The Long and Winding Road: What We Think We Know About The Treatment of Proliferative Lupus Nephritis

This is Part 1 of a 2-part series. Part 2 focuses on a recent meta-analysis published in AJKD by Palmer et al.

The history of the treatment of proliferative lupus nephritis is a long journey that spans over half a century and travels down many often-divergent roads. This past tells the story of the renal biopsy, as well as the paths to the use of corticosteroids, azathioprine, cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors, and even rituximab. There is no shortage of treatment options for lupus nephritis, but it is important to know this history to understand the strength of the evidence (or lack thereof) on which we base our treatment decisions.

Your standard induction treatment may be high dose oral steroids and mycophenolate mofetil, which is a sensible option, but other very reasonable options exist. Evidence strongly supporting one strategy over the other is rarely available and the tie-breakers may often be related to considerations of compliance, side effects, availability, route of administration, and cost. Lupus nephritis was once a terminal disease but this changed with the availability of steroids, the workhorse of essentially all induction protocols for proliferative lupus nephritis. This is where the story begins.

In 1930, an adrenal extract was found to prolong the life of patients with Addison’s disease. It took 20 years of painstaking laboratory work to develop cortisone, which had miraculous effects on patients with debilitating arthritis, and led to a Nobel Prize in Medicine in 1950! Prednisone became available 5 years later and had the advantage of being a potent oral glucocorticoid with essentially no mineralocorticoid effect.

In 1957, lupus giants Muehrcke, Pollack, Pirani, and Kark reported 10 patients in the new field of renal biopsy proven lupus nephritis who received 50 mg of cortisone a day (equivalent to about 10 mg of prednisone/d) with abysmal outcomes, watching all 10 die, 8 of renal failure. Then in 1961, they reported their results using “large doses” (47.5 mg/d) of the now readily available and much stronger prednisone in 16 patients with lupus nephritis. Only 7 died, 5 in renal failure, but 9 survived. This was confirmed in Pollack’s 1964 report comparing histology and clinical outcomes in patients receiving high v low dose prednisone. Prednisone at 1 mg/kg/day eventually became a standard of care for baseline induction therapy for patients with proliferative lupus nephritis.

While steroids became the critical element in any lupus nephritis induction protocol, the future introduced many immunosuppressive agents that were either added to steroid induction protocols or found a role as “steroid sparing” for the maintenance phase of the treatment. Although the alkylating agent mechlorethamine (nitrogen mustard) and the antimetabolites 6-mercaptopurine and 6-thioguanine (precursors to azathioprine) were starting to be used in the early 1960s for autoimmune diseases including lupus nephritis, it wasn’t until the 1970s when azathioprine and cyclophosphamide (another alkylating agent) were added to steroid protocols for lupus nephritis. The evidence that these combinations were superior to prednisone alone was not strong, with most studies flawed by small patient numbers, inconsistent histologic classification, and short term follow-up.

In 1984, a meta-analysis by Felson and Anderson published in the NEJM determined that the addition of azathioprine or oral cyclophosphamide (CycP) to prednisone provided superior renal outcomes than when using prednisone alone. In 1986, also in the NEJM, the NIH group led by Balow and Austin reported their experiences with immunosuppressive agents for lupus nephritis in an article entitled “Therapy of lupus nephritis: Controlled trial of prednisone and cytotoxic drugs” which was a pooling of their experiences treating 107 patients with lupus nephritis from 1969-1981, and thus, was not at all controlled. This report was novel, however, in that they reported the use of CycP administered as monthly intravenous boluses (IV-CycP). By 1987, they were using the IV bolus route exclusively. Simultaneously, the Collaborative Study Group (CSG) led by Lewis et al was studying the effect of plasmapheresis added to daily oral CycP and prednisone in 86 patients with severe lupus nephritis (the addition of pheresis did not improve clinical outcome).

However, as the NIH group’s data had wide exposure by nature of being the lead article in the NEJM, the intermittent method using IV-CycP bolus became a popular treatment option. The two different routes of CycP administration have never been compared in a randomized clinical trial, but a meta-analysis by Bansal and Beto in 1997, as well as a 2006 retrospective comparison by Mok et al of 212 patients (½ receiving IV and the other ½ oral CycP) failed to find one route superior to the other. In that regard, McKinley et al reported their experiences with oral and IV-CycP were similar, but that oral CycP was considerably cheaper and more convenient than the IV route and considered oral CycP “an underused therapeutic option.”

