Autoimmunity Reviews 13 (2014) 206–214

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Review

Prednisone in lupus nephritis: How much is enough? Guillermo Ruiz-Irastorza a,b,⁎, Alvaro Danza a,c,d, Isabel Perales a,e, Irama Villar a,b, Miriam Garcia a, Sonia Delgado f, Munther Khamashta g a

Autoimmune Diseases Research Unit, Department of Internal Medicine, Biocruces Health Research Institute, Hospital Universitario Cruces, Spain University of the Basque Country, Bizkaia, The Basque Country, Spain Department of Internal Medicine, Hospital Pasteur, Montevideo, Uruguay d Facultad de Medicina, Universidad de la Republica, Uruguay e Service of Internal Medicine, Hospital Rey Juan Carlos, Madrid, Spain f Service of Nephrology, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain g Graham Hughes Lupus Research Laboratory, Division of Women's Health, The Rayne Institute, King's College, London, UK b c

a r t i c l e

i n f o

Article history: Received 20 October 2013 Accepted 26 October 2013 Available online 2 November 2013 Keywords: Systemic lupus erythematosus Glucocorticoids Hydroxychloroquine Adverse effects Osteonecrosis Osteoporosis

a b s t r a c t Objective: To assess the effectiveness and safety of a protocol using medium doses of prednisone to treat lupus nephritis. Methods: Patients receiving the ‘Cruces-protocol cohort’ (CPC) were paired 1:2 with patients from the ‘historic cohort’ (HC). The CPC received medium doses of prednisone combined with methyl-prednisolone pulses, hydroxychloroquine and immunosuppressive drugs, usually cyclophosphamide. The HC received cyclophosphamide and high-dose prednisone. Partial and complete remission rates and glucocorticoid-related toxicity were assessed. Results: 15 CPC and 30 HC patients were analysed. The mean (SD) initial dose of prednisone was 22 (8) mg/d in the CPC vs. 49 (19) mg/d in the HC (p b 0.001). The 6-month mean (SD) cumulative dose of prednisone was 1.7 (0.5) g (average daily dose 9 mg) vs. 4.5 (2.1) g (average daily dose 25 mg), respectively (p b 0.001). The median cumulative dose of cyclophosphamide at six months was 3 (0–4.5) g in the CPC vs. 5 (0–16.8) in the HC (p b 0.001). 15/15 (100%) vs. 10/30 (33%) patients were treated with hydroxychloroquine (p b 0.001). At six months, 12/15 (80%) patients in the CPC achieved partial or complete remission vs. 14/30 (47%) in the HC (p = 0.015). At 12 months, 13/15 (87%) vs. 19/30 (63%) patients, respectively, were in complete or partial remission (p = 0.055). Toxicity attributable to glucocorticoids was observed in 1/15 (7%) vs. 20/30 (67%) patients, respectively (p b 0.0001). Conclusion: A combination of medium-dose prednisone, methylprednisolone pulses, cyclophosphamide and hydroxychloroquine is at least as effective in achieving remission of lupus nephritis as regimes containing high-dose prednisone and causes less toxicity. © 2013 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . 2.1. Study design and patients . . . . . . . 2.2. The lupus nephritis cruces protocol . . 2.3. Historic cohort treatment . . . . . . . 2.4. Variables studied . . . . . . . . . . 2.5. Remission criteria . . . . . . . . . . 2.6. Statistical analysis . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . 3.1. Demographic and SLE-related variables 3.2. Treatment received (Table 3) . . . . . 3.3. Renal response at six months . . . . . 3.4. Renal response at twelve months . . .

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⁎ Corresponding author at: Unidad de Enfermedades Autoinmunes, Hospital Universitario Cruces, 48903 Bizkaia, Spain. Tel.:+34 94 600 63 48; fax: +34 94 600 66 17. E-mail address: [email protected] (G. Ruiz-Irastorza). 1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autrev.2013.10.013

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3.5. Long-term response 3.6. Adverse events . . 4. Discussion . . . . . . . . Competing interests . . . . . . Take-home messages . . . . . Acknowledgements . . . . . . References . . . . . . . . . .

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1. Introduction Lupus nephritis (LN) is present in 35 to 40% of adults with systemic lupus erythematosus (SLE), being a well recognized factor of morbidity and mortality [1]. Several consensus guidelines focusing on the management of LN have been recently developed [2–4]. All agree in recommending a 3 to 6-month induction phase, followed by a maintenance phase of variable duration [2–5]. The induction phase usually includes the combination of glucocorticoids with an immunosuppressive agent [6]. Different clinical trials have addressed the efficacy of immunosuppressive drugs, such as cyclophosphamide, azathioprine and mycophenolate mofetil [7–13]. Concomitant therapy with glucocorticoids, usually at high doses, is the rule; however the impact of steroids in both response and toxicity has been insufficiently analysed. Glucocorticoid schedules are only partially explained in most studies and dosages are frequently modified during the follow up [14]. Due to the lack of solid evidence supporting the use of high dose glucocorticoids and given our concern for adverse effects, our group has been using reduced doses of prednisone in the treatment of lupus, on the assumption that they can be as effective as and safer than higher doses. Our aim in this study is to address the effectiveness and safety of our therapeutic scheme in patients with LN. 2. Patients and methods 2.1. Study design and patients We designed a comparison study between two groups of patients with LN from the Lupus-Cruces observational cohort: those patients treated with a defined protocol using medium doses of prednisone at induction, the ‘Cruces-protocol cohort’ (CPC), and with at least one year of follow-up, were compared with those from the ‘historic cohort’ (HC), treated with a protocol similar to the National Institute of Health (NIH) scheme. Each of the 15 patients of the CPC was matched with two patients from the HC, according to the age at the diagnosis of LN

