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Wnt Pathway in Rheumatology

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1. Wnt Signaling - Overview

• Canonical (β-catenin-dependent): LRP5/6 is phosphorylated, β-catenin accumulates in the cytoplasm, translocates to the nucleus, and drives gene transcription. This arm primarily regulates osteoblast differentiation, proliferation, and survival.
• Non-canonical pathways (β-catenin-independent): includes the PCP (planar cell polarity) and Wnt/Ca²⁺ pathways; relevant in chondrocyte differentiation and fibrosis.

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2. Key Endogenous Wnt Inhibitors

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3. Wnt in Rheumatoid Arthritis (RA)

Bone Erosion - The DKK1 Paradox

• Blocking DKK1 de-represses Wnt signaling → reversal of bone damage
• Direct Wnt agonism (R-Spondin 1) reversed both bone and cartilage damage (Kelley, p. 148)

Suppression of Bone Formation

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4. Wnt in Spondyloarthritis (SpA / axSpA / AS)

DKK1 and Syndesmophyte Formation

• In r-axSpA, high circulating levels of DKK1 are inversely related to syndesmophyte formation - i.e., when DKK1 is suppressed (less Wnt inhibition), new bone forms more readily
• Functional deletion of DKK1 in hTNF-transgenic mice induced ankylosis of the sacroiliac joint (Hochberg, block16)

Sclerostin in AS

• Sclerostin expression by osteocytes is highly impaired in r-axSpA patients
• Low serum sclerostin concentrations correlate with structural progression (ankylosis)
• This relative absence of sclerostin allows unopposed Wnt signaling → osteoid formation at entheses and vertebral edges (Hochberg, block16)

TNF - Dual Role Through Wnt

Bone Marrow Fat Metaplasia → Ankylosis

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5. Wnt in Osteoarthritis (OA)

• Excessive/uncontrolled Wnt activation → reprogramming of articular chondrocytes toward catabolism, cartilage breakdown, increased MMP-3 expression
• Loss of Wnt inhibitor FRZB → increased OA susceptibility in humans and mice
• WNT16 acts as a "buffer" - weak activator that prevents overactivation by more potent canonical Wnts; Wnt16 gene disruption increases OA susceptibility and depletes articular cartilage progenitors
• Controlled, temporary β-catenin activation in mice leads to chondrocyte proliferation and cartilage thickening - demonstrating repair potential (Kelley, pp. 148-149)

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6. Wnt in Systemic Sclerosis (SSc) / Fibrosis

• Constitutive Wnt-β-catenin signaling is active in SSc, partly due to epigenetic silencing of endogenous Wnt inhibitors including DKK1
• Genome-wide transcriptome analysis of SSc skin biopsies shows elevated Wnt ligands, receptors, and targets
• Transgenic mice overexpressing Wnt10b or constitutively active β-catenin develop non-inflammatory tissue fibrosis and scleroderma-like skin induration
• Cross-talk with TGF-β drives fibroblast proliferation, activation, and epithelial-mesenchymal transition (EMT) (Kelley, block21; Hochberg, block19)

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7. Therapeutic Targeting of Wnt in Rheumatology

Key therapeutic challenge: The dose and spatiotemporal control of Wnt signaling is critical. Both excessive activation AND excessive inhibition cause cartilage catabolism. Systemic Wnt inhibition risks osteoporosis. (Kelley, p. 149)

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Summary Framework

                    RA                  axSpA / AS              OA                   SSc
Wnt tone         Suppressed           Permissive              Overactive           Overactive
Key driver       TNF ↑ DKK1           ↓ DKK1, ↓ Sclerostin   Loss of FRZB/WNT16   Epigenetic loss of DKK1
Effect           Bone erosion         Syndesmophytes           Cartilage breakdown   Fibrosis
Therapeutic goal De-repress Wnt       Dampen excess Wnt        Buffer Wnt           Inhibit Wnt/β-catenin

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Rituximab and IVIg in Inflammatory Myositis

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Part 1 - RITUXIMAB

Background and Rationale

• B cell involvement in muscle inflammation and autoantibody production (anti-Jo-1, anti-Mi-2, anti-MDA5, anti-SRP, anti-HMGCR)
• Pathogenic autoantibodies as drivers of muscle, lung, and skin damage
• Case series showing responses in refractory PM, DM, and antisynthetase syndrome