One major difference between the two routes is the cumulative dose (CD) of CycP. While the NIH protocol originally recommended 1.0 gm/m2 q 3 months for 4 years (CD ~ 28 grams), by 2004 the IV route morphed into 6 monthly IV-CycP boluses of 0.5-1.0 g/m2,  followed by maintenance boluses every three months for 1-3 years. If this were done for 2 years, the CD of IV-CycP would be 24 grams. The CSG protocol with 6-8 weeks of oral CycP at 150 mg/day would have a maximum CD of 9 grams. Thus, the main difference between the two routes, besides the potential cost considerations, is that the CSG protocol has a lower CD that is administered in a much more “up-front” manner, with completion of the cytotoxic element of therapy in only 8 weeks as opposed to 1-3 years as seen in the typical IV protocols. And just when you think you might have the CycP story into perspective, along comes “Eurolupus” (n=90), in which 3 grams (the lowest CD yet of 3 grams) of IV-CycP (500 mg q2 weeks for 6 doses over 3 months) was found to be non-inferior to 8.5 grams over a year using a monthly IV bolus regimen.

The next big addition to the lupus armamentarium came with the FDA’s approval of mycophenolate mofetil (MMF) for its use in transplantation in 1995. MMF inhibits inosine monophosphate dehydrogenase (IMP) and, as such, has effects similar to the other antimetabolites. It was originally found to have antibiotic activity but was eventually found to also have antiviral, antifungal, and anti-cancer properties. However, it wasn’t until the 1980s that MMF was determined to have potent immunosuppressive effects that led to studies in organ transplantation.

It did not take long before this exciting new drug was being used in lupus nephritis. By 2000, Chan et al from Hong Kong (n=42) reported MMF to be equivalent to oral CycP (12 months MMF v 6 months CycP followed by 6 months azathioprine) for induction therapy. In 2005, Ginzler et al reported a US only study in which the majority of the participants were African-American. They concluded that MMF was superior to and with fewer side effects than IV-CycP for induction (n=140). Finally, in 2009, Appel et al reported the ALMs trial (n=370) that essentially repeated their earlier MMV v IV-CycP comparison but on an international scale; however, this time they determined MMF to be similar to IV-CycP in renal and mortality outcomes, although MMF led to improved renal outcomes in the African-American subset. It is worth considering that “the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis,” and also that the follow-up maintenance phase of ALMs reported that patients in the MMF induction arm of the trial were twice as likely to fail maintenance (renal relapse) than those that received induction with IV-CycP (21% v 11%). While this difference was not statistically significant, it may be a signal that represents a tangible difference between these induction options.

Even though azathioprine (MMF’s little brother) was left behind as an induction therapy for the last 20 years, a report from Grootscholten et al in 2006 compared azathioprine to IV-CycP pulse therapy (n=87) and found no difference between the groups in the end-point of doubling of serum creatinine. However, with the large and well-publicized success of MMF, azathioprine didn’t stand a chance.

Calcineurin inhibitors (MMF’s cousins?) have also been studied for a host of renal lupus presentations. While there are efficacy signals with the use of cyclosporine and tacrolimus for induction therapy (especially in the Asian population), they are still not generally considered a first-line induction option for proliferative lupus nephritis. This uncertainty is underscored in the 5-part “Pro and Con” section on this topic in NDT in 2016.  A newer CNI, voclosporin, is presently undergoing study in patients with active lupus nephritis.

If MMF was the “new kid on the block”, rituximab became the “golden boy” with FDA approval in 1997 for the treatment of B-cell non-Hodgkin lymphomas. Rituximab, an antibody against CD20 that is expressed on most early and differentiated B-cells, alters the cell surface and allows natural killer cells to attack and kill B-cells. With an appreciation for the role of B-cells in autoimmune diseases, rituximab has been used in many of these conditions, including lupus nephritis. The LUNAR trial reported by Rovin et al (n=144) compared MMF and prednisone to MMF and prednisone with the addition of rituximab. The results were similar in both study arms but since rituximab was added to standard therapy, the question of rituximab as a stand-alone therapy remained. The nonrandomized “Rituxilup” trial (n=50) used rituximab (two 1 gram rituximab doses and two 500mg doses of methylprednisolone both on days 1 and 15), followed by MMF maintenance (but without further induction or maintenance period steroids), and reported 90% of patients achieving a partial or complete remission by 37 weeks. Rituxilup specifically represents the first induction protocol that is essentially steroid-free. A recent study in 44 pediatric (< 14 years of age) patients comparing rituximab to MMF and IV-CycP found that flare-free survival was significantly higher and steroid requirements were significantly less at 3 years in the patients receiving rituximab compared to either MMF or IV-CycP. While the experience with rituximab as an induction therapy for lupus nephritis is still significantly less than with either MMF or IV-CycP, these data are encouraging that rituximab’s future looks bright.