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(+/− 5 years), gender and LN class. If any of the matches could not be fulfilled, the closest patient was chosen (i.e., same gender, same LN class, different age). All patients fulfilled the updated American College of Rheumatology (ACR) criteria for the classification of SLE [15] and had biopsy-proven LN, classified according to the 1982 histopathologic criteria by the World Health Organization [16]. The local institutional review board of the Hospital Universitario Cruces approved the study protocol (study code CEIC E10/57), in compliance with the Helsinki Declaration. All patients joining the LupusCruces cohort gave informed consent before being included in our database. 2.2. The lupus nephritis cruces protocol The detailed protocol is shown in Table 1. In brief, starting doses of prednisone ranged between 15 and 30 mg/d depending on LN class and clinical status. This dose was quickly tapered every 2 weeks until 10 mg/d (class III and IV) or 7.5 mg/d (class II and V), being then reduced by 2.5 mg/d every 4 weeks to a maintenance dose of 2.5–5 mg/d. In class II, we associated azathioprine. In class V LN we associated mycophenolate mofetil. For class III and IV, the induction treatment started with three consecutive daily intravenous methyl-prednisolone pulses of 250–500 mg. Then, 6 to 12 fortnightly intravenous pulses of 500 mg of cyclophosphamide were administered, the final number depending on renal response. One methylprednisolone 125 or 250 mg pulse was given just before each dose of cyclophosphamide. Mycophenolate mofetil was used as induction therapy in one selected woman. In all LN cases we prescribed coadjuvant treatment with hydroxychloroquine. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers were used as needed according to blood pressure and the degree of proteinuria. All patients were prescribed calcium and vitamin D. All patients were followed with regular visits every 2 to 4 weeks during the first 6 months and every 1 to 3 months (depending on

Table 1 The Lupus-Cruces protocol for the treatment of lupus nephritis.

Class II Class III–IV

Class V

Prednisone tapering scheme Class II and V Class III–IV

Coadjuvant treatment All classes All classes If high blood pressure and/or proteinuria N 1 gr/24 h

Induction

Maintenance

Prednisone initial dose up to 15 mg/d (depending on clinical status) + azathioprine Methyl-prednisolone 250–500 mg iv, three consecutive days Prednisone initial dose 20 to 30 mg/d (depending on clinical status) + methyl-prednisolone 125 mg iv + cyclophosphamide 500 mg, both fortnightly, to complete 6, 9 or 12 doses (depending on renal response). Prednisone initial dose 15 mg/d + mycophenolate mofetil (cyclophosphamide optional depending on clinical status)

Prednisone 2.5–5 mg/d + azathioprine Prednisone 2.5–5 mg/d + mycophenolate mofetil or azathioprine

15 mg/d 2 weeks, 10 mg/d 2 weeks, 7.5 mg/d 4 weeks, reduction from 5 mg/d to 2.5 mg/d according to clinical status 30 mg/d 2 weeks, 20 mg/d 2 weeks, 15 mg/d 2 weeks, 10 mg/d 4 weeks, 7.5 mg/d 4 weeks, reduction from 5 mg/d to 2.5 mg/d according to clinical status

Hydroxychloroquine Calcium + vitamin D Angiotensin converting enzyme inhibitors or angiotensin receptor blockers

