 (1.3–4.7) | 4.9 (3–7) | NS |
Arterial hypertension | 53% | 70% | NS |
Fever | 53% | 70% | NS |
Arthralgia | 87% | 53% | NS |
Malar rash | 60% | 59% | NS |
Serositis | 13% | 18% | NS |
Cerebritis | 13% | 12% | NS |
Lymphadenopathy | 20% | 29% | NS |
MP pulse therapy | 80% | 82% | NS |
Oral prednisone | 20% | 18% | NS |
Immunosuppressive therapy | 93% | 59% | NS |
Time of first remission after renal biopsy | 14 (9–27) | 11 (5–19) | NS |
Time from last remission to stop therapy | 24 (18–41) | 12 (7–20) | 0.02 |
Months of therapy before stopping | 57 (41.5–113.5) | 30 (18–41) | 0.009 |
. | Group 1 . | Group 2 . | P-value . |
---|---|---|---|
Gender (female/male) | 14/1 | 16/1 | NS |
Age (years) | 26 (21.5–30.5) | 31 (23–35) | NS |
WHO class IV–IV + V | 12/1 | 14/0 | NS |
WHO class III–III + V | 1/1 | 3/2 | NS |
Activity index | 10 (8.2–13.5) | 8 (5–9) | NS |
Chronicity index | 2 (2–3) | 2 (0–2) | NS |
Plasma creatinine (mg/dl) | 1.06 (0.85–1.5) | 1.2 (1–1.8) | NS |
Proteinuria (g/24 h) | 2.6 (1.3–4.7) | 4.9 (3–7) | NS |
Arterial hypertension | 53% | 70% | NS |
Fever | 53% | 70% | NS |
Arthralgia | 87% | 53% | NS |
Malar rash | 60% | 59% | NS |
Serositis | 13% | 18% | NS |
Cerebritis | 13% | 12% | NS |
Lymphadenopathy | 20% | 29% | NS |
MP pulse therapy | 80% | 82% | NS |
Oral prednisone | 20% | 18% | NS |
Immunosuppressive therapy | 93% | 59% | NS |
Time of first remission after renal biopsy | 14 (9–27) | 11 (5–19) | NS |
Time from last remission to stop therapy | 24 (18–41) | 12 (7–20) | 0.02 |
Months of therapy before stopping | 57 (41.5–113.5) | 30 (18–41) | 0.009 |
Data are presented as number, percentage or median (25th–75th IQR).
MP, methylprednisolone.
Fifty patients who never discontinued therapy served as controls. Of them, 18 patients did not achieve a renal remission, in 10 patients remission was not long enough for therapy to be discontinued and in 13 patients with renal remission, low-dose prednisone was continued because of arthralgias and/or cutaneous disorders. In the remaining nine patients we did not try to stop therapy in spite of the achievement of renal remission, since remission occurred after a number of renal and extra-renal flares, which suggested the possibility of new recurrences. Their clinical, histological and biochemical characteristics at presentation were similar to those of the 32 patients who discontinued therapy (Table 2).
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Gender (female/male) | 30/2 | 45/5 |
Age (years) | 28.5 (21.7–34) | 28 (21.2–38.7) |
WHO class IV–IV + V | 26/0 | 31/3 |
WHO class III–III + V | 4/3 | 11/5 |
Activity index | 9 (5.5–11) | 7 (5–10.2) |
Chronicity index | 2 (0.5–3) | 1 (0–3) |
Plasma creatinine (mg/dl) | 1.2 (0.9–1.6) | 0.9 (0.8–1.3) |
Proteinuria (g/24 h) | 4.5 (1.9–5.7) | 3.0 (2–5) |
Arterial hypertension | 62.5% | 54% |
Fever | 62.5% | 62% |
Arthralgia | 69% | 88% |
Malar rash | 59% | 66% |
Serositis | 12.5% | 24% |
Cerebritis | 9% | 2% |
Lymphadenopathy | 19% | 14% |
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Gender (female/male) | 30/2 | 45/5 |
Age (years) | 28.5 (21.7–34) | 28 (21.2–38.7) |
WHO class IV–IV + V | 26/0 | 31/3 |
WHO class III–III + V | 4/3 | 11/5 |
Activity index | 9 (5.5–11) | 7 (5–10.2) |
Chronicity index | 2 (0.5–3) | 1 (0–3) |
Plasma creatinine (mg/dl) | 1.2 (0.9–1.6) | 0.9 (0.8–1.3) |
Proteinuria (g/24 h) | 4.5 (1.9–5.7) | 3.0 (2–5) |
Arterial hypertension | 62.5% | 54% |
Fever | 62.5% | 62% |
Arthralgia | 69% | 88% |
Malar rash | 59% | 66% |
Serositis | 12.5% | 24% |
Cerebritis | 9% | 2% |
Lymphadenopathy | 19% | 14% |
Data are presented as number, percentage or median (25th–75th IQR).