Maintenance therapy for lupus nephritis relies on the concept that while induction protocols are effective in inducing a remission, relapses (“flares”) are common. Without a strategy to keep the disease quiescent, you will have cycles of induction followed by drug-free remission, followed by the need for re-induction. Induction takes its toll and while maintenance therapies is not entirely benign, the side effects are considered minimal compared to the risks associated with repeated induction. In the CSG’s lupus nephritis plasmapheresis trial, oral CycP was administered for only two months, but the steroid taper schedule lasted for 3 years. At that point, only if the patient was considered “no disease activity” were steroids stopped.

The paradigm of maintenance therapies subsequently shifted to a more rapid taper of steroids, with the introduction of chronic steroid sparing agents (initially azathioprine and then MMF) that were continued for an indefinite period. As would be expected, these two non-steroid maintenance options were compared. The aforementioned ALMs trial had a follow-up maintenance phase (n=227) in which patients were randomized to receive either MMF or azathioprine for 36-months. The results of this trial found MMF to be the clearly superior maintenance option. On the other hand, the “Eurolupus” trial also had a similar follow-up phase “MAINTAIN Nephritis“ (n=105) in which they found no difference between azathioprine and MMF as maintenance agents for both 4– and 10-year follow-up periods.

In these protocol comparisons, I did not discuss toxicity differences except for the implications of cumulative dosing of CycP. It is also worth pointing out that there were few consistencies between treatment protocols. In these various studies, CycP was used orally for 2-12 months and intravenously for 3-48 months. Some induction trials included high-dose IV steroid “pulses,” others did not. These protocol discrepancies are ubiquitous and make treatment comparisons very difficult. Primary outcomes were typically centered around some measure of remission, but these definitions also varied markedly both in what was being measured (absolute level or % change in proteinuria, serum creatinine, or both) and how long a follow-up time was utilized for that determination (months to years).

To further confuse matters, histologic inclusion criteria were not consistent. All lupus nephritis is not the same. For example, many of the studies included a significant percentage of patients without proliferative lesions (WHO V membranous as the only glomerular pathology). In addition, the mean serum creatinine values at baseline varied from 1-2.0 mg/dl. These are two major predictors of outcome independent of treatment (see table below).

Study

WHO V alone Serum Creatinine
NIH 1986 15 % 1.0 mg/dl
CSG 1992 0% 2.0 mg/dl
Eurolupus 2002 8% 1.2 mg/dl
ALMs 2009 32% 1.1 mg/dl

With all the heterogeneity in inclusion criteria, treatment protocols, and outcome metrics, picking a winner is like the game of rock-paper-scissors. You can always determine a winner when you compare one treatment strategy to another, but there is no clear winner when you look at them all.

To summarize, what has the last 50 years taught us about the treatment of proliferative lupus nephritis?

  • High dose steroids are better than low dose steroids.
  • Adding a cytotoxic agent is probably better than steroids alone but adding plasmapheresis doesn’t help.
  • Steroid sparing maintenance protocols are an important adjunct to induction.

However, many questions remain, such as:

  • Does it matter if you use an oral or an IV-CycP route?
  • Can you get away with the “Eurolupus” protocol using a cumulative IV-CycP dose of only 3 grams, and if so, does that apply only to those of white European descent where it was studied?
  • Should MMF be the preferred induction therapy for African-Americans?
  • Is there really no role for azathioprine in induction?
  • Will rituximab provide improved results or at least be more steroid sparing than MMF or CycP?
  • Should CNIs even be seriously considered for induction at this point?
  • Is MMF really better than azathioprine for maintenance?
  • Should maintenance therapy be continued only for a finite time period?