Prednisone 2.5–5 mg/d + mycophenolate mofetil

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clinical status) afterwards. Maintenance therapy was given with lowdose prednisone, hydroxychloroquine and azathioprine or mycophenolate mofetil (Table 1). 2.3. Historic cohort treatment Patients with proliferative forms of LN were treated with an NIH protocol-based scheme. Patients received monthly cyclophosphamide pulses therapy (1 g/m2) followed by the same doses quarterly up to two years after remission. Prednisone was given usually at high doses (1 mg/kg/d) with variable duration and tapering scheme, according to the discretion of the treating physicians. Likewise, hydroxychloroquine and antiproteinuric drugs were not used as per protocol. Patients with other types of LN were treated with combinations of prednisone and immunosuppressive drugs (azathioprine or mycophenolate mofetil). High doses of prednisone were also used for other classes of LN, combined or not with immunosuppressive drugs at the discretion of the attending physician. Maintenance therapy usually included prednisone and azathioprine or mycophenolate mofetil. 2.4. Variables studied In both cohorts, we analysed the following baseline variables: gender, age, class of LN, race, urinary protein/creatinine ratio or 24 hour proteinuria, hematuria (≥5 RBC/hpf), C3 titres, estimated glomerular filtration rate (GFR) by the abbreviated MDRD study equation [17], serum albumin levels and positivity of anti-DNA antibodies. The following therapeutic variables were compared between both groups: initial dose of prednisone during induction therapy, prednisone cumulative dose at six months, average daily dose of prednisone by six months, weeks spent until reducing prednisone dose to 5 mg/d, number of pulses of methyl-prednisolone and total dose given, cyclophosphamide cumulative dose at six months, proportion of patients treated with hydroxychloroquine and with angiotensin converting enzyme inhibitors/angiotensin receptor blockers. Potential glucocorticoid-related side effects were analysed: metabolic disorders (new diabetes mellitus, new hypercholesterolemia, new obesity and/or Cushingoid features), new avascular osteonecrosis, new osteoporotic fractures, and new cataracts. Infections were excluded from this analysis given the potential additional effect of other medications.

relapse; and number of patients on complete or partial remission at the end of the follow-up. Time dependent analysis was performed by Cox regression, whilst comparisons at specified time points were done using conditional logistic regression. In all regression models, the comparisons between both cohorts were adjusted by the level of initial proteinuria. Chi-square/Fisher exact test was used to compare the crude frequency of toxicity attributed to glucocorticoids (metabolic disorders, avascular osteonecrosis, osteoporotic fractures, cataracts, or any of them) in both cohorts. In addition, Cox regression analysis was performed in order to control for the different follow-up time. Potential independent predictors for glucocorticoid-attributed toxicity were analysed using Cox regression backwards selection models for each of the dependent variables (global toxicity, metabolic toxicity, fractures, osteonecrosis and cataracts) after grouping patients of both cohorts. Age at the diagnosis of LN, gender, initial dose of prednisone, weeks to a dose of prednisone of 5 mg/d and cumulative prednisone dose at 6 months were set as independent variables. In addition, antiphospholipid syndrome was included for osteonecrosis and treatment with calcium plus vitamin D for osteoporotic fractures. The same dependent variables were tested by Cox regression with the total dose of intravenous methyl-prednisolone as the independent variable instead of prednisone-related variables, in order to disclose the toxic effects of methyl-prednisolone pulses. The statistical analysis was done using STATA 11.1.

3. Results 3.1. Demographic and SLE-related variables Forty-five patients were included in the analysis. The demographic and baseline clinical characteristics of the patients are shown in Table 2. At the time of the diagnosis of LN, the GFR, serum albumin levels, C3 values and the proportion of patients with anti-dsDNA antibodies were similar in both cohorts. Hematuria was almost universal. The mean 24 hour proteinuria was significantly higher in the HC. Three of 15 patients (20%) had hypertension in the CPC vs. 12/30 patients (40%) in the HC. The median (range) follow up from the diagnosis of LN up to the time of the study was 35 (13–122) months in the CPC and 156 (52–285) months in the HC.

2.5. Remission criteria 3.2. Treatment received (Table 3) Remission was assessed according to the last Spanish LN consensus document criteria, based on the ALMS study [4]. Complete remission was defined as a GFR ≥ 60 ml/min/1.73 m2 (or return to initial GFR or ±15% to the initial value in those with GFR b 60 ml/min/1.73 m2 at diagnosis), proteinuria ≤ 0.5 g/24 h, inactive sediment (≤ 5 red blood cells, ≤5 leucocytes and absence of hematic casts) and serum albumin N3 g/dl. Partial remission was defined as a decrease in proteinuria below 3.5 g/24 h in patients with initial nephrotic proteinuria or N 50% reduction of proteinuria in those with initial values below 3.5 g/24 h; in both cases, with stabilization (±25%) or improvement in the baseline GFR [4]. 2.6. Statistical analysis Descriptive data were generated. Univariate comparisons between both cohorts were performed using Chi-square test or the Fisher's exact test, as appropriate, for qualitative variables, unpaired Student's t-test for quantitative variables with normal distribution and Mann– Whitney test for quantitative variables with non-normal distribution. The outcome of both cohorts was compared by several means: patients achieving complete, partial or any (complete or partial) remission at 6 and 12 months; time to achieving complete remission; time to