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Gender (female/male) | 30/2 | 45/5 |
Age (years) | 28.5 (21.7–34) | 28 (21.2–38.7) |
WHO class IV–IV + V | 26/0 | 31/3 |
WHO class III–III + V | 4/3 | 11/5 |
Activity index | 9 (5.5–11) | 7 (5–10.2) |
Chronicity index | 2 (0.5–3) | 1 (0–3) |
Plasma creatinine (mg/dl) | 1.2 (0.9–1.6) | 0.9 (0.8–1.3) |
Proteinuria (g/24 h) | 4.5 (1.9–5.7) | 3.0 (2–5) |
Arterial hypertension | 62.5% | 54% |
Fever | 62.5% | 62% |
Arthralgia | 69% | 88% |
Malar rash | 59% | 66% |
Serositis | 12.5% | 24% |
Cerebritis | 9% | 2% |
Lymphadenopathy | 19% | 14% |
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Gender (female/male) | 30/2 | 45/5 |
Age (years) | 28.5 (21.7–34) | 28 (21.2–38.7) |
WHO class IV–IV + V | 26/0 | 31/3 |
WHO class III–III + V | 4/3 | 11/5 |
Activity index | 9 (5.5–11) | 7 (5–10.2) |
Chronicity index | 2 (0.5–3) | 1 (0–3) |
Plasma creatinine (mg/dl) | 1.2 (0.9–1.6) | 0.9 (0.8–1.3) |
Proteinuria (g/24 h) | 4.5 (1.9–5.7) | 3.0 (2–5) |
Arterial hypertension | 62.5% | 54% |
Fever | 62.5% | 62% |
Arthralgia | 69% | 88% |
Malar rash | 59% | 66% |
Serositis | 12.5% | 24% |
Cerebritis | 9% | 2% |
Lymphadenopathy | 19% | 14% |
Data are presented as number, percentage or median (25th–75th IQR).
Initial treatment
Of the 32 patients who interrupted therapy, 26 were given intravenous methylprednisolone pulses (0.5–1 g each) for three consecutive days after renal biopsy followed by oral prednisone 0.5–1 mg/kg/day for 1–3 months, which was gradually tapered to a maintenance of 5–15 mg/day. The other six patients were given oral prednisone 1 mg/kg/day for 1–3 months, which was gradually tapered to maintenance. Oral cyclophosphamide (1.5–2 mg/kg/day) was added in 12 patients, chlorambucil (0.15–0.2 mg/kg/day) in five and azathioprine (2 mg/kg/day) in seven. All patients rapidly achieved complete remission of extra-renal manifestations. Complete (20 patients) or partial remissions (12 patients) of nephritis were reached after a median period of 12.5 months (IQR: 5–19.2 months). Before attempting to withdraw therapy, 12 patients experienced renal or extra-renal flares (six patients proteinuric flares, two nephritic flares, one patient proteinuric and nephritic flares, three patients extra-renal flares characterized by fever and malar rash in two patients and arthralgias in the other one). In all cases, steroid and immunosuppressive therapy was reinforced with a new remission of the renal and extra-renal manifestations.
The 50 controls were given an induction treatment with methylprednisolone pulses (42 patients) or high-dose prednisone (eight patients) plus an alkylating agent in 30 patients, azathioprine in six patients and cyclosporin in one patient. Then they continued with small doses of prednisone and azathioprine for maintenance.
Withdrawal of therapy
Treatment was stopped in a median of 38 months (IQR: 24.2–81 months) from the start of the first therapy for lupus nephritis. When the decision to stop therapy was taken, four patients were receiving only azathioprine (25–50 mg/day). Azathioprine was halved every 2 months until discontinuation. The other 28 patients were taking low doses of only prednisone, either daily or every other day. Prednisone was tapered by halving the dose every 2–3 months until withdrawal.
Clinical outcome after withdrawal of therapy
After therapy was stopped, patients were followed for a median of 203 months (IQR: 116–230 months).