To fall back on the ubiquitous cop-out of “larger studies are required to answer these questions” is unrealistic. Lupus nephritis is not a common or homogeneous condition and more “definitive” studies are unlikely to occur. And as the past has taught us, just when we think we may have it figured out, a new monoclonal antibody or class of drugs will emerge. It will be compared to the most recent popular therapy in a modestly sized population of patients with diverse histology and renal function. It may be found only to be “non-inferior,” and we will likely be left with as many questions as answers. Fortunately, this long and winding road of therapy options may not be getting any straighter, but it does keep getting wider.

– Post prepared by Roger Rodby, AJKD Social Media Advisory Board Member. Follow him @NephRodby.

This is Part 1 of a 2-part series. Part 2 focuses on a recent meta-analysis published in AJKD by Palmer et al (Open Access).

6 Comments on The Long and Winding Road: What We Think We Know About The Treatment of Proliferative Lupus Nephritis

  1. This is an excellent review with expert commentary. Great work! Remember readers Nephrologists are encouraged to use Hydroxychloroquine. We are not great at initiating it. @DoctorGates

  2. Dear Roger – great overview and always like going back to the history. BUT would argue with your statement “High dose steroids are better than low dose steroids”. Actually I think there’s a lot of evidence (other than our’s which you kindly cite!) which supports exactly the opposite. Indeed, everywhere where lower doses have been tried, less is definitely more.
    1. We know that adding a biologic in transplantation has allowed the development of steroid sparing protocols.
    In lupus –
    2. Quote from Coplon NS et al NEJM 1983; 308:186-90 – “In an attempt to define the long-term clinical course of systemic lupus erythematosus followed by endstage renal disease, we studied 28 patients with lupus nephritis at Stanford University between January 1969 and December 1980. The clinical and serologic manifestations of both renal and nonrenal disease improved with long-term hemodialysis despite the withdrawal of immunosuppressive drugs in almost all the patients. Rehabilitation was excellent, and a return to normal physical activity was generally the rule. The mortality rate was low (6 of the 28 patients died), but death occurred primarily in patients receiving high doses of prednisone. Recovery from renal failure and discontinuation of dialysis were not rare (eight patients recovered) despite the reduction in immunosuppressive drugs” – note more deaths in those on more steroids.
    3. Edwards JC et al Ann Rheum Dis 1987 – RCT SLE 21 patients with severe disease- compared 100mg (milligrams!) x 3 vs 1000mg x 3 in efficacy – no advantage to the bigger dose
    4. Badsha H Lupus 2002 11:508-13 – retrospective study. Similar baseline SLEDAI. 26 patients had 1-1.5grams methyl pred (“low dose”) (+ IV CyP) and 29 patients had 3-5g MP (high dose !). Looked at SLEDAI at baseline and 6 months. NO difference in efficacy but way more serious infections in the high dose group and way way higher mortality in high dose if albumin 20mg po at baseline with those who had received <20mg pred po at baseline – NO difference in renal outcomes and not more likely to flare over 10 years f/up
    6. MYLUPUS open label 24 week RCT – Myfortic plus 1mg/kg/day oral steroid starting dose vs 0.5mg/kg/day for nephritis – absolutely no difference between any renal outcome at 24 weeks despite 50% less steroid dose but far fewer severe infections and no zoster in low dose patients 7/42 in 1mg/kg group).
    7. Ruiz-Irastorza et al, Autoimmunity Rev 2014; 13: 206-14 – tapers oral pred to 5mg by 16 weeks and uses pulses of low dose MP for flares) plus MMF. Current group vs control historical group with much higher doses of steroid – much better renal remission and way lower toxicity.
    8. Recent Aurinia trial of MMF and steroids plus placebo or Voclosporin. Radical steroid taper – 1g MP at start, max oral dose 25mg od and down to 5mg by 8 weeks and 2.5mg by 12 weeks. Control arm better outcomes than ALMS trial at 24 weeks despite much lower doses of steroid and 48 week data even better.

    SO – we really really need to be using far lower doses of steroids. The evidence is growing and the original evidence really wasn't based on much!

    And absolutely agree with the comment re hydroxychloroquine – should be there from the start.