All patients in both groups received daily oral prednisone. The mean (SD) initial dose of prednisone was 22 (8) mg/d in the CPC vs. 49 (19) mg/d in the HC (p b 0.001). The mean (SD) cumulative doses of prednisone at six months were 1.7 (0.5) g vs. 4.5 (2.1) g (p b 0.001), in the CPC and HC, respectively, which resulted in average doses of 9 mg/d and 25 mg/d, respectively. The mean (SD) weeks to the reduction of prednisone to 5 mg/d were 16 (9) weeks in the CPC vs. 130 (146) weeks in the HC (p b 0.001). The median (range) number of intravenous pulses of methylprednisolone was 8 (0–13) in the CPC and 0 (0–6) in the HC (p b 0.001). The median (range) cumulative dose of methylprednisolone in six months was 1.5 (0–2.4) g in the CPC and 0 (0–1) g in the HC (p b 0.001). All patients were treated with hydroxychloroquine in the CPC vs. 10/30 (33%) in the HC (p b 0.001). Induction treatment with cyclophosphamide was used in 13/15 patients (86%) in the CPC and in 26/30 (86%) patients in the HC (p = 1); the median (range) cumulative dose of cyclophosphamide within six months was 3 (0–4.5) g and 5 (0–17) g, respectively (p b 0.001). Ten patients in both cohorts received angiotensin converting enzyme inhibitors or angiotensin receptor blockers (p = 0.56). Fourteen patients (93%) in the CPC received supplemental calcium and D vitamin vs. 9/30 (30%) in the HC (p b 0.001).

G. Ruiz-Irastorza et al. / Autoimmunity Reviews 13 (2014) 206–214 Table 2 Baseline data and characteristic of lupus nephritis in the cohorts.

Gender (female/male) Age at the diagnosis of SLE (yrs) mean (SD) Age at the diagnosis of LN (yrs) mean (SD)

Cruces protocol cohort (CPC) (n = 15)

Historic cohort (HC) (n = 30)

11/4 37 (13.9)

27/3 32 (12.9)

39 (13.8)

35 (13.2)

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(75%) patients in the CPC vs. 10/21 (47%) patients in HC (adjusted OR 5.9, 95%CI 0.7–48.1, p = 0.09). Complete or partial remission was thus achieved by 13/15 patients (87%) in the CPC vs. 19/30 (63%) in the HC (adjusted OR 5.6, 95%CI 0.97–33.2, p = 0.055). 3.5. Long-term response All patients in the CPC eventually achieved complete remission vs. 21/30 (70%) in the HC (adjusted HR 2.5, 95%CI 1.2–5.1, p = 0.013) (Fig. 1). Two patients (13.3%) in the CPC had a relapse of LN vs. 14/30 (47%) in the HC (adjusted HR 0.21, 95%CI 0.03–1.25, p = 0.088). At the end of the follow-up, all patients in the CPC were in complete or partial remission, vs. 21/30 patients (70%) in the HC (p = 0.02). The status of the 9 patients in the HC who were not in remission was as follows: 2 patients died with active LN, 4 received renal transplant and the remaining 3 were on hemodialysis.

Race: White Black Others

12 2 1

27 1 2

WHO class LN: Type II Type III Type IV Type V

1 3 9 2

2 5 21 2

SLE manifestations: Rash Arthritis Serositis Haematological Thrombosis Antiphospholipid syndrome Proteinuria (g/24 h) mean (SD) Microhematuria (N5 rbc/hpf) Serum albumin (g/dl) mean (SD) GFR (ml/min/1.73 m2) mean (SD) C3 titers (mg/dl) mean (SD) Anti-DNA antibodies

12 12 7 12 0 0 2.4 (2) 15 3.08 (0.73) 76 (26.8) 52.5 (19.3) 14

21 25 15 22 6 2 3.7 (3.1) 29 2.9 (0.56) 71.5 (22) 47.3 (22.7) 27

SLE: systemic lupus erythematosus. LN: lupus nephritis. rbc/hpf: red blood cells per high power field. GFR: glomerular filtration rate.

3.3. Renal response at six months At six months, proteinuria was significantly reduced by a mean 1.79 gr/d in the CPC (p = 0.003) and 1.83 gr/d in the HC (p = 0.002). Consistently, serum albumin increased in both groups by a mean 0.98 mg/dl (p b 0.0001) and 0.54 mg/dl (p = 0.0007), respectively. Mean C3 levels rose from 52 to 83 mg/dl in the CPC (p b 0.0001) and from 46 to 73 mg/dl in the HC (p b 0.0001). The mean GFR remained stable in both groups: 75 and 84 ml/min/1.73 m2 in the CPC (p = 0.13) vs. 71.5 and 76 ml/min/1.73 m2 in the HC (p = 0.4). Six patients (40%) achieved complete remission in the CPC vs. 3/30 (10%) in the HC (adjusted OR 4.4, 95%CI 0.8–23.4, p = 0.08). Among those not getting complete remission, partial remission was achieved by 6/9 (67%) patients in the CPC and by 11/27 (41%) in the HC (adjusted OR 9.2, 95%CI 1.1–78.2, p = 0.04). Thus, complete or partial remission was achieved by 12/15 patients (80%) in the CPC vs. 14/30 (47%) in the HC, respectively (adjusted OR 7.3, 95%CI 1.5–36.4, p = 0.015). 3.4. Renal response at twelve months At 12 months, 7/15 patients (47%) achieved complete remission in the CPC vs. 9/30 (30%) in the HC (adjusted OR 1.8, 95%CI 0.5–6.7, p = 0.38). Partial remission was accomplished by an additional 6/8