Group 1 included 15 patients who had never developed any renal or extra-renal flare. These patients did not resume steroid or immunosuppressive therapy until the end of the observation, a median 136 months after therapy had been stopped (IQR: 82–219.5 months). Group 2 included 17 patients who developed new flares in median 34 months after therapy had been stopped (IQR: 29–52 months).
The clinical characteristics of Groups 1 and 2 at stopping of therapy are reported in Table 3.
. | Group 1 (n = 15) . | Group 2 (n = 17) . | P-value . |
---|---|---|---|
Complete remission (patients) | 12 | 12 | NS |
Partial remission (patients) | 3 | 5 | NS |
Serum creatinine (mg/dl) | 0.8 (0.75–1) | 0.8 (0.8–1) | NS |
Proteinuria (g/24 h) excluding 24 patients with protein <0.2 g/24 h | 0.6, 0.64, 1.1 | 0.8, 0.9, 1, 1.1, 2.37 | |
Anti-DNA Ab positivity (patients) | 5 | 4 | NS |
Patients with serum C3<80 mg/dl | 3 | 4 | NS |
aPL positivity (patients) | 3 | 5 | NS |
Arterial hypertension (patients) | 5 | 7 | NS |
White blood cells (count/mm3) | 5.550 (5000–6350) | 4500 (4200–5400) | NS |
Haemoglobin (g/dl) | 14 (12–14) | 13.4 (12.5–14) | NS |
Renal flares before stopping therapy | 7 | 5 | NS |
Extra-renal flares before stopping therapy | 4 | 6 | NS |
. | Group 1 (n = 15) . | Group 2 (n = 17) . | P-value . |
---|---|---|---|
Complete remission (patients) | 12 | 12 | NS |
Partial remission (patients) | 3 | 5 | NS |
Serum creatinine (mg/dl) | 0.8 (0.75–1) | 0.8 (0.8–1) | NS |
Proteinuria (g/24 h) excluding 24 patients with protein <0.2 g/24 h | 0.6, 0.64, 1.1 | 0.8, 0.9, 1, 1.1, 2.37 | |
Anti-DNA Ab positivity (patients) | 5 | 4 | NS |
Patients with serum C3<80 mg/dl | 3 | 4 | NS |
aPL positivity (patients) | 3 | 5 | NS |
Arterial hypertension (patients) | 5 | 7 | NS |
White blood cells (count/mm3) | 5.550 (5000–6350) | 4500 (4200–5400) | NS |
Haemoglobin (g/dl) | 14 (12–14) | 13.4 (12.5–14) | NS |
Renal flares before stopping therapy | 7 | 5 | NS |
Extra-renal flares before stopping therapy | 4 | 6 | NS |
Data are presented as number or median (25th–75th IQR).
Ab, antibody.
. | Group 1 (n = 15) . | Group 2 (n = 17) . | P-value . |
---|---|---|---|
Complete remission (patients) | 12 | 12 | NS |
Partial remission (patients) | 3 | 5 | NS |
Serum creatinine (mg/dl) | 0.8 (0.75–1) | 0.8 (0.8–1) | NS |
Proteinuria (g/24 h) excluding 24 patients with protein <0.2 g/24 h | 0.6, 0.64, 1.1 | 0.8, 0.9, 1, 1.1, 2.37 | |
Anti-DNA Ab positivity (patients) | 5 | 4 | NS |
Patients with serum C3<80 mg/dl | 3 | 4 | NS |
aPL positivity (patients) | 3 | 5 | NS |
Arterial hypertension (patients) | 5 | 7 | NS |
White blood cells (count/mm3) | 5.550 (5000–6350) | 4500 (4200–5400) | NS |
Haemoglobin (g/dl) | 14 (12–14) | 13.4 (12.5–14) | NS |
Renal flares before stopping therapy | 7 | 5 | NS |
Extra-renal flares before stopping therapy | 4 | 6 | NS |
. | Group 1 (n = 15) . | Group 2 (n = 17) . | P-value . |
---|---|---|---|
Complete remission (patients) | 12 | 12 | NS |
Partial remission (patients) | 3 | 5 | NS |
Serum creatinine (mg/dl) | 0.8 (0.75–1) | 0.8 (0.8–1) | NS |
Proteinuria (g/24 h) excluding 24 patients with protein <0.2 g/24 h | 0.6, 0.64, 1.1 | 0.8, 0.9, 1, 1.1, 2.37 | |
Anti-DNA Ab positivity (patients) | 5 | 4 | NS |
Patients with serum C3<80 mg/dl | 3 | 4 | NS |
aPL positivity (patients) | 3 | 5 | NS |
Arterial hypertension (patients) | 5 | 7 | NS |
White blood cells (count/mm3) | 5.550 (5000–6350) | 4500 (4200–5400) | NS |
Haemoglobin (g/dl) | 14 (12–14) | 13.4 (12.5–14) | NS |
Renal flares before stopping therapy | 7 | 5 | NS |
Extra-renal flares before stopping therapy | 4 | 6 | NS |
Data are presented as number or median (25th–75th IQR).