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The RIM Trial (Rituximab in Myositis) - The Landmark RCT

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Predictors of Response to RTX - RIM Trial Post-hoc Analysis

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2022 Meta-analysis (Zhen C et al., Front Immunol. 2022) [PMID: 36578492]

• 26 studies, quantitative meta-analysis
• Overall response rate: 65% (95% CI: 54-75%)
• Complete response: 45% (95% CI: 22-70%)
• Partial response: 39% (95% CI: 26-53%)
• By subtype: DM/PM 68%; antisynthetase syndrome 62%; refractory IIMs 62%
• By organ: muscle 59%; skin 81%; lungs (ILD) 65%
• Safety: severe adverse events 8%; severe infections 2%
• Conclusion: RTX is effective and relatively safe, particularly in skin disease and ILD

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2025 Meta-analysis (Rojas LO et al., J Clin Rheumatol. 2025) [PMID: 39527803]

• 17 studies (1 RCT + 16 observational), 362 patients
• Overall pooled response rate: 70% (95% CI: 57-82%; I² = 74%)
• Complete remission: 13% (95% CI: 3-25%)
• Partial response: 48% (95% CI: 30-67%)
• By subtype: IMNM 86% (highest); PM 69%; antisynthetase syndrome 70%; DM 67%; juvenile DM 60%
• Two dosing regimens showed similar response: 1g IV on days 0 and 14 (68%) vs. 375 mg/m² weekly × 4 (71%)
• Adverse events: infusion reactions 18.5%; infections 12.4%

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Dosing in Clinical Practice

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Rituximab in Specific Myositis Subtypes

Myositis-ILD

• RTX is the second-line treatment of choice for myositis patients with ILD (Harrison's 2025)
• Especially effective in anti-MDA5 positive amyopathic DM with rapidly progressive ILD
• The RECITAL trial (Maher TM et al., Lancet Respir Med 2023; [PMID: 36375479]) compared RTX vs. IV cyclophosphamide in CTD-associated ILD (including myositis-ILD) - RTX was non-inferior and better tolerated

IMNM (Immune-Mediated Necrotizing Myopathy)

• Anti-SRP and anti-HMGCR myopathies often require triple therapy (prednisone + MTX + IVIg)
• RTX is used when triple therapy fails (Harrison's 2025)
• The 2025 meta-analysis showed the highest RTX response rate in IMNM (86%)

Juvenile DM

• RIM trial showed juvenile DM had the strongest predictor of improvement after anti-Jo-1/anti-Mi-2
• Hochberg notes: "data suggested that rituximab provided valuable steroid-sparing effect and clinical improvement in patients with juvenile-onset disease"

IBM (Inclusion Body Myositis)

• Not effective. IBM does not respond to any known immunotherapy, including RTX (Harrison's 2025, Goldman-Cecil Medicine)

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Part 2 - IVIg (Intravenous Immunoglobulin)

Mechanisms of Action in Myositis

• Neutralizes pathogenic autoantibodies (anti-complement mechanism)
• Blocks Fc receptors on macrophages and NK cells
• Downregulates complement deposition on muscle capillaries
• Restores capillary density in DM (as demonstrated on muscle biopsy)
• Modulates T cell function and cytokine network

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The Dalakas 1993 NEJM RCT - The Original Landmark Trial

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The ProDERM Trial - Pivotal Phase III RCT

• 113 IVIg-related TEAEs in 30/52 patients (57.7%) vs. 38 TEAEs in 11/48 placebo patients (22.9%)
• Most common: headache (42%), pyrexia (19%), nausea (16%)
• Serious: 6 thromboembolic events in 5 patients (possibly/probably related to IVIg); patients with TEEs had more baseline risk factors
• No haemolytic reactions; no deaths
• Dose reduction to 1 g/kg or slower infusion rate reduced TEE risk
• 8 patients discontinued due to IVIg-related adverse events

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Predictors of IVIg Response - ProDERM Sub-analysis

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Meta-analyses of IVIg in IIM

Goswami RP et al., Autoimmun Rev. 2022 [PMID: 34800685]

