van Vollenhoven’s Treatment Advances in Lupus Save

5 Key Takeaways

• Better Biomarkers in SLE should guide biologic choice. Belimumab favors serologically active disease (high dsDNA, low C3/C4). Anifrolumab may be best with IFN-signature positivity and excels in cutaneous disease.
• Glucocorticoid stewardship is now explicit. The chronic ceiling is ≤5 mg/day, with a goal of zero or NO steroids; using a treat-to-target framework that targets remission (DORIS) or LLDAS at 3–6-month intervals.
• The emerging SLE pipeline introduces new mechanisms and targets - TYK2, pDC/BDCA2, CD40L, S1P1, BAFF-R depletion, and JAK1 agents are all in Phase III. Oral options would add convenience. Head-to-head data will be lacking.
• CAR-T may potentially reset the therapeutic ceiling, but it is not yet a strategy and we still do not have any controlled randomized trial data. Drug-free remission appears more achievable. Conditioning, toxicity, cost, and inpatient burden will confine near-term use to refractory, organ-threatening disease.
• Endpoints and definitions are being rebuilt. TRM-SLE, DORIS+, and ENDORSED will shape both future trials and how “cure-like” outcomes are labeled and approved.

Professor van Vollenhoven has compiled a state-of-the-art review on lupus treatment advances – current and future. SLE management is entering an unprecedented phase. Four agents are now approved for lupus nephritis (voclosporin, belimumab, anifrolumab, obinutuzumab), seven or more are in late-stage development, and CD19-directed CAR-T therapies are in development with the hope of even better outcomes.

Current Armamentarium: Calibrated Expectations

• Glucocorticoids: the chronic ceiling is now ≤5 mg/day prednisone equivalent, with tapering to zero increasingly advocated. Pulse dosing is 1000 mg/day × 3 days; severe flares use 0.5–1.0 mg/kg/day; moderate flares use 15–20 mg/day.
• Hydroxychloroquine: remains foundational for all patients, but it is slow, modest in potency, and rarely sufficient alone.
• Belimumab is most effective in patients with high anti-dsDNA and low complement. It reduces flares, GC use, and damage, with full effect at 3–6 months.
• Anifrolumab has demonstrable efficacy only in IFN-signature–positive patients. It is especially effective for cutaneous disease, often within weeks. Zoster is the only clearly overrepresented infection. A subcutaneous formulation succeeded in Phase III.
• Rituximab failed both RCTs (LUNAR, EXPLORER) but remains widely used off label for refractory disease.

Lupus Nephritis

• MMF and Euro-Lupus cyclophosphamide (6 biweekly 500 mg infusions, then AZA/MMF maintenance) remain backbone induction regimens.
• Belimumab (BLISS-LN) and obinutuzumab add renal response. Obinutuzumab is given as 2 infusions repeated every 6 months.
• Voclosporin (AURORA 1) is effective without the hypertension seen with cyclosporine.
• Tacrolimus outperformed MMF in Asian trials.

Late-Stage Pipeline (Phase III)

Dapirolizumab and cenerimod are notable because they add new mechanisms: T-cell costimulation blockade and lymphocyte trafficking.

Cellular Therapies

• The Erlangen CD19 CAR-T experience grew from 5 to 15 patients. It showed near-universal responses, with drug-free remissions lasting months to years.
• Repopulating B cells appear naïve and non-autoimmune.
• Persistent caveats:
  • Confounding: the fludarabine/cyclophosphamide conditioning confounds attribution of benefit and carries fertility risk.
  • Toxicity: CRS, ICANS, and ICAHS can occur.
  • Logistics: inpatient stays of 1–3 weeks are standard.
  • Unknowns: long-term risks are undefined, as is whether re-treatment is feasible.
• Emerging alternatives:
  • Bispecific T-cell engagers (teclistamab case report in NEJM 2024), which require repeated rather than one-off dosing.
  • Allogeneic “off-the-shelf” CAR-T.
  • In vivo CAR-T generation.
  • Antigen-specific CAAR-T.
  • Treg-directed strategies, which are thus far disappointing.

Regulatory and Definitional Infrastructure

• TRM-SLE: a new trial endpoint intended to replace SRI and BICLA, which the author criticizes as complex and nonintuitive.
• DORIS+: a definition of deep, drug-free remission with immunologic quiescence.
• ENDORSED: a definition of severe lupus.
• Lupus ABC: a consortium working on the regulatory pathways that unblinded cell therapies will require.

Author’s Predictions

• By 2028: at least 3–4 new SLE approvals.
• In 3–5 years: tightly restricted CAR-T approval for multi-refractory or organ-threatening disease.
• By 2032: multiplied options, with care organized around autoimmunity rather than organ systems, and a shift toward pathophysiology-based nomenclature.

SLE therapeutics are shifting from broad immunosuppression to targeted, biomarker-informed, and potentially immune-resetting approaches. The near-term challenge for rheumatologists will be choosing among many options without comparative data.