3.6. Adverse events Global toxicity attributable to glucocorticoids was seen in 1/15 patients (7%) in the CPC vs. 20/30 patients (67%) in the HC (p b 0.0001). No patients in the CPC had new osteoporotic fractures during the follow-up vs. 3/30 (10%) patients in the HC (p = 0.5). Such fractures happened at 24, 29 and 72 months after the diagnosis of LN. Likewise, there were no cases of osteonecrosis in the CPC vs. 7/30 (23%) cases in the HC (p = 0.07). Four of these complications happened within the first two years of follow-up, and the remaining at 45, 91 and 138 months. One patient (7%) developed metabolic disorders (diabetes mellitus) in the CPC vs. 16/30 (53%) in the HC (p = 0.007). No cases of cataracts were observed in the CPC whilst 2 cases (7%) were detected in the HC (p = 0.5). In the time-dependent analysis, patients in the HC were significantly more likely to suffer global glucocorticoid toxicity (HR 13, 95%CI 1.7– 98.1, p = 0.012) (Fig. 2) and metabolic toxicity (HR 10.6, 95%CI 1.4– 80.2, p = 0.022). Despite the absolute lack of events in the CPC, no significant differences were obtained for fractures (p = 0.54), osteonecrosis (p = 0.38) or cataracts (p = 0.69). Regarding the independent predictors of toxicity, the cumulative dose of prednisone at 6 months was independently associated with global glucocorticoid toxicity (HR 1.4, 95%CI 1.17–1.65, p b 0.0001) and with metabolic toxicity (HR 1.38 95%CI 1.14–1.66, p = 0.001), whilst the age at the diagnosis of LN was inversely related with metabolic toxicity (HR 0.95, 95%CI 0.91–1.003, p = 0.064). Osteoporotic fractures were predicted by the number of weeks on prednisone over 5 mg/d (HR 1.01, 95%CI 1.00–1.02, p = 0.064) Osteonecrosis was independently predicted by the initial prednisone dose received (HR 1.09, 95%CI 1.03– 1.15, p = 0.002) and antiphospholipid syndrome (HR 27.6, 95%CI 1.5– 509, p = 0.026). No predictors were found for cataracts (Table 4). With regard to methyl-prednisolone pulses, the total dose received was inversely related with the global glucocorticoid toxicity (OR 0.35, 95%CI 0.14–0.86, p = 0.022) and with metabolic side effects (OR 0.33, 95%CI 0.12–0.91, p = 0.034). No associations were found with any of the remaining side effects: fractures (p = 0.45), osteonecrosis (p = 0.50) and cataracts (p = 0.69).

Table 3 Treatment received within the first six months.

Prednisone initial daily doses, mg/d median (range) Cumulative prednisone doses, g median (range) Weeks to prednisone 5 mg/d median (range) Number of intravenous methylprednisolone pulses median (range) Methylprednisolone cumulative dose, g median (range) Cyclophosphamide cumulative doses, g median (range) Number of patients treated with hydroxychloroquine (%)

Cruces-protocol cohort (CPC) (n = 15)

Historic cohort (HC) (n = 30)

P value

20 (5–30) 1.65 (0.9–2.9) 16 (0–40) 8 (0–13) 1.5 (0–2.4) 3 (0–4.5) 15 (100)

50 (15–90) 4.2 (1.7–11.9) 87 (29–800) 0 (0–6) 0 (0–1) 5 (0–16.8) 10 (33)

b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001

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Fig. 1. Patients eventually achieving complete remission. Footnotes: CPC: Cruces protocol cohort HC: Historic cohort.

4. Discussion High-dose glucocorticoids, usually 1 mg/kg/d of prednisone for periods not shorter than 2 to 4 weeks with variable tapering schedules, have been the rule to treat severe manifestations of SLE whatever the accompanying immunosuppressive regime [13,18,19]. However, the basis for using such doses, the duration of therapy and the tapering schedule are essentially empirical [20,21]. The anti-inflammatory properties of glucocorticoids mediated by transrepression at the genomic level [22] are tightly linked to transactivation, which is responsible for most of glucocorticoidrelated side effects. Additional non-genomic ways exist, including activation of anti-inflammatory intracellular proteins and interaction with cellular membranes, which result in rapid and potent inhibitory effects on immune cells, without transactivation-mediated unwanted effects

[22]. From a pharmacological point of view, glucocorticoids doses can be divided in low (≤ 7.5 mg/d), medium (N 7.5 to ≤ 30 mg/d), high (N30 to ≤ 100 mg/d), very high (N100 mg/d) and pulse (≥ 250 mg/d). Genomic effects, and thus transactivation-associated toxicity, are maximum in the high dose range [21,23]. Thus, osteoporosis, osteonecrosis, myopathy, hyperglycaemia, Cushing syndrome, cataracts, glaucoma, weight gain and susceptibility to infections may be minimized by using doses of prednisone – or equivalent – lower than 5 to 7.5 mg/d [20,23–25]. Doses higher than 100 mg/d progressively activate non-genomic mechanisms, with higher potency and lower toxicity if used short-term [21]. In addition, the relative activation of the genomic and non-genomic ways differs among the several glucocorticoid compounds: prednisone works similarly by both ways whilst methylprednisolone is almost three times more active by the nongenomic way [26].