• 29 studies, n=576 (544 IIM + 32 JDM)
• Muscle power partial response: 88.5% (95% CI: 80.6-93.5%)
• SCIg (subcutaneous Ig) response: 96.6% (95% CI: 87.4-99.2%)
• First-line IVIg pooled partial response: 77.1% (95% CI: 61.3-92.9%)
• Mean time to response: 2.9 months (95% CI: 1.9-4.1)
• Relapse rate: 22.8% (95% CI: 14.9-33%)
• Cutaneous disease and dysphagia: significant treatment responses
• Glucocorticoid-sparing: 40.9%; immunosuppressant-sparing: 42.2%
• Infection risk: low (1.37%; 95% CI: 0.1-2.6%)
• Conclusion: Add-on Ig improves muscle strength in refractory IIM

Xiong A et al., Mod Rheumatol. 2023 [PMID: 35660927]

• 17 papers
• IVIg significantly improved CK, MMT, MRC scale, and ADL scores (all p<0.001)
• Pooled muscle power improvement rate: 77% (95% CI: 66-87%)
• First-line IVIg: significant CK improvement
• Esophageal/dysphagia improvement: 88% (95% CI: 80-95%)
• Corticosteroid-sparing success: 81.8%
• Adverse events mostly mild and transient; 7 serious adverse events total

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Dosing of IVIg in Myositis

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IVIg in Specific Subtypes

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Part 3 - Comparison and Clinical Positioning

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Clinical Algorithm (Harrison's 2025 Framework)

All IIM subtypes:
  → Prednisone ± early DMARD (MTX or AZA)
       ↓ insufficient response (2-4 months)
  → Add IVIg (especially DM, IMNM, dysphagia, ILD)
       ↓ still refractory
  → Add or switch to Rituximab
       (First-line for ILD with anti-MDA5 or anti-Jo-1)

IMNM (anti-SRP / anti-HMGCR):
  → Triple: Prednisone + MTX + IVIg from outset
  → Anti-HMGCR: IVIg monotherapy often sufficient
  → Anti-SRP refractory: Rituximab

IBM:
  → Immunotherapy NOT effective
  → PT/OT + swallowing therapy only

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Summary of Key Trials

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Rituximab and IVIg in Inflammatory Myositis

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Background: The Therapeutic Challenge

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PART 1 - RITUXIMAB

Rationale

• B cells are abundant in muscle infiltrates in DM/PM
• Myositis-specific autoantibodies (MSAs: anti-Jo-1, anti-Mi-2, anti-MDA5, anti-SRP, anti-HMGCR, anti-TIF1-γ) are pathogenic drivers
• Depletion of B cells removes both autoantibody production and antigen-presenting cell function
• Multiple case reports and open-label series documented positive responses in refractory PM and DM prior to the landmark RCT

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The RIM Trial - The Only RCT of Rituximab in Myositis

Design

• Randomized, double-blind, placebo-phase trial (not a true placebo-controlled trial)
• Patients received either rituximab early (weeks 0+1) or rituximab late (weeks 8+9) - all patients eventually received RTX
• Background glucocorticoids and immunosuppressants were permitted at study entry
• 44-week total follow-up at 4 academic centers

Patients

• 200 randomized patients: 76 PM (adults), 76 DM (adults), 48 juvenile DM
• All had refractory disease: prior failure of glucocorticoids + at least one DMARD
• Entry required: muscle weakness + ≥2 abnormal core set measures (CSMs) in adults; ≥3 abnormal CSMs (with or without weakness) in juvenile DM
• RTX early n=93; RTX late n=102

Primary Endpoint

• Time to achieve the DOI (IMACS Preliminary Definition of Improvement = ≥20% improvement in ≥3 of 6 CSMs with no more than one CSM worsening by >25%) between early and late groups

Results

Interpretation

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Predictors of Response - RIM Post-Hoc Analysis

• The predictive effect of damage and JDM diminished by week 20 (early predictor only)
• RTX treatment assignment itself did not affect these associations
• Seronegative patients (no MSA) and those with high damage scores had the least benefit

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Biologic Predictors - Further RIM Analysis

• Examined B cell depletion kinetics and correlation with clinical response
• Complete B cell depletion achieved in nearly all patients
• B cell repopulation preceded clinical relapse in some patients
• Suggested B cell monitoring could guide retreatment timing

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2022 Systematic Review and Meta-analysis

• 26 studies included in quantitative analysis (mostly observational + RIM trial)
• Excluded sporadic IBM