    Thanks
    Liz Lightstone, Prof of Renal Medicine, Imperial College Lupus Centre and Hammersmith Hospital.
    @kidneydoc101

  3. Roger Rodby // May 26, 2017 at 6:09 pm // Reply

    Professor Lightstone,

    Firstly I want to thank you for your interest in Lupus Nephritis and your contributions to this most interesting and challenging field. You have been an anti-steroid advocate for a long time. Even just considering designing a steroid free trial such as Rituxilup is impressive. Few medicines have more challenging side effects than corticosteroids including weight gain, mood swings, osteoporosis, bruising, GI intolerability, cataracts, insomnia, myopathy, Cushingoid features among other things. Who wouldn’t want to use less steroids?

    I said “high dose steroids are better than low dose steroids”. This statement was simply in historical reference to the very beginning of the use of steroids in lupus nephritis in which ~10 mg of prednisone/d had 100% mortality in 10 patients (1957) followed by 47.5 mg/d in 16 patients reporting only 7 deaths (1961). Eventually this higher dose moved up to 1 mg/kg/day of prednisone.

    Note that this all happened in the ABSENCE of steroid sparing adjunct therapies. These steroid sparing drugs are usually “sparing” in the maintenance phase, and not in the induction phase. Most major lupus nephritis trials all used essentially 1 mg/kg/day of prednisone in the induction phase, perhaps with the exception of your Rituxilup trial. But even in that study you front loaded your patients with 2 pulses of methylprednisolone in addition to the rituximab followed by MMF. We know almost nothing about the magnitude and length of the immunosuppressive effects of pulse dose steroids. And not to beat a dead horse, your study had 40% of the patients with membranous lupus as their only pathology.

    You listed 7 studies and points that challenge that statement. I will address each of them.

    1. “We know that adding a biologic in transplantation has allowed the development of steroid sparing protocols.”

    Of course, but apples and oranges here as transplant induction is a nuclear attack on the immune system that may need steroids.
    In lupus

    2. “Quote from Coplon NS et al NEJM 1983; 308:186-90 – “In an attempt to define the long-term clinical course of systemic lupus erythematosus followed by endstage renal disease, we studied 28 patients with lupus nephritis at Stanford University between January 1969 and December 1980. The clinical and serologic manifestations of both renal and nonrenal disease improved with long-term hemodialysis despite the withdrawal of immunosuppressive drugs in almost all the patients. Rehabilitation was excellent, and a return to normal physical activity was generally the rule. The mortality rate was low (6 of the 28 patients died), but death occurred primarily in patients receiving high doses of prednisone. Recovery from renal failure and discontinuation of dialysis were not rare (eight patients recovered) despite the reduction in immunosuppressive drugs” – note more deaths in those on more steroids.”

    It is well established that the immunologic and clinical activity of SLE decreases in ESRD. ESRD is associated with suppression of essentially all aspects of the immune system: Uremia is immunosuppressive. Steroid toxicity (infections) in that setting cannot be blamed on steroids alone.

    3. “Edwards JC et al Ann Rheum Dis 1987 – RCT SLE 21 patients with severe disease- compared 100mg (milligrams!) x 3 vs 1000mg x 3 in efficacy – no advantage to the bigger dose”

    This was a study in which 21 (21!) SLE patients received 3 doses of IV steroids, and only 6 had “nephritis”, whatever that referred to. I cannot make anything of that in the context of my original point.

    4. “Badsha H Lupus 2002 11:508-13 – retrospective study. Similar baseline SLEDAI. 26 patients had 1-1.5grams methyl pred (“low dose”) (+ IV CyP) and 29 patients had 3-5g MP (high dose !). Looked at SLEDAI at baseline and 6 months. NO difference in efficacy but way more serious infections in the high dose group and way way higher mortality in high dose if albumin 20mg po at baseline with those who had received <20mg pred po at baseline – NO difference in renal outcomes and not more likely to flare over 10 years f/up"

    Again this was pulse dosing, n = 26, only 50% had “nephritis”, and I would argue that 1.5 grams is not a low dose but that 3-5 grams is an excessive dose and that explains the poorer outcomes, which by the way occurred 75% of the time in the first month following the pulses.

    5. 5 was omitted

    6. "MYLUPUS open label 24 week RCT – Myfortic plus 1mg/kg/day oral steroid starting dose vs 0.5mg/kg/day for nephritis – absolutely no difference between any renal outcome at 24 weeks despite 50% less steroid dose but far fewer severe infections and no zoster in low dose patients 7/42 in 1mg/kg group)."

    MyLupus: N=81 Maximum prednisone dose 35 mg/day v 70 mg/day after three 500 mg pulses. All but 7 patients had biopsy proven proliferative lupus nephritis. Responses were similar at 24 weeks (too early to know long term-outcome) but you may have something here!