Fig. 2. Survival free of corticosteroid-associated toxicity. Footnotes: CPC: Cruces protocol cohort HC: Historic cohort.

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Table 4 Independent predictors for the different types of prednisone-attributed toxicity. Dependent variable

Independent predictors

HR (95%CI)

P value

Global prednisone toxicity Metabolic toxicitya

Cumulative dose of prednisone at 6 months (gr) Cumulative dose of prednisone at 6 months (gr) Age at the diagnosis of LN Initial dose of prednisone (mg/d) Antiphospholipid syndrome Time to prednisone dose of 5 mg/d (weeks) No predictors

1.4 (1.17–1.65) 1.38 (1.14–1.66) 0.95 (0.91–1.003) 1.03 (1.01–1.3) 27.6 (1.5–509) 1.01 (1.00–1.02)

b0.0001 0.001 0.064 0.007 0.026 0.064

Osteonecrosis Osteoporotic fractures Cataracts a

Including Cushingoid features, new diabetes mellitus, new obesity, hypercholesterolemia.

In patients with SLE, the use of glucocorticoids has been associated to irreversible damage accrual. In an inception cohort study by the Toronto group in 73 patients with at least 15 years of follow up, glucocorticoids were considered responsible for most part of the damage accrued at 5, 10 and 15 years of disease [27]. A study of 539 patients from the Hopkins Lupus Cohort showed that a cumulative dose of oral prednisone of 36.5 g doubled the risk of osteoporotic fractures, cataracts and coronary heart disease [28]. The risk of osteonecrosis and cerebrovascular events was increased 1.2-fold for every 2 months receiving doses of 60 mg/d or higher. None of these associations were found for methylprednisolone intravenous pulses. A second study by the Hopkins group showed a progressive increase of irreversible damage once doses equivalent to 6 mg/d of prednisone were reached [29]. Susceptibility to major infections has been shown to increase with the use of oral prednisone at doses over 7.5 mg/d [30]. Insulin resistance also increases among SLE patients treated with prednisone doses ≥7.5 mg/d, but it is less likely to occur at low doses [31]. In terms of efficacy, no clinical trial has compared the effects of high vs. medium doses of prednisone in the induction therapy of LN or other severe manifestations of SLE. However, some indirect comparisons suggest that prednisone doses could be reduced in LN without losing efficacy (Table 5). In the “Euro-Lupus nephritis trial”, designed to test two regimes using different doses of cyclophosphamide, patients in both arms were treated with prednisone at doses of 0.5 mg/kg/d for four weeks [9]. Likewise, the study by Illei at al. compared methylprednisolone pulses, cyclophosphamide pulses or both as induction therapy of proliferative lupus nephritis [8]. Patients included were all treated with prednisone 0.5 mg/kg/d for four weeks. A smallrandomised clinical trial sponsored by the EULAR compared continuous vs. pulse cyclophosphamide therapy in patients with proliferative LN [10]. Patients in the continuous therapy group received prednisone at an initial dose of 0.85 mg/kg/d whilst those in the pulse therapy group were initially treated with 0.3 mg/kg/d. A recent observational German study compared the differences in complete or partial remission rates between LN patients treated with prednisone doses b 20 mg/d and those treated with prednisone ≥20 mg/d [32]. In contrast, several trials that were designed to compare cyclophosphamide therapy to mycophenolate mofetil (MMP) used prednisone at 1 mg/kg/d in both treatment arms [7,11–13]. It is noteworthy that pulse methyl-prednisolone has been usually given in those regimes using lower doses of prednisone and in none of those trials using high-doses (Table 5). Despite the variable definitions of remission used in the different studies and the wide range of response rates reported after the induction phase of LN, Table 5 shows that the results obtained with regimes using initial doses of prednisone of 0.5 mg/kg/d or lower were at least as good as those reported by using doses of 1 mg/kg/d. Moreover, the results of a series of 50 patients with class III, IV and V biopsy-proven LN treated with a prednisone-free regime have been recently published [33]. This therapeutic protocol included two doses of rituximab combined with intravenous methyl-prednisolone (days 1 and 15) followed by MMP without oral glucocorticoids at all. The remission rate at 37 weeks was 90%, almost maintained until 52 weeks [33]. The same group had previously reported favourable results in a cohort of 18 patients with the same class of LN using reduced doses of prednisone

