Stem Cell Therapy in Rheumatology

Overview

1. Types of Stem Cells Used

Hematopoietic Stem Cells (HSCs)

• Myeloablative: uses high-dose chemotherapy ± total body irradiation (TBI) to completely ablate the marrow
• Non-myeloablative (immunoablative): less intensive conditioning, preserves some marrow function, lower treatment-related mortality (TRM)

Mesenchymal Stem Cells (MSCs)

• Suppression of T-cell proliferation and activation
• Promotion of regulatory T cell (Treg) differentiation
• Inhibition of Th17 cells
• Paracrine anti-inflammatory cytokine secretion (TGF-β, IL-10, PGE2)
• Direct cell-cell contact via PDL1 and Fas-FasL
• Differentiation potential into cartilage, bone, and fat

2. Autologous HSCT in Systemic Sclerosis (SSc) - The Landmark Data

ASTIS Trial (Autologous Stem Cell Transplantation International Scleroderma)

• Design: European multicenter RCT comparing autologous non-myeloablative HSCT vs. monthly IV cyclophosphamide (CYC) x12 months in early diffuse cutaneous SSc
• Key results: Despite higher early transplant-related mortality, HSCT showed superior long-term event-free and overall survival
• HSCT rapidly controlled skin disease (mRSS), stabilized lung function (FVC), and improved quality of life

ASSIST Trial (American Scleroderma Stem Cell versus Immune Suppression Trial)

• Design: Small, single-site US RCT comparing non-myeloablative HSCT vs. IV CYC x6 months
• Key results: Highly promising; confirmed improvement in skin and lung; limited by small size and short follow-up; included patients with milder disease

SCOT Trial (Scleroderma Cyclophosphamide Or Transplantation)

• Design: US multicenter RCT - myeloablative HSCT (n=36) vs. CYC (n=39); unique addition of total body irradiation (TBI) to conditioning; CYC was NOT used for stem cell mobilization
• Primary endpoint: Global Rank Composite Score (GRCS) - hierarchy of death, event-free survival, FVC, HAQ-DI, mRSS
• Results at 54 months: 67% of pairwise comparisons favored HSCT vs. 33% favoring CYC (p=0.01)
• At 72 months: Event-free survival 74% (HSCT) vs. 47% (CYC); overall survival 86% vs. 51% (p=0.03 and 0.02)
• TRM: 3% at 54 months, 6% at 72 months in transplant group; 0% in CYC group

Hochberg/Rheumatology 2022 Perspective

• Patient selection is "extremely challenging" - patients must be sick enough to need transplant yet well enough to tolerate TRM
• Long-term organ effects remain unclear
• A systematic review/meta-analysis concluded HSCT should only be performed at specialty centers in high-risk early-stage patients with lung and diffuse skin involvement
• Guidelines defining sequential order of treatments in SSc are still warranted

Meta-Analysis (Higashitani et al., 2023 - PMID 35285885)

• HSCT significantly improved skin thickness (mRSS) and lung function
• Kaplan-Meier analysis showed high 2-year post-transplant survival (log-rank p=0.004)
• Pooled transplant-related death rate: 6.30% (95% CI 4.21-8.38%) - but this has been declining over the past decade
• Conclusion: HSCT is effective for SSc; optimal indications must carefully balance risks

3. HSCT in Systemic Lupus Erythematosus (SLE)

Autologous HSCT

• Non-myeloablative or myeloablative conditioning followed by autologous HSC rescue
• Demonstrates complete clinical remission or reduction of disease activity in 30-70% of patients
• Decreases anti-dsDNA antibodies, ANA titers
• Improves Th1/Th2 ratio (favoring Th2) and Th17/Treg balance (favoring Treg)
• Complications: infection, secondary autoimmune disease, recurrence

Allogeneic MSC Transplantation in SLE

• Allogeneic MSCs derived from umbilical cord or bone marrow infused IV in refractory SLE
• Significant reduction in SLEDAI scores and anti-dsDNA
• Improved renal function in lupus nephritis
• Meta-analysis (Zeng et al., 2025; 42 RCTs, 2183 participants) confirmed: MSC transplantation significantly improved SLEDAI (SMD = -2.32; 95% CI -3.59 to -1.06; p=0.0003) without increasing adverse events (RR=0.83; p=0.76)

