Clinical Challenges in SLE: Glucocorticoids—How Much Is Too Much?

EULAR 2022 (VIRTUAL)—Since its discovery in the 1950s, prednisone has revolutionized our ability to care for patients with rheumatic disease. However, prednisone has two faces—good and evil. And despite a growing array of old and novel therapeutics, prednisone remains a prominent part of care for many patients with systemic lupus erythematosus (SLE).

At the 2022 Congress of the European Alliance of Associations for Rheumatology (EULAR), Guillermo Ruiz-Irastorza, MD, PhD, professor of medicine, BioCruces Bizkaia Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Bizkaia, Spain, shared data from his institution regarding its approach to glucocorticoid usage in SLE.

A Patient with Severe SLE

A 52-year-old woman with severe SLE was admitted with acute onset of fever, hemoptysis, bilateral lung infiltrates and hypoxia. One month earlier, she was diagnosed with lupus nephritis class IV and treated with 200 mg of hydroxychloroquine daily, 10 mg of prednisone daily (maximum dose 20 mg) and 500 mg of intravenous cyclophosphamide every 14 days as per the Euro-Lupus protocol, adding 125 mg of methylprednisolone with each cyclophosphamide dose.¹ Bronchoalveolar lavage confirmed diffuse alveolar hemorrhage. Blood cultures grew Streptococcus pneumoniae, which was treated with antibiotics.

For treatment of severe SLE, she received 250 mg of intravenous methylprednisolone daily for three days, and rituximab was added to her prior regimen. Her prednisone taper was resumed as per center protocol, with no increase from her pre-flare dose of 10 mg daily. Her oxygenation status improved, and she ultimately achieved a complete renal response.

2 Faces, 2 Mechanisms of Action

Glucocorticoids operate via two separate mechanisms of action: genomic and nongenomic.² The genomic effects of glucocorticoids occur when binding to the cytosolic glucocorticoid receptor to induce or inhibit the synthesis of regulator proteins. The genomic mechanism of action is fully active from both an anti-inflammatory and toxic perspective at a 30–40 mg dose of prednisone daily.

On the other hand, the nongenomic effects of glucocorticoids, which don’t induce regulator proteins, occur only at high doses (e.g., 125 mg of prednisone daily, with peak effect at 250–500 mg daily).² Nongenomic effects are anti-inflammatory, but nontoxic.

“We could say in a simplistic view that the genomic way is the ‘crappy’ way since patients suffer toxic effects,” Dr. RuizIrastorza explained. “The nongenomic way is the ‘cool’ way in which we have big anti-inflammatory and immunomodulatory effects without the toxicity.”

Pulse doses of glucocorticoids (e.g., 500 mg of intravenous methylprednisolone) are commonly used to treat SLE flares. “We can get maximal anti-inflammatory effects from the genomic and nongenomic pathway by giving these high doses for a short period of time. [And by only using high doses as a short pulse], there’s less time for the toxic genomic effects of glucocorticoids to appear,” Dr. Ruiz-Irastorza said.

Tip of the Iceberg

Most of us are familiar with the SLE iceberg analogy, which depicts disease activity as the tip of the iceberg and damage as the mass of ice below the surface. Studies confirm that damage doesn’t come from active SLE alone; glucocorticoid exposure contributes as well.³

In addition, damage as measured by clinical trial damage indices isn’t the only consequence of glucocorticoids. Cosmetic side effects, such as abdominal striae, are also distressing to patients. “These must be taken into consideration since they can result in a high impact on quality of life,” Dr. Ruiz-Irastorza noted.

Can We Use Less?

And now, the million-dollar question: Can we use less glucocorticoids to care for our SLE patients? “There’s growing evidence that lower doses of prednisone work well, especially in lupus nephritis,” said Dr. RuizIrastorza. “Studies show we may even be able to stop glucocorticoids completely in some patients; however, about 20% of these patients will flare, and half of those flares will be severe.”⁴

The 2019 EULAR recommendations for the management of SLE state that “during chronic maintenance treatment, glucocorticoids should be minimized to less than 7.5 mg per day (prednisone equivalent) and, when possible, withdrawn.”⁵ However, neither EULAR nor ACR guidelines provide specific instructions on how to taper prednisone, and the use of high-dose oral prednisone (1 mg/kg/day) has become standard for treating moderate to severe lupus activity. Prednisone tapering schedules vary by institution.

“In the last 15 years in our unit,” said Dr. Ruiz-Irastorza, “we’ve been using a slightly different way of tapering glucocorticoids, which we’ve based on three basic principles of action.” These include:

1. Hydroxychloroquine as the cornerstone of SLE treatment for all patients;
2. Maintenance prednisone doses no greater than 5 mg daily; and
3. Pulse doses of methylprednisolone in combination with immunosuppressives at first, with a transition to low-medium glucocorticoid doses that are quickly tapered.

“A patient who’s in ‘clinical remission’ on [maintenance] prednisone 10 mg daily is not actually in clinical remission. We must do whatever it takes to reduce this dose. Until then, we must not consider the patient in remission,” he explained.

Cruces’ Recipe

“Our scheme revolves around brief methylprednisolone pulses,” said Dr. RuizIrastorza. “We believe this approach allows rapid remission with very low toxicity cost to the patient.” By using only brief, highdose pulses, they aim to maximize the nongenomic effects of glucocorticoids, while avoiding the toxic genomic effects that accrue with longer time on prednisone doses upward of 30 mg daily.