with a median dose at the induction phase of 10 mg/d. In no case prednisone was used at doses over 20 mg/d [34]. In addition to glucocorticoids and immunosuppressive drugs, hydroxychloroquine may play an important adjuvant role in the treatment of LN [35–37]. Apart from the specific effects on renal disease, antimalarials have shown to reduce lupus activity and irreversible damage accrual and to increase long-term survival [38,39]. Our results show that a therapeutic protocol using medium doses of prednisone (i.e. not higher than 30 mg/d) with rapid reduction, combined with hydroxychloroquine, immunosuppressive drugs (mainly cyclophosphamide), methyl-prednisolone pulses in more severe cases and ACE inhibitors may be more effective and with lower associated toxicity than those schemes using high doses of oral glucocorticoids. We found that remission was achieved significantly earlier in the medium dose group, differences in partial or complete remission rates persisting at 12 months with less relapses and higher long-term complete remission rates. Of note, a reduction in the levels of proteinuria within the first three to six months after LN diagnosis has been associated with an improvement in long-term renal outcome [40–42]. Part of these good results can be explained by the adjuvant therapy routinely used in the CPC: all patients were treated with hydroxychloroquine, the majority of them with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and methylprednisolone pulses were given before starting cyclophosphamide and then on a regular fortnightly basis in patients with proliferative LN. However, it is also possible that high dose oral glucocorticoids are actually deleterious for the kidney. Animal and human models show that glucocorticoids may increase the glomerular filtration rate, with proteinuria resulting from the higher intraglomerular pressure, damage to the glomerular barrier and decreased tubular reabsorption [43–45]. In addition, hypertension and obesity, common complication of glucocorticoids, can worsen proteinuria [46]. The lack of serious toxicity secondary to glucocorticoids was noteworthy in the CPC, with only one patient suffering side effects. The starting doses of prednisone not higher than 30 mg/d and the quick tapering to doses not higher than 5 mg/d resulted in a mean daily dose of prednisone below 10 mg/d within the first six months of therapy. Intravenous methyl-prednisolone pulses, used as adjuvant therapy, added no steroid-associated toxicity. Some limitations of this study are worth noting. First, the observational design, with a relatively small number of patients. Second, the majority of patients was Caucasian, although similarly good outcomes were seen in the two Afro-Caribbean women included in the CPC. Third, baseline proteinuria was lower in the CPC than in the HC, a fact that may contribute to a better prognosis. To overcome this bias, the analysis of all outcome variables was controlled for the level of initial proteinuria. Fourth, the time of follow up was significantly shorter in the CPC, with the resulting less chance for developing long term unfavourable outcomes. This bias was somewhat minimised by using time-dependent analysis, in which differences in efficacy and toxicity persisted. It was noteworthy that 70% of long-term complications such as osteonecrosis and osteoporotic fractures happened before the 4th year of follow up. On the other hand, the occurrence of mild adverse events could have been spuriously reduced in the HC, given the

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Table 5 Prednisone doses and response rates in lupus nephritis studies. Lupus nephritis class

N patients

Induction therapy

MTP

Prednisone initial doses

Start of tapering

Prednisone mean daily dose (mg) a

Response rateb

Chan [7]

IV

25

0.5 mg/kg/dd

4 weeks (5 mg every week up to 0.25 mg/kg/d)

12.8

Houssiau [9]

III, IV, Vc, Vd

0.5 mg/kg/dd

4 weeks (2.5 mg every 2 weeks)

18.5

Yee [10]

Proliferative nephritis

Contreras [11] Ginzler [12]

III, IV, Vb III, IV, V

0.85 mg/kg/d 0.3 mg/kg/d 0.5 mg/kg 1 mg/kg/d

2 weeks (protocolized tapering scheme) 1 week (up to 0.05 mg/kg/d) 4 months 1–2 weeks (10–20 mg; depending on clinical improvement)

20 6.4 27 23

Appel [13]

III, IV, V

60 mg/d

Not specified

26

Fischer-Benz [32]

III, IV, V II, III, IV, V

9.4 mg/d e 40 mg/d e 20 mg/d 50 mg/d

Not specified

This study

No No Yes No Yes Yes Yes No Yes In 39/60 patients No No No No No No Yes No

2 weeks (5 mg every 2 weeks)

IV

MMP CYC (continuous oral) MTP 1 g/m2 (12–36 bolus) CYC IV 1 g/m2 (12 bolus) Combination of both regimens CYC IV “high dose” CYC IV “low dose” CYC (continuous, oral) CYC IV (pulse therapy) CYC IV MMP CYC MMP CYC IV CYC CYC CYC “low dose” CYC “high dose”

0.8 mg/kg/d

Illei [8]

21 21 27 27 28 46 44 16 16 60 71 69 185 185 21 19 15 30

8.7e 19.2e 9 25

95% 90% 33% 63% 81% 54% 71% 6% doubled serum Cr 0% doubled serum Cr 81.5% c 52% 30% 56% 53% 85.7% 78.9% 87% 63%

CYC: cyclophosphamide. MTP: methyl-prednisolone. MMP: mycophenolate mofetil. NA: Not available. Cr: creatinine. a Mean daily doses within the first six months of treatment, calculated on the basis of data provided by the authors. b Includes “complete” and “partial remission” or “response” depending on the results reported by the authors. c At the end of the induction phase. d In case of severe flares patients could receive prednisone 1 mg/kg/d for 2 weeks. e Median daily dose.