Ab, antibody.
In Group 2, four patients had an extra-renal flare, five patients a nephritic flare and eight patients a proteinuric flare. All patients of Group 2 received new courses of therapy at flares and again entered remission.
Eight patients continued therapy until the last observation (median: 69 months; IQR: 60–173 months). In the other nine patients, therapy was stopped again after a median period of therapy of 46 months (IQR: 18.5–68.5 months). Two of them continued to be followed without any therapy until their last visit (85 and 145 months later, respectively) while the other seven patients had to be re-treated in a median 39 months (IQR: 21–100 months) after stopping therapy because of new SLE flares (three patients had proteinuric flares and four extra-renal flares characterized by arthralgias in two and malar rash in the other two). The therapy was continued until the end of the observation in four patients (median: 77.5 months) while in three patients therapy was stopped for the third time without further flares after a median period of 60 months. At the last observation, five patients of Group 2 had not received any therapy for a median period of 85 months (IQR: 50.5–124.5 months) (Figure 1).
Overall, the patients of Group 2 did not receive any therapy for a median period of 114 months (IQR: 45–152.5 months), corresponding to 48% of their cumulative follow-up.
Risk of flares after stopping therapy
In Group 2, the rate of flares was not significantly different before and after therapy was stopped. Six renal flares (two nephritic and four proteinuric) and two extra-renal flares occurred before stopping therapy during a cumulative period of 59 years, i.e. a cumulative risk of 0.13 flares/patient/year (renal flares: 0.10/patient/year; extra-renal flares: 0.03/patient/year). After stopping therapy, 29 renal flares (22 proteinuric and seven nephritic) and 15 extra-renal flares occurred during a cumulative period of 318 years, a rate of 0.14 flares/patient/year (renal flares: 0.09/patient/year; extra-renal flares: 0.05/patient/year).
Extra-renal complications in patients who stopped therapy
Two patients died. A woman in Group 1, who had positive anti-phospholipid antibodies (aPL), died from cerebral haemorrhage 12 years after therapy was stopped whilst in complete clinical remission. Of note, she had normal blood pressure for the whole follow-up. In Group 2, a woman developed breast cancer 14 years after the first stopping of immunosuppressive therapy. She died 2 years later with normal renal function and proteinuria of 1.8 g/day.
Two patients of Group 2 had a vascular accident. One patient had a non-fatal myocardial infarction 15 months after therapy was stopped while she was in complete remission. She developed a proteinuric flare 17 months later. The other patient had a cerebral thrombosis 15 years after therapy was stopped (see below). Both patients were aPL-positive.
The median value of total serum cholesterol decreased from 249 mg/dl (IQR: 209–298 mg/dl) during therapy to 210 mg/dl (IQR: 83–240 mg/dl) (P<0.0001) after stopping therapy in Group 1 and from 244 mg/dl (IQR: 204–274 mg/dl) to 205 mg/dl (IQR: 171–227 mg/dl) (P<0.0001) in Group 2. The median value of serum triglyceride decreased from 134 mg/dl (IQR: 95–191 mg/dl) to 83 mg/dl (IQR: 61–1362 mg/dl) (P<0.0001) in Group 1 and from 139 mg/dl (IQR: 105–190 mg/dl) to 94 mg/dl (IQR: 75–121 mg/dl) (P<0.0001) in Group 2. Patients in Group 1 were exposed to hypercholesterolaemia (>200 mg/dl) and hypertriglyceridaemia (>170 mg/dl) for a shorter period (1240/3560 months, 34% of the whole follow-up) than patients of Group 2 (2178/4190 months, 52% of the whole follow-up; P = 0.0001).
Moderate–severe osteoporosis, as evaluated by quantitative mineralometry, occurred in six out of 13 patients of Group 2 and in none of the 11 of Group 1 (P = 0.033).