After the methylprednisolone pulses of one to three days’ duration, the prednisone taper starts at a maximum dose of 20–30 mg daily, and is decreased to 5 mg daily by 12 weeks.⁶ For example, in an SLE patient with mild-to-moderate disease manifestations (e.g., arthritis, serositis), Dr. Ruiz-Irastorza and colleagues treat with a three-day, 125 mg methylprednisolone pulse, followed by 5–10 mg of prednisone for two to four weeks, and resumption of 5 mg of prednisone daily thereafter.

For major organ manifestations (e.g., lupus nephritis), they treat with a three-day, 250–500 mg methylprednisolone pulse, followed by a fixed prednisone taper scheme that begins at a maximum of 30 mg daily for seven days down to 5 mg daily within 12 weeks. They also administer single 125 mg doses of methylprednisolone every two weeks alongside Euro-Lupus cyclophosphamide dosing.⁶

“The methylprednisolone doses are for increasing the nongenomic effects, while decreasing the genomic effects from the oral prednisone taper as quickly as possible,” he explained.

Dr. Ruiz-Irastorza continued, “For lifethreatening SLE flares, we do almost the same thing, but add rituximab [and/or other agents]. We keep the prednisone tapering scheme the same, and continue to give methylprednisolone pulses with the Euro-Lupus protocol.”

‘There’s growing evidence that lower doses of prednisone work well, especially in lupus nephritis.’ —Guillermo Ruiz-Irastorza, MD, PhD

Their Evidence

In 2019, Dr. Ruiz-Irastorza et al. published observational data that speaks to the success of their glucocorticoid dosing approach.⁷ They compared their SLE cohort with a cohort at the University of Bordeaux and found statistically significant differences in clinical remission on treatment at year one (84% vs. 43%, P<0.001), as well as prolonged remission at year one to five (70% vs. 28%, P<0.001).

In 2021, they published further observational data regarding the addition of 125 mg of methylprednisolone to the Euro-Lupus protocol for lupus nephritis. Additional methylprednisolone pulses improved complete renal response rates above 80% at 12 months and reduced the need for oral glucocorticoids.⁸ Of note, the AURORA 1 trial that led to approval of voclosporin for the treatment of lupus nephritis used a similar prednisone tapering scheme, but achieved lower remission rates.⁹

When Dr. Ruiz-Irastorza et al. compared their patients with historical controls over the last 20 years, they found their glucocorticoid scheme reduced glucocorticoid-related damage and cardiovascular disease without compromising SLE disease control.¹⁰ “Our patients must not pay the price of glucocorticoid toxicity to get SLE well controlled,” said Dr. Ruiz-Irastorza. We now have ways to treat the disease in a different manner.”

In Sum

Glucocorticoids are a necessary yet toxic component of SLE treatment, and tapering schemes differ by institution and individual prescriber. Dr. Ruiz-Irastorza and colleagues shared captivating data from their experience treating patients with brief methylprednisolone pulses and more rapid, lower dose tapering prednisone schemes. In the future, we hope further studies will confirm the safety and efficacy of this approach and spare our patients from glucocorticoid-related damage.

---

Samantha C. Shapiro, MD, is an academic rheumatologist and an affiliate faculty member of the Dell Medical School at the University of Texas at Austin. She is also a member of the ACR Insurance Subcommittee.

References

1. Houssiau FA, Vasconcelos C, D’Cruz D, 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 Aug;46(8):2121–2131.
2. Buttgereit F, Straub RH, Wehling M, Burmester G-R. Glucocorticoids in the treatment of rheumatic diseases: An update on the mechanisms of action. Arthritis Rheum. 2004 Nov;50(11):3408–3417.
3. Ugarte-Gil MF, Mak A, Leong J, et al. Impact of glucocorticoids on the incidence of lupus-related major organ damage: A systematic literature review and meta-regression analysis of longitudinal observational studies. Lupus Sci Med. 2021 Dec;8(1):e000590.
4. Ji L, Xie W, Zhang Z. Low-dose glucocorticoids should be withdrawn or continued in systemic lupus erythematosus? A systematic review and meta-analysis on risk of flare and damage accrual. Rheumatology (Oxford). 2021 Dec 1;60(12):5517–5526.
5. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019 Jun;78(6):736–745.
6. Ruiz-Irastorza G, Bertsias G. Treating systemic lupus erythematosus in the 21st century: New drugs and new perspectives on old drugs. Rheumatology (Oxford). 2021 Dec 5;59(Suppl5):v69–v81.
7. Ruiz-Irastorza G, Ruiz-Estevez B, Lazaro E, et al. Prolonged remission in SLE is possible by using reduced doses of prednisone: An observational study from the Lupus-Cruces and Lupus-Bordeaux inception cohorts. Autoimmun Rev. 2019 Sep;18(9):102359.
8. Ruiz-Irastorza G, Dueña-Bartolome L, Dunder S, et al. Eurolupus cyclophosphamide plus repeated pulses of methyl-prednisolone for the induction therapy of class III, IV and V lupus nephritis. Autoimmun Rev. 2021 Oct;20(10):102898.
9. Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021 May 29;397(10289):2070–2080.
10. Ruiz-Arruza I, Lozano J, Cabezas-Rodriguez I, et al. Restrictive use of oral glucocorticoids in systemic lupus erythematosus and prevention of damage without worsening long-term disease control: An observational study. Arthritis Care Res (Hoboken). 2018 Apr;70(4):582–591.