4. HSCT in Juvenile Idiopathic Arthritis (JIA) - Hochberg Textbook Data

• Autologous HSCT (Netherlands cohort - largest series): Used predominantly for systemic JIA
  • Complete drug-free remission: ~50%
  • Partial response (Pediatric ACR criteria): ~20%
  • No improvement: ~20%
• Allogeneic HSCT (16 patients; systemic arthritis n=11, RF-negative polyarthritis n=5):
  • 80% (11/14) achieved complete drug-free remission at last follow-up
  • Long-term follow-up required
• Mortality: ~10% for either autologous or allogeneic SCT
• Viral infections post-SCT: high incidence
• Status: Still considered experimental; reserved for severe, unremitting disease despite all modern therapies including biologics (anti-IL-1, anti-IL-6)

5. HSCT in Osteonecrosis

Pathophysiology rationale

• Corticosteroids shift mesenchymal stem cell differentiation from osteogenesis toward adipogenesis in bone marrow
• Also reduce VEGF → decreased angiogenesis → bone death
• Alcohol has a similar effect on progenitor cell differentiation

Clinical evidence

• Pilot study: Core decompression + autologous bone marrow cell implantation vs. core decompression alone
  • At 24 months: 5/8 control hips progressed to stage 3 vs. only 1/10 treatment hips
  • Greater improvement in pain and joint symptoms in treatment group
• 28-patient series (44 necrotic hips): Percutaneous decompression + autologous bone marrow mononuclear cell infusion
  • Minimum 2-year follow-up
  • Mean Harris Hip Score improved from 58 to 86
  • Slowing of disease stage progression
• 2014 literature review: Core decompression + MSC infusion leads to improved pain and function, halts progression of osteonecrosis, potentially avoids total hip replacement
• Updated evidence: Bone marrow MSC transplantation with core decompression lowered total hip replacement conversion rate vs. core decompression alone (though no impact on ARCO staging)

6. MSC Therapy in Rheumatoid Arthritis (RA)

• MSCs suppress synovial inflammation by inhibiting T-cell proliferation and inducing Treg expansion
• In animal models: reduction of joint swelling, bone erosion, and inflammatory cytokines
• Clinical trials have shown improvements in DAS28, VAS pain, and inflammatory markers
• Meta-analysis (Zeng 2025): MSC transplantation may improve spondyloarthritis and RA (systematic review; RCT evidence limited)
• Review (Hetta et al., 2025): MSC therapy in RA shows potential for symptom relief and disease progression delay; challenges include variability in response, optimal cell source/dosing, and long-term safety

7. MSC Therapy in Osteoarthritis (OA)

Cochrane Review (Whittle et al., 2025 - PMID 40169165)

• 25 RCTs (1341 participants) comparing stem cell injections vs. placebo, hyaluronic acid, PRP, and others
• vs. placebo (8 trials, 445 participants):
  • Pain (0-10 scale): 1.2 points better with stem cells vs. placebo
  • Function (0-100 scale): 14.2 points better with stem cells
  • High heterogeneity (I² = 80-82%)
  • Very low certainty evidence overall
• Most trials were small (6-252 participants); only 2 had >100 participants
• Placebo-controlled trials largely free from bias; open-label trials susceptible to performance bias

Meta-Analysis on MSCs in OA (Zeng 2025)

• Bone marrow MSC (SMD = -0.95; 95% CI -1.55 to -0.36; p=0.002) - VAS pain reduction
• Umbilical cord MSC (SMD = -1.25; 95% CI -2.04 to -0.46; p=0.002)
• Adipose-derived MSC (SMD = -1.26; 95% CI -1.99 to -0.52; p=0.0009)
• No increase in adverse events (RR=1.23; p=0.15)

8. MSC Therapy in Systemic Sclerosis (SSc)

• Zare Moghaddam et al. (2023): MSC therapy in SSc - showed potential for modulating fibroblast activation and reducing fibrosis in preclinical models
• The 2025 meta-analysis (Zeng): MSC transplantation may NOT improve symptoms of systemic sclerosis based on available RCT evidence - distinguishing it from HSCT where the evidence is strong
• MSCs in SSc remain investigational, with ongoing trials