    7. "Ruiz-Irastorza et al, Autoimmunity Rev 2014; 13: 206-14 – tapers oral pred to 5mg by 16 weeks and uses pulses of low dose MP for flares) plus MMF. Current group vs control historical group with much higher doses of steroid – much better renal remission and way lower toxicity."

    The title of this article is “Prednisone in lupus nephritis: How much is enough?” This is a comparison of the Cruces-protocol cohort (N = 15) in which

    Induction
    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).
    Maintenance
    Prednisone 2.5–5 mg/d + mycophenolate mofetil or azathioprine 

    This doesn’t sound like low dose to me when you add up all the IV steroids.
    To a historical control used NIH based protocol (N = 30). Non-ramdomized, and these treatment protocols are so vastly different I would not make anything out of this.

    8. "Recent Aurinia trial of MMF and steroids plus placebo or Voclosporin. Radical steroid taper – 1g MP at start, max oral dose 25mg od and down to 5mg by 8 weeks and 2.5mg by 12 weeks. Control arm better outcomes than ALMS trial at 24 weeks despite much lower doses of steroid and 48 week data even better."

    This is not published yet, but from an internet search:
    “Complete remission occurred at 24 weeks in 32.6% of 89 subjects who received 23.7 mg of voclosporin twice daily and standard of care therapy and in 19.3% of 88 control subjects who received placebo and standard of care therapy”
    19.3% does not sound very successful to me.

    HOWEVER, to be fair to you, I agree that the standard 1 mg/kg/day dosing may be excessive, but I am hardly convinced one way or the other based on the data, and we really have no idea what role steroid pulsing plays when followed by “lower dose” prednisone. If 1 mg/kg/day is unnecessary, is .75 mg/kg/day or even .5 mg/kg/day enough. I strongly doubt we will ever know that.

    To be fair to me, my statement only really said that 10 mg/day was too little.

    Dr. Edmund Lewis always preached that the risk of undertreating can lead to much more immunosuppression in the end, as you have to add higher dose induction to the cumulative dose of the first lower dose induction. Induction is TOUGH, but do it right the first time, then taper steroids and use a real dose of some steroid sparing immunosuppressive agent for maintenance, and prevent further flares. That is how I believe lupus nephritis should be treated.

    In the CSGs plasmapheresis in severe lupus nephritis trial, NEJM 1992, induction was with cyclophosphamide and prednisone, and the prednisone taper lasted forever (not off prednisone for years in some circumstances), there was no good steroid sparing maintenance regimen at that time. I followed a number of these patients for years, replacing hips and shoulders…

    Now we know better and we initiate a steroid sparing maintenance therapy much sooner. We also continue maintenance to avoid flares that would require steroid rich reinduction. Those two steroid sparing maneuvers are much more important to me than the dose of steroids for the first couple of months.

  4. Hi Roger – I think we largely agree – there are inadequate data on the right dose, duration and how to wean steroids. We need studies to address these. However, my argument is that wherever people have tried lower doses the results have been just fine with far fewer adverse events. We’ve moved beyond short term health of patients with lupus nephritis – we want them to have long term good quality lives – and minimising steroids has to be central to that.

    I would argue with your tendency to dismiss small studies. Just because they are small does not make them irrelevant. Chan changed practice overnight with his MMF vs Oral CyP study in 2000 – NEJM 343:1156-2 Chan TM et al – but the study only included 42 patients in each arm. We were all desperate to hear that MMF was safe and efficacious vs all the problems of high dose IV CyP or oral CyP (which TM Chan uses and which leads to very high cumulative doses). Importantly, they published an extended study with a few more patients (31 in each arm) but with long term follow up (median 63 months) (JASN 2005; 16:1076-84 Chan TM et al) – critical for the management of lupus nephritis. The similarity in efficacy for induction was maintained in the extended group as was the relapse rate and numbers developing renal impairment. There’s no power given in either paper but the statistical analysis plan was about 3 times as long in the 2005 vs the 2000 paper. However, this tiny study changed practice almost overnight. It showed equivalence. The ALMS study confirmed our beliefs – it was a failed study (was designed to show superiority of MMF over CyP but did not) but we mostly interpreted it as showing equivalence. A study of 370 patients largely confirmed the study of 42 patients from Chan. I’m in no way knocking the ALMS study – it was a massive achievement to do a global LN study on that scale. But it used a lot of steroids and the taper was just based on historical “we’ve always done that” rather than there is firm evidence to support it. I use the same taper in my Rituxilup trial control arm and it’s a lot of steroids.