No patient developed diabetes or cataracts or aesthetic disfiguration. One patient in Group 1 and three patients in Group 2 developed obesity (body mass index >30).
Three women from Group 1 (20%) and seven in Group 2 (41%) entered menopause before the age of 45 years (P = NS).
At the last observation, three patients in Group 1 (20%) and nine patients in Group 2 (53%) had arterial hypertension (P = NS), which was well controlled with antihypertensive therapy in all cases. Two patients in Group 1 and seven patients in Group 2 were treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor antagonists.
Renal status at the last observation
See Table 4 for results.
. | Group 1 (n = 15) . | Group 2 (n = 17) . |
---|---|---|
Follow-up after stopping therapy (months) | 136 (82–219.5) | 215 (187–227) |
Complete remission | 13a | 14 |
Plasma creatinine (mg/dl) | 0.8 (0.7–0.9) | 0.9 (0.8–1) |
Partial remission | 2 | 2a |
Plasma creatinine (mg/dl) | 0.8, 1.1 | 0.9, 1 |
Proteinuria (g/24 h) | 0.7, 0.95 | 0.9, 1.8 |
Renal insufficiency | 0 | 1 |
Plasma creatinine (mg/dl) | 2.3 | |
Proteinuria (g/24 h) | 0.35 | |
Arterial hypertension | 3 | 9 |
. | Group 1 (n = 15) . | Group 2 (n = 17) . |
---|---|---|
Follow-up after stopping therapy (months) | 136 (82–219.5) | 215 (187–227) |
Complete remission | 13a | 14 |
Plasma creatinine (mg/dl) | 0.8 (0.7–0.9) | 0.9 (0.8–1) |
Partial remission | 2 | 2a |
Plasma creatinine (mg/dl) | 0.8, 1.1 | 0.9, 1 |
Proteinuria (g/24 h) | 0.7, 0.95 | 0.9, 1.8 |
Renal insufficiency | 0 | 1 |
Plasma creatinine (mg/dl) | 2.3 | |
Proteinuria (g/24 h) | 0.35 | |
Arterial hypertension | 3 | 9 |
Data are presented as number or median (25th–75th IQR).
aOne patient in each group died.
. | Group 1 (n = 15) . | Group 2 (n = 17) . |
---|---|---|
Follow-up after stopping therapy (months) | 136 (82–219.5) | 215 (187–227) |
Complete remission | 13a | 14 |
Plasma creatinine (mg/dl) | 0.8 (0.7–0.9) | 0.9 (0.8–1) |
Partial remission | 2 | 2a |
Plasma creatinine (mg/dl) | 0.8, 1.1 | 0.9, 1 |
Proteinuria (g/24 h) | 0.7, 0.95 | 0.9, 1.8 |
Renal insufficiency | 0 | 1 |
Plasma creatinine (mg/dl) | 2.3 | |
Proteinuria (g/24 h) | 0.35 | |
Arterial hypertension | 3 | 9 |
. | Group 1 (n = 15) . | Group 2 (n = 17) . |
---|---|---|
Follow-up after stopping therapy (months) | 136 (82–219.5) | 215 (187–227) |
Complete remission | 13a | 14 |
Plasma creatinine (mg/dl) | 0.8 (0.7–0.9) | 0.9 (0.8–1) |
Partial remission | 2 | 2a |
Plasma creatinine (mg/dl) | 0.8, 1.1 | 0.9, 1 |
Proteinuria (g/24 h) | 0.7, 0.95 | 0.9, 1.8 |
Renal insufficiency | 0 | 1 |
Plasma creatinine (mg/dl) | 2.3 | |
Proteinuria (g/24 h) | 0.35 | |
Arterial hypertension | 3 | 9 |
Data are presented as number or median (25th–75th IQR).
aOne patient in each group died.
In Group 1, excluding the patient who died while in complete remission, at the last visit 12 patients were in complete remission. Two other patients continued to have normal renal function with a mean proteinuria of 0.9 and 0.7 g/24 h, respectively. Three patients had arterial hypertension, which was well controlled by therapy.
In Group 2, excluding the patient who died from cancer, 14 patients were in complete remission and another patient had normal renal function and proteinuria of 0.9 g/24 h. Another patient developed renal function deterioration (serum creatinine: 2.3 mg/dl). This aPL-positive patient had been in complete clinical remission without specific therapy for 15 years when she developed a cerebral thrombosis and was hospitalized in a neurological unit. During her long hospitalization, nephrotic syndrome and renal insufficiency developed. The patient was treated with low-dose prednisone only, due to her severe neurological condition. Nine patients in Group 2 had arterial hypertension, which was well controlled by therapy.