9. MSC Therapy in Sjögren's Syndrome

• MSCs derived from umbilical cord administered IV to primary Sjögren's patients
• Results: improvement in dry eye/dry mouth symptoms, salivary flow rates, parotid biopsy lymphocytic foci
• Increased Treg cells, decreased Th17 cells
• Meta-analysis: MSC may improve primary Sjögren's syndrome
• 2024 review (Lu et al., PMID 39438246): Cell therapy offers opportunities but faces challenges in standardization and durability

10. CAR-T Cell Therapy - The Emerging Frontier

Rationale

• Autoreactive B cells are pathogenic in SLE, RA, and other autoimmune diseases
• Rituximab (anti-CD20) has poor efficacy in autoimmune disease because autoreactive B cells persist in lymphatic organs and inflamed tissues (inaccessible to antibody)
• CAR-T cells, engineered to express chimeric antigen receptors against B cell antigens, can traffic to these sites

CD19 CAR-T in Autoimmune Disease

• Anti-CD19 CAR-T cells (targeting all B cells) administered to patients with refractory SLE and dermatomyositis
• Results: rapid and sustained depletion of circulating B cells + complete clinical and serological remission
• Unlike in cancer (where CAR-T causes prolonged B-cell aplasia), immune reconstitution occurred with reappearance of "naive" non-autoreactive B cells post-depletion
• This "deep immune reset" mechanism parallels HSCT but with targeted B-cell elimination

Key Applications

• Refractory SLE (anti-dsDNA normalization, lupus nephritis remission)
• Dermatomyositis (muscle enzyme normalization)
• Early data in systemic sclerosis and RA

11. Mechanisms of Action Summary

12. Patient Selection Criteria and Indications

HSCT (SSc) - Current Criteria from Textbooks

• Early diffuse cutaneous SSc (within 2-4 years of non-Raynaud onset)
• Rapidly progressive skin (mRSS >15) or significant internal organ involvement
• Contraindicated/high-risk: severe pulmonary hypertension, renal crisis, LVEF <45%, established end-organ damage
• Must be performed at specialty centers with HSCT expertise
• Patient must be "sick enough to need transplant yet well enough to tolerate TRM"

HSCT (JIA)

• Severe, unremitting disease despite all modern therapies including anti-IL-1, anti-IL-6
• Considered experimental

MSC therapy

• Refractory SLE after conventional immunosuppressives
• OA not responding to conventional management
• Generally investigational except in select programs

13. Risks and Complications

14. Current Status and Future Directions

• HSCT for SSc is the most evidence-supported stem cell therapy in rheumatology, backed by 3 large RCTs (ASTIS, ASSIST, SCOT), with long-term survival benefit demonstrated (Kelley/Firestein)
• MSC therapy for SLE and OA shows promising signal from multiple RCTs but evidence quality remains low-to-moderate
• CAR-T cell therapy represents the most transformative new approach - early human data is remarkable but follow-up is short and scale is small
• Ongoing challenges (Hetta 2025): variability in MSC sources (BM vs. adipose vs. umbilical), dosing protocols, timing, patient heterogeneity, regulatory hurdles
• The field is moving toward: combination strategies (e.g., HSCT followed by CAR-T), genetically modified MSCs, and extracellular vesicle (exosome)-based therapy as a cell-free alternative

Key References

• Firestein & Kelley's Textbook of Rheumatology (9780323935364) - Chapters on SSc management, osteonecrosis, autoinflammatory diseases
• Rheumatology, 2-Volume Set (Hochberg/Elsevier, 2022; 9780702081330) - Chapters on SSc skin, JIA, SLE

1. Higashitani K et al. Benefits and risks of HSCT for systemic sclerosis: systematic review and meta-analysis. Mod Rheumatol 2023. [PMID: 35285885]
2. Zeng L et al. Efficacy and safety of MSC transplantation in autoimmune/rheumatic diseases: systematic review and meta-analysis of 42 RCTs. Stem Cell Res Ther 2025. [PMID: 39934871]
3. Whittle SL et al. Stem cell injections for osteoarthritis of the knee (Cochrane Review). Cochrane Database Syst Rev 2025. [PMID: 40169165]
4. Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet 2023. [PMID: 37748491]
5. Hetta HF et al. Clinical Progress in MSC Therapy: A Focus on Rheumatic Diseases. Immun Inflamm Dis 2025. [PMID: 40353645]
6. Zare Moghaddam M et al. Stem cell-based therapy for SLE. J Transl Autoimmun 2024. [PMID: 38737817]
7. Keyes-Elstein L et al. Clinical and Molecular Findings After Autologous SCT or CYC for Scleroderma (SCOT trial analysis). Arthritis Care Res 2023. [PMID: 34533286]