2 weeks (see Table 1) Variable, not specified

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non-systematic recording of variables like obesity and Cushingoid appearance. Despite these limitations, we believe that our results support the use of an induction regime for LN combining immunosuppressive agents, hydroxychloroquine, methylprednisolone and antiproteinuric drugs with prednisone at medium doses, with rapid tapering to maintenance doses not higher than 5 mg/d. Indeed, the use of lower doses of glucocorticoids was already advised by Hughes back in 1982 [47]. More recently, Spanish and European consensus documents recommend reducing the initial doses of prednisone below 1 mg/kg/d and emphasize the need for using low maintenance doses [3,4]. Therefore, the need for high dose glucocorticoid regimes is now being put into question, with several possible alternatives that can be tailored to the specific clinical situation. A longer follow-up of our cohort, with the inclusion of new patients and, hopefully, future similar studies, will eventually confirm the goodness of this therapeutic approach. Competing interests The authors declare that they have no competing interests. Take-home messages • Although empirical, schemes containing high-dose prednisone are almost universally used for the induction therapy of lupus nephritis. • This study shows that combination therapy using medium-dose prednisone is associated with less glucocorticoid-related toxicity. • Our results also point to a quicker and sustained response in patients treated with medium-dose prednisone regimes. Acknowledgements Dr. Álvaro Danza was supported by a grant from the Universidad de la República (Uruguay). References [1] Huong DL, Papo T, Beaufils H, Wechsler B, Blétry O, Baumelou A, et al. Renal involvement in systemic lupus erythematosus. A study of 180 patients from a single center. Medicine (Baltimore) 1999;78:148–66. [2] Hahn BH, McMahon MA, Wilkinson A, Wallace WD, Daikh DI, Fitzgerald JD, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012;64:797–808. [3] Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71:1771–82. [4] Ruiz Irastorza G, Espinosa G, Frutos MA, Jiménez-Alonso J, Praga M, Pallarés L, et al. Diagnosis and treatment of lupus nephritis. Consensus document from the systemic autoimmune disease group (GEAS) of the Spanish Society of Internal Medicine (SEMI) and Spanish Society of Nephrology (S.E.N.). Nefrologia 2012;32(Suppl. 1):1–35. [5] Jayne D. Current management of lupus nephritis: popular misconceptions. Lupus 2007;16:217–20. [6] Bansal VK, Beto JA. Treatment of lupus nephritis: a meta-analysis of clinical trials. Am J Kidney Dis 1997;29:193–9. [7] Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156–62. [8] Illei GG, Austin HA, Crane M, Collins L, Gourley MF, Yarboro CH, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248–57. [9] Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon-Garrido E, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis. The Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46:2121–31. [10] Yee CS, Gordon C, Dostal C, Petera P, Dadoniene J, Griffiths B, et al. EULAR randomized controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophsphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis 2004;63:525–9. [11] Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971–80.

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Maternal and neonatal outcomes in pregnancies complicated by systemic lupus erythematosus: a population-based study. Nili F, et al. (J Obstet Gynaecol Can 2013; 35:323-8) performed a retrospective cohort study using the Nova Scotia Atlee Perinatal Database, 97 pregnancies in women with SLE, with 99 live births, were compared with 211 355 pregnancies in women without SLE and their 214 115 babies. All were delivered in Nova Scotia between 1988 and 2008. It was found that in women with SLE, gestational age at birth and mean neonatal birth weight were lower (P b 0.001) than in women without SLE. On bivariate analysis, severe preeclampsia, Caesarean section, newborn resuscitation for N 3 minutes, respiratory distress syndrome, assisted ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, mild to moderate intraventricular hemorrhage, retinopathy of prematurity, and congenital heart block in neonates were significantly more frequent in the women with SLE. Logistic regression analysis identified that having SLE increased the risks of Caesarean section (OR 1.8; 95% CI 1.1 to 2.8, P = 0.005), postpartum hemorrhage (OR 2.4; 95% CI 1.3 to 4.3, P = 0.003), need for blood transfusion (OR 6.9; 95% CI 2.7 to 17, P = 0.001), postpartum fever (OR 3.2; 95% CI 1.7 to 6.1, P = 0.032), small for gestational age babies (OR 1.7; 95% CI 1.005 to 2.9, P = 0.047), and gestational age ≤ 37 weeks (OR 2.1; 95% CI 1.3 to 3.4, P = 0.001). Neonatal death was not shown to be more common in women with SLE (RR 3.05; CI 0.43 to 21.44, P = 0.28). The authors concluded that mothers with SLE have an increased risk of Caesarean section, postpartum hemorrhage, and blood transfusion. They are more likely to deliver premature babies, smaller babies, and babies with congenital heart block.