    The other small study that has massively impacted practice is the Eurolupus study. Just 90 patients were randomised to either high dose (NIH IV CyP) or low dose (500mg IV CyP x 6 then aza) – the patient population was almost entirely northern European caucasian the low dose group was as efficacious as the high dose group. (Houssiau F et al, Arthritis Rheum 2002 46:2121-31). This study too has stood the test of time – they have reported 10 year follow up confirming similar efficacy vis a vis flares and renal endpoints and less toxicity (Houssiau F et al Ann Rheum Dis 2010; 69:61-4). Moreover, Dall-Era (Arthritis Rheumatol 2015; 67:1305-13) showed that the data from the ELNT trial support a less stringent proteinuria endpoint at 1 year to define those who will have preserved renal function at 7 years. I stress this detail because the original small study, likely to be dismissed on the basis of size, was powered at 20% – 20%!! Because Houssiau recognised this is a challenging condition, it is hard to recruit, it was an investigator led, unfunded study and he was being realistic. He has changed practice with his small study.

    I understand all the limitations of small studies especially if single centre. But it does not mean they are wrong. Doing large trials in LN is challenging and yet it does not mean that we should dismiss the data of smaller studies. We desperately need to know how little steroid we can use and for how long we should use it. There are very strong small studies out there suggesting the current approach is just wrong.

  5. Roger Rodby // May 29, 2017 at 6:34 pm // Reply

    Professor Lightstone,

    I have no issue with a single word of your latest post. You make important points using good examples.
    In my part two editorial on the SLE meta-analysis https://ajkdblog.org/2017/05/25/the-good-news-and-the-good-news-about-the-treatment-of-lupus-nephritis/, I end it by saying “Steroids are the workhorses of induction. Steroids have immediate anti-inflammatory effects that immunosuppressive agents lack” … This is a basic tenet that I feel cannot be ignored. “Hot lupus” needs to be hit hard and hit now. But does that require the doses of steroids that we give, for as long as we give. I don’t think we know. If you pulse a patient how long does that last? Is a 1 gram pulse better than a 500 mg pulse or even a 250 mg pulse? 250 mg of solumedrol is a HUGE dose of steroids, and we often give 3 consecutive daily pulses when we pulse. The number 1000 (1 gram) is a nice round number, and is thus totally arbitrary. I am unaware of any lupus trial that has tested pulsing v no pulsing. Additionally, orally 1 mg/kg is also a nice round number but is also arbitrary. I hope you are right that we can get away with lower doses of steroids. Perhaps we only need 2 weeks (an arbitrary number I make up) of 1 mg/kg/d until the other induction medication kicks in and we could taper twice as fast as what we are used to. Perhaps if you pulse you could start at 0.5 mg/kg/d and not need the higher initial dose. These are questions that need to be answered that I hope my colleagues “across the pond” will continue to answer. Clearly Rituxilup and EuroLupus (Europe) and MMF (China) shows me that thinking outside the cyclophosphamide/high-dose steroids default box is not coming from the States.

  6. Guillermo Ruiz-Irastorza // June 3, 2017 at 6:04 pm // Reply

    Dear Roger and Liz,
    Can I join the discussion?
    I have not much to add to your thorough review of the literature. I absolutely stand by Prof. Lightstone regarding the need to lowering the amount of ORAL glucocorticoids. And this is the point I would like to make clear. Pulse methyl-prednisolone over 100 mg activates the non-genomic way of glucocorticoids, which is free from most side effects attributed to the genomic way. If given in short courses, pulses of steroids have not been linked to damage accrual in SLE. That is the rationale of the Lupus-Cruces protocol: using intermittent iv. pulses to start at lower doses of oral prednisone (20-30 mg/d) and getting to 5 mg/d in 12-14 weeks. Our experience has grown up and the results are just the same: very low toxicity, very high rates of response.
    I agree with Liz, we need to expand the idea that reducing the dose of prednisone is possible!

    Thank you for your great comments.

    Guillermo Ruiz-Irastorza. Autoimmune Diseases Research Unit. Hospital Universitario Cruces.

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