Bispecific T Cell Engagers (BiTEs) in Autoimmune Diseases

1. Definition and Molecular Architecture

2. Textbook Coverage - Hochberg/Elsevier Rheumatology 2022

The Rationale for Bispecific Approaches

• Limitation of anti-CD20 monotherapy (rituximab): After rituximab, B-cell depleting activity triggers a significant rise in B-cell activating factor (BAFF) in patients with RA and SLE - which drives B-cell repopulation and may facilitate tissue B-cell survival
• This creates a strong rationale for combination or bispecific approaches that simultaneously target B cells and their survival signals
• Phase 3 trials of rituximab + belimumab combination were ongoing in SLE at time of publication

Bispecific Antibody Formats Described

1. Bispecific IgG: Each of the two Fab fragments carries different target specificity
2. VH/VL fragment combinations (reviewed in Schmid and Neri)
3. Fynomers: Antibody mimetics - Fyn SH3 domain modified to recognize a specific protein, linked to a conventional antibody

Bispecific in Rheumatology: Status at 2022

• COVA322: Bispecific TNF-α/IL-17 fusion protein (FynomAb) - well tolerated preclinically, but clinical trial in psoriasis terminated prematurely
• IL-6/IL-17 FynomAb: Under development (Lyman et al., 2018 - a bispecific antibody targeting both IL-6R and IL-17A for autoimmune/inflammatory diseases)
• Biological therapies have transformed rheumatic disease management; bispecific structures offer new opportunities to modulate pharmacokinetic and pharmacodynamic profiles

3. Mechanism of Action in Autoimmune Disease

Why target B cells in autoimmune disease?

• Production of autoantibodies (anti-dsDNA, anti-CCP, ANA, anti-Jo-1, etc.)
• Antigen presentation to T cells
• Cytokine secretion (IL-6, IL-10, LT-α)
• Formation of ectopic lymphoid structures in inflamed tissues

Why conventional B cell depletion fails in some patients

• Rituximab (anti-CD20) fails in refractory AID due to persistence of:
  • IgD-CD27+ switched memory B cells (rituximab-resistant)
  • CD19+CD20- B cells (not targeted by anti-CD20)
  • Long-lived plasma cells (CD20-negative; express CD19)
• B-T cell collaboration occurs predominantly in lymphoid tissues and inflamed sites (joint, kidney) where B-cell depletion by rituximab is inefficient due to poor effector cell access

How BiTEs overcome these limitations

• CD19-targeting BiTEs: Cover the full B cell lineage including memory B cells and plasmablasts (CD19 is expressed throughout B cell development, unlike CD20 which is lost at plasma cell stage)
• BCMA-targeting BiTEs: Target long-lived plasma cells - the source of persistent autoantibodies - which are CD20-negative but BCMA-positive
• CD20-targeting BiTEs (mosunetuzumab, glofitamab, epcoritamab): May provide deeper B-cell depletion than anti-CD20 monoclonal antibodies alone through T-cell mediated killing

4. BiTEs vs. CAR-T Cells: Key Differences

5. Key BiTE Agents and Their Targets

A. CD19 × CD3 BiTEs

• Approved 2014 for B-cell precursor ALL and minimal residual disease
• MW: ~54 kDa (much smaller than IgG ~150 kDa)
• Short half-life requires continuous IV infusion
• Targets CD19 on ALL blasts; in autoimmune use, targets autoreactive B cells
• Results in lysis of CD19+ cells, inflammatory cytokine release, T-cell proliferation
• Major adverse effects: cytokine release syndrome (CRS), neurological toxicities, neutropenic fever, sepsis
• From Goodman & Gilman's, block 19, line 4478; Katzung, line 1110

B. CD20 × CD3 BiTEs

• Mosunetuzumab, glofitamab, epcoritamab - approved in lymphoma, now being studied in autoimmune disease
• Cover CD20+ B cells including naive and memory B cells
• Do not reach plasma cells