Comparison with patients who continued therapy
At the last follow-up visit, 97% of patients who stopped therapy had complete or partial remission vs 80% of patients who continued treatment. One patient (3%) who stopped therapy had a doubling of plasma creatinine as opposed to 10 (20%) patients in the group that continued therapy (Table 5). Levels of cholesterol and triglycerides were significantly higher in patients who continued treatment. Renal flares and cardiovascular complications were significantly more frequent in patients who continued treatment (Table 6).
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Follow-up months | 239.5 (198–290) | 139 (58–194) |
Complete remission | 27/32 (84%) | 34/50 (68%) |
Partial remission | 4/32 (13%) | 6/50 (2%) |
Renal insufficiency | 1/32 (3%) | 10/50 (20%) |
Double plasma creatinine | 1 | 5 |
End-stage renal disease | 0 | 5 |
Deaths | 2/32 (6%) | 5/50 (10%) |
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Follow-up months | 239.5 (198–290) | 139 (58–194) |
Complete remission | 27/32 (84%) | 34/50 (68%) |
Partial remission | 4/32 (13%) | 6/50 (2%) |
Renal insufficiency | 1/32 (3%) | 10/50 (20%) |
Double plasma creatinine | 1 | 5 |
End-stage renal disease | 0 | 5 |
Deaths | 2/32 (6%) | 5/50 (10%) |
Data are presented as number or median (25th–75th IQR).
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Follow-up months | 239.5 (198–290) | 139 (58–194) |
Complete remission | 27/32 (84%) | 34/50 (68%) |
Partial remission | 4/32 (13%) | 6/50 (2%) |
Renal insufficiency | 1/32 (3%) | 10/50 (20%) |
Double plasma creatinine | 1 | 5 |
End-stage renal disease | 0 | 5 |
Deaths | 2/32 (6%) | 5/50 (10%) |
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . |
---|---|---|
Follow-up months | 239.5 (198–290) | 139 (58–194) |
Complete remission | 27/32 (84%) | 34/50 (68%) |
Partial remission | 4/32 (13%) | 6/50 (2%) |
Renal insufficiency | 1/32 (3%) | 10/50 (20%) |
Double plasma creatinine | 1 | 5 |
End-stage renal disease | 0 | 5 |
Deaths | 2/32 (6%) | 5/50 (10%) |
Data are presented as number or median (25th–75th IQR).
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . | P-value . |
---|---|---|---|
Cholesterol (mg/dl) | 226 (192–266) | 245 (205–292) | 0.00001 |
Triglyceride (mg/dl) | 129 (85–166) | 142 (105.2.198.5) | 0.00001 |
Proteinuric flares (number/patient/year) | 0.0445 | 0.0721 | 0.00001 |
Nephritic flares (number/patient/year) | 0.0141 | 0.0519 | 0.00001 |
Extra-renal flares (number/patient/year) | 0.0243 | 0.0150 | NS |
Arterial hypertension (number of patients) | 12/32 (37.5%) | 25/50 (50%) | NS |
Cardiovascular complications (number/patient/year) | 0.003 | 0.033 | 0.03 |
Osteoporosis | 6/28 (21%) | 12/27 (44%) | NS |
Diabetes | 1/32 (3%) | 0 | NS |
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . | P-value . |
---|---|---|---|
Cholesterol (mg/dl) | 226 (192–266) | 245 (205–292) | 0.00001 |
Triglyceride (mg/dl) | 129 (85–166) | 142 (105.2.198.5) | 0.00001 |
Proteinuric flares (number/patient/year) | 0.0445 | 0.0721 | 0.00001 |
Nephritic flares (number/patient/year) | 0.0141 | 0.0519 | 0.00001 |
Extra-renal flares (number/patient/year) | 0.0243 | 0.0150 | NS |
Arterial hypertension (number of patients) | 12/32 (37.5%) | 25/50 (50%) | NS |
Cardiovascular complications (number/patient/year) | 0.003 | 0.033 | 0.03 |
Osteoporosis | 6/28 (21%) | 12/27 (44%) | NS |
Diabetes | 1/32 (3%) | 0 | NS |
Data are presented as number or median (25th–75th IQR).