C. BCMA × CD3 BiTEs

• Teclistamab (approved for multiple myeloma): One arm binds BCMA on plasma cells, other arm binds CD3 on T cells
• BCMA (B-cell maturation antigen) is expressed on long-lived plasma cells - the source of pathogenic autoantibodies in SLE, RA, SSc, and myositis
• Critical for diseases driven by persistent plasma cell-derived autoantibodies
• Other BCMA-directed BiTEs: elranatamab, linvoseltamab (oncology-approved)
• Katzung's Basic and Clinical Pharmacology, line 1058

D. Dual-cytokine targeting BiTEs (non-TCE)

• COVA322 (TNF-α/IL-17 FynomAb): Terminated in psoriasis trial
• IL-6R/IL-17A bispecific (Lyman 2018): Still in development
• These are not T-cell engagers per se, but bispecific cytokine/receptor targeting molecules
• Rheumatology (Hochberg 2022), block 8, lines 5523-5526

6. Clinical Evidence in Rheumatic Diseases

Clinical Outcomes

• Early signs of clinical improvement observed: rapid disease activity reduction, improvement in organ-specific manifestations, normalization of serologic biomarkers
• However: persistent or recurrent disease activity after treatment discontinuation in many patients
• Substantial heterogeneity in dosing strategies
• Lower cumulative exposure and shorter treatment duration vs. oncology regimens suggests potential undertreatment contributing to disease recurrence

Safety Profile (from 80 patients)

• CRS: 46% overall
  • Grade 1: 33%
  • Grade 2: 12%
  • Grade 3: 1%
• No neurotoxicity (ICANS) reported in any autoimmune patient
• No deaths reported related to TCE treatment
• Notably safer profile than CAR-T cells in this population

7. Disease-Specific Evidence

Systemic Lupus Erythematosus (SLE)

• Blinatumomab in SLE: Case reports and small series showing:
  • Rapid reduction in anti-dsDNA titers
  • Improvement in SLEDAI scores
  • Improvement in proteinuria in lupus nephritis
  • B-cell depletion more complete and durable than rituximab in some patients
• Rationale for BCMA BiTEs in SLE: Long-lived plasma cells in bone marrow persist despite rituximab and sustain anti-dsDNA production. Teclistamab-type BCMA-directed BiTEs can target these cells, potentially providing more durable autoantibody reduction.
• Ongoing trials: Multiple phase I/II studies evaluating TCEs in refractory SLE (ClinicalTrials.gov)

Rheumatoid Arthritis (RA)

• Anti-CCP (ACPA) and RF produced by synovial plasma cells
• Rituximab resistance in RA partly due to synovial tissue B-cell and plasma cell persistence
• TCEs can potentially access the synovium where conventional B-cell depleting antibodies have limited penetration
• Early results suggest DAS28 reduction and normalization of ACPA in some patients

Systemic Sclerosis (SSc)

• SSc is driven by autoantibodies (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III) and fibroblast activation
• CD19+ B cells and plasmablasts in SSc promote TGF-β-mediated fibrosis
• BiTE therapy may address the B-cell/plasma cell axis without requiring HSCT
• Initial reports: skin score improvement, stabilization of pulmonary fibrosis

Idiopathic Inflammatory Myopathies (IIM)

• MSAs (anti-Jo-1, anti-Mi-2, anti-MDA5, anti-SRP) are pathogenic autoantibodies from plasma cells
• Rituximab has variable efficacy (limited by plasma cell persistence)
• Groener and Paik (Front Immunol, 2025 [PMID: 40746557]) highlight BCMA-targeted BiTEs as promising given that both plasmablasts and plasma cells contribute to MSA production
• CD19 CAR-T in myositis/SSc (Cell, 2024 [PMID: 39013470]): Allogeneic CD19-directed CAR-T in severe myositis and SSc demonstrated efficacy - data extrapolated to BiTE strategy

Primary Sjögren's Syndrome (pSS)

• Anti-Ro/SSA and anti-La/SSB autoantibodies
• Ectopic lymphoid structures (germinal center-like structures in salivary glands) are sites of local B-cell activation resistant to systemic therapies
• TCEs might better access these sites via T-cell trafficking

8. Comparison with Other B-Cell Targeting Strategies

9. Advantages and Challenges

Advantages of BiTEs over CAR-T in autoimmune disease

1. No need for T-cell engineering: Off-the-shelf availability; faster access
2. No lymphodepletion required: Avoids chemotherapy-related toxicity and prolonged cytopenias
3. Lower cost: Significant cost reduction compared to individualized CAR-T manufacturing
4. Controllability: Short half-life means effects are reversible when drug is stopped (unlike persistent CAR-T cells)
5. Comparable B/plasma cell depletion depth in early data
6. Lower neurotoxicity: No ICANS reported in autoimmune BiTE use to date

Challenges and Limitations

1. Shorter exposure and possible undertreatment: Optimal dosing for autoimmune disease (vs. higher cancer doses) not yet defined
2. Disease recurrence after discontinuation: Without long-term immune reset, B cells may reconstitute with autoreactive repertoire
3. CRS risk: 46% overall; requires monitoring and management protocols
4. No established dosing protocols for autoimmune indications
5. Very small patient numbers in current evidence (total n=80 patients across all autoimmune diseases)
6. Short follow-up: Durability of response unclear
7. Access to tissue-resident plasma cells: Long-lived plasma cells in bone marrow niches may not be fully eliminated
8. Regulatory status: Not approved for any autoimmune indication as of 2026; all use is investigational or compassionate
9. CRS management requires corticosteroids + IL-6 blockade, which further increases infection risk (Harrison's 22e, block 8, line 2212)

10. Key Mechanistic Distinction: BiTEs vs. Rituximab

• BAFF rises significantly in RA and SLE patients
• This drives B-cell repopulation
• Hence combination (rituximab + belimumab) or bispecific strategies are theoretically superior

1. Depleting B cells and plasmablasts (via CD19)
2. Depleting long-lived plasma cells (via BCMA)
3. Not being dependent on ADCC or complement (which are blocked in hypogammaglobulinemic patients)
4. Accessing tissue sites of B-T cell collaboration via T-cell homing

11. Ongoing and Future Directions

1. Dedicated autoimmune BiTE trials: Phase I/II studies of blinatumomab, mosunetuzumab, and teclistamab in SLE, SSc, and myositis are enrolling
2. Optimal dosing strategy: Lower doses than oncology? Continuous vs. intermittent? Subcutaneous formulations being developed
3. Combination approaches: BiTEs + BAFF/APRIL inhibition to prevent B-cell reconstitution
4. Treg-engaging bispecifics: CD3 × CD25 constructs to expand regulatory T cells rather than deplete B cells
5. FcRn-directed bispecifics: To enhance clearance of circulating autoantibodies
6. Tri-specific engagers: Simultaneously targeting T cells, B cells, and a third immunomodulatory target
7. Non-T cell engagers: IL-6/IL-17 bispecifics (Lyman 2018 concept) for inflammatory/fibrotic rheumatic disease

Summary

Key References

• Rheumatology, 2-Volume Set (Hochberg/Elsevier, 2022) - "Using Multiple Antibodies and Bispecific Molecules" (Ch. 8)
• Goodman & Gilman's Pharmacological Basis of Therapeutics - "Bispecific Antibodies: CD19 and CD3" (Ch. 72, Fig. 72-5)
• Katzung's Basic and Clinical Pharmacology, 16e - Bispecific T cell engagers/Teclistamab
• Harrison's Principles of Internal Medicine 22e - Bispecific antibodies, CRS management

1. Nordmann-Gomes A et al. T-cell engagers in rheumatology. Best Pract Res Clin Rheumatol 2026. [PMID: 41951534] - 80-patient multicenter analysis
2. Larue M et al. Bispecific T-cell engagers in autoimmune diseases: mechanisms, clinical evidence, challenges. Autoimmun Rev 2026. [PMID: 42002248] - Comprehensive mechanistic review
3. Shah K et al. Disrupting B and T-cell collaboration: T-cell engagers vs. CAR-T in autoimmune disease. Clin Exp Immunol 2024. [PMID: 38642912]
4. Li J et al. CAR-T and BiTE: new horizons in treatment of rheumatic autoimmune diseases. Front Immunol 2026. [PMID: 41694371]
5. Groener M, Paik JJ. Emerging B and plasma cell-targeting immune therapies in IIM. Front Immunol 2025. [PMID: 40746557]