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . | P-value . |
---|---|---|---|
Cholesterol (mg/dl) | 226 (192–266) | 245 (205–292) | 0.00001 |
Triglyceride (mg/dl) | 129 (85–166) | 142 (105.2.198.5) | 0.00001 |
Proteinuric flares (number/patient/year) | 0.0445 | 0.0721 | 0.00001 |
Nephritic flares (number/patient/year) | 0.0141 | 0.0519 | 0.00001 |
Extra-renal flares (number/patient/year) | 0.0243 | 0.0150 | NS |
Arterial hypertension (number of patients) | 12/32 (37.5%) | 25/50 (50%) | NS |
Cardiovascular complications (number/patient/year) | 0.003 | 0.033 | 0.03 |
Osteoporosis | 6/28 (21%) | 12/27 (44%) | NS |
Diabetes | 1/32 (3%) | 0 | NS |
. | Patients who discontinued therapy (n = 32) . | Patients who never tried to stop therapy (n = 50) . | P-value . |
---|---|---|---|
Cholesterol (mg/dl) | 226 (192–266) | 245 (205–292) | 0.00001 |
Triglyceride (mg/dl) | 129 (85–166) | 142 (105.2.198.5) | 0.00001 |
Proteinuric flares (number/patient/year) | 0.0445 | 0.0721 | 0.00001 |
Nephritic flares (number/patient/year) | 0.0141 | 0.0519 | 0.00001 |
Extra-renal flares (number/patient/year) | 0.0243 | 0.0150 | NS |
Arterial hypertension (number of patients) | 12/32 (37.5%) | 25/50 (50%) | NS |
Cardiovascular complications (number/patient/year) | 0.003 | 0.033 | 0.03 |
Osteoporosis | 6/28 (21%) | 12/27 (44%) | NS |
Diabetes | 1/32 (3%) | 0 | NS |
Data are presented as number or median (25th–75th IQR).
Discussion
Although therapeutic strategies aimed at using low doses of corticosteroid and immunosuppressive agents during the inactive phases of SLE may reduce the side effects of therapy [21,22], a period without corticosteroids and immunosuppressive agents could be particularly useful for preventing iatrogenic morbidity. However, the few attempts to discontinue therapy in patients with lupus nephritis reported conflicting results. Some old studies showed that an abrupt withdrawal of cytotoxic drugs was often complicated by severe clinical exacerbations and deterioration of kidney function [13,14], but anecdotal cases of transient [15,16] or longer successful interruption of treatment also have been reported [4,17].
In this study, we have shown that discontinuation of a ‘specific’ therapy is feasible in a number of patients with proliferative lupus nephritis who have entered a stable and prolonged remission. As previous experiences [13,14] have shown that an abrupt discontinuation of treatment may lead to severe and even irreversible renal failure, we decided to reduce the dosage of drugs very slowly before interruption. Out of 44 patients in whom complete withdrawal was planned, 12 showed signs of SLE activity. After therapy was reinforced, all patients again entered remission. The remaining 32 patients were able to tolerate the discontinuation of treatment without any early renal or extra-renal exacerbation of SLE. Of them, 14 patients who never had treatment restarted were still in remission with normal renal function after a mean follow-up of 13 years, while an aPL-positive woman died from a stroke whilst in complete remission. Apart from this woman, very few patients from this group showed morbidity. The other 17 patients developed signs of SLE activity during their follow-up. The only significant differences with the group of patients who did not show SLE exacerbation were shorter periods of therapy and remission before discontinuation. The late onset of flares was not unexpected, as it is well known that reactivation of lupus may occur even after many years [23]. As the occurrence of flares needs an aggressive treatment, one might speculate that those patients lost the potential advantage of interrupting therapy. Nevertheless, the results were good in those patients. They remained without specific therapy for a median of 34 months, before developing a flare of SLE. Only in a few cases was the flare characterized by an increase in serum creatinine and in all cases flares reversed after re-treatment. Nine patients were able again to discontinue treatment for many months. The incidence of renal and extra-renal flares before and after therapy was stopped was not different in this group of patients. This might be attributed to the low-dose treatment before attempting the discontinuation of therapy. Even more important, after a median period of 16 years, 14 out of 17 patients were in complete remission; one patient had non-nephrotic proteinuria, another patient had a doubling of serum creatinine after 15 years of complete remission and a third patient died from cancer whilst in partial remission. In spite of relapses of SLE, these patients remained without specific therapy for about half of their cumulative follow-up period. Arterial hypertension, osteoporosis, obesity or premature ovarian failure occurred more frequently in this group than in Group 1, but the difference was statistically significant for osteoporosis only. Patients who had steroids reintroduced had a significantly longer exposure to hypercholesterolaemia and hypertriglyceridaemia. Although the small number of patients in the study invites caution in drawing statistical conclusions, these data seem to suggest that the longer the duration of treatment and remission, the safer the discontinuation of therapy in patients who entered remission.
When compared with the 50 patients who continued therapy, the 32 patients who were in a condition to stop treatment had fewer renal flares, lower levels of cholesterol and triglycerides and had fewer cardiovascular complications. It should be pointed out, however, that the median follow-up of patients who stopped therapy was >8 years longer when compared with the median follow-up of the patients who continued treatment. Therefore, it is difficult to draw firm conclusions from this analysis.
In conclusion, this study demonstrates that a subset of patients with severe lupus nephritis who enter stable and prolonged remission can be maintained without any treatment for many years. Other patients can also maintain remission for many years after therapy has been stopped, but may show a late exacerbation of lupus. However, they may again obtain remission with an appropriate treatment. Since there is no convincing evidence that treatment of patients in remission actually improves their long-term prognosis [24], while the side effects of a protracted steroids and immunosuppressive therapy are well known, full discontinuation of therapy seems to be justified for the subset of patients with persistent remission of renal disease. However, we recommend trying discontinuation only in selected patients, treated for ≥5 years. Drugs should be tapered off very slowly under strict surveillance. If these prerequisites are respected, the withdrawal of therapy in patients with diffuse lupus nephritis may be considered safe and may help in improving patients’ quality of life.
The study was supported by the grant ‘Project in Glomerulonephritis’ in memory of Pippo Neglia.
Conflict of interest statement. None declared.
(See related article by Grootscholten and Berden. NDT, doi: 10.1093/ndt/gfl208.)
References
Moroni G, Quaglini S, Maccario M, Banfi G, Ponticelli C. Nephritic flares are predictors of bad long-term outcome in lupus nephritis.
Mosca M, Bencivelli V, Neri R et al. Renal flares in 91 patients with diffuse proliferative glomerulonephritis.
Illei GG, Takada K, Parkin D et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies.
Bono L, Cameron JS, Hicks JA. The very long term prognosis and complications of lupus nephritis and its treatment.
Font J, Ramos-Casals M, Cervera R et al. Cardiovascular risk factors and the long-term outcome of lupus nephritis.
Manzi S, Meilahn EN, Rairie JE et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study.
Hosenpud JD, Montanaro A, Hart MV et al. Myocardial perfusion abnormalities in asymptomatic patients with systemic lupus erythematosus.
Bruce IN, Urowitz MB, Gladman DD, Hallett DC. Natural history of hypercholesterolemia in systemic lupus erythematosus.
Petri M. Detection of coronary artery disease and the role of traditional risk factors in the Hopkins Lupus Cohort.
Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.
Boumpas DT, Austin HA,III, Vaughan EM, Yarboro CH, Klippel JH, Balow JE. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy.
Ponticelli C, Moroni G, Banfi G. Discontination of therapy in diffuse proliferative lupus nephritis.
Aptekar RG, Decker JL, Steinberg AD. Exacerbation of SLE nephritis after cyclophosphamide withdrawal.
Sharon E, Kaplan D, Diamond HS. Exacerbation of systemic lupus erythematosus after withdrawal of azathioprine therapy.
Drenkard C, Villa AR, Garcia Padilla C, Perez-Vazquez ME, Alarcon-Segovia D. Remission of systemic lupus erythematosus.
Euler HH, Schroeder JO, Harten P, Zeuner RA, Gutschmidt HJ. Treatment-free remission in severe systemic lupus erythematosus following synchronization of plasmapheresis with subsequent pulse cyclophosphamide.
Tozman ECS, Urowits MB, Gladman DD. Prolonged complete remission in previously severe SLE.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
Churg J, Sobin LH. Lupus nephritis. In: Churg J, Sobin LH, ed.
Austin HA,III, Muenz LR, Joyce KM et al. Prognostic factors in lupus nephritis: contributions of renal histological data.
Moroni G, Greloni GC, Ponticelli C. Late recurrence of lupus nephritis after long-term clinical remission.
Author notes
1Divisione di Nefrologia, Ospedale Maggiore IRCCS, Milan, 2Dipartimento di Informatica e Sistemistica, Universita degli studi di Pavia and 3Divisione di Immunologia, IRCCS Istituto Auxologico Italiano, Milan, Italy
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