• DM + PM combined: 68%
• Antisynthetase syndrome: 62%
• Refractory IIMs: 62%

• Muscle: 59%
• Skin: 81% (highest)
• Lung (ILD): 65%

• Germany: 90%; United States: 77%

• Severe adverse events: 8%
• Severe infections: 2%
• Infusion reactions: reported

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2025 Systematic Review and Meta-analysis

• 17 studies (1 RCT + 16 observational), 362 patients
• PROSPERO-registered (CRD42022353740)
• Random-effects model; Newcastle-Ottawa Scale quality assessment

• 1g IV on days 0 and 14: 68%
• 375 mg/m² weekly × 4 weeks: 71%
• Both regimens equivalent - choice based on preference/practice

• Infusion reactions: 18.5%
• Infections: 12.4%

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2025 Cochrane Review

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Rituximab in Myositis-ILD - RECITAL Trial

• Phase 2b, double-blind, double-dummy RCT
• RTX vs. IV cyclophosphamide in CTD-associated ILD (including myositis-ILD)
• RTX was non-inferior to IV cyclophosphamide in FVC change at 24 weeks
• RTX had a more favorable safety profile
• This trial supports RTX as the preferred agent over IV CYC in myositis-ILD

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Rituximab Dosing in Myositis

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RTX Clinical Role by Subtype

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PART 2 - IVIg (INTRAVENOUS IMMUNOGLOBULIN)

Mechanisms of Action in Myositis

1. Fc receptor blockade on macrophages, NK cells, dendritic cells - inhibits antibody-dependent cellular cytotoxicity
2. Complement neutralization - IVIg neutralizes activated complement components (C3b, C4b), preventing membrane attack complex (MAC) deposition on muscle capillaries
3. Anti-idiotypic antibodies - neutralize pathogenic autoantibodies (anti-Jo-1, anti-Mi-2, etc.)
4. B cell inhibition - via FcγRIIB (inhibitory receptor) signaling
5. T cell modulation - downregulates T cell activation and cytokine production
6. Restoration of capillary integrity - demonstrated by Dalakas 1993 biopsy data showing increased capillary number and reduced complement deposits after IVIg

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The Dalakas 1993 NEJM RCT - The Foundational Trial

Design

• Double-blind, placebo-controlled crossover RCT
• Setting: NIH
• Duration: 3 months per arm; crossover permitted after 3 months

Patients

• 15 patients, age 18-55 years
• Biopsy-proven treatment-resistant DM
• Continued prednisone (mean 25 mg/day) throughout
• Randomized: IVIg n=8 (first period), placebo n=7

Treatment

• IVIg: 2 g/kg per infusion, given once monthly for 3 months
• Placebo: matched infusion

Results

• Muscle strength: significantly improved in IVIg group (p=0.018)
• Neuromuscular symptoms: significantly improved (p=0.035)
• 9/12 IVIg-treated patients with severe disabilities improved to near-normal function
• Mean muscle strength score: improved from 74.5 → 84.7 in IVIg group

Biopsy Findings (5 patients with near-normal recovery):

• ↑ Muscle fiber diameter (p<0.04)
• ↑ Number of capillaries; ↓ capillary diameter (p<0.01)
• Resolution of complement (C5b-9 MAC) deposits on capillaries
• ↓ ICAM-1 expression
• ↓ MHC class I antigen expression on muscle fibers

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The ProDERM Trial - Pivotal Phase III RCT

Design

• Randomized, double-blind, placebo-controlled, multicenter, Phase III
• Two periods:
  • Period 1 (weeks 0-16): IVIg vs. placebo, every 4 weeks (4 cycles)
  • Period 2 (weeks 16-40): Open-label IVIg extension for all patients (6 additional cycles); dose reduction to 1 g/kg permitted in stable patients
• ClinicalTrials.gov: NCT02728752

Patients

• 95 adults with active DM by ENMC 2004 criteria
• IVIg n=47; placebo n=48
• Corticosteroids and/or immunosuppressants were permitted as background therapy
• Active disease required (elevated muscle enzymes or abnormal muscle MRI)

Treatment

• IVIg: Octagam 10% (Octapharma) at 2.0 g/kg every 4 weeks
• Given over 2-5 days per cycle

Primary Endpoint

1. Physician global disease activity (20 points weight)
2. Patient/parent global disease activity (10 points)
3. Manual muscle testing (MMT-8) (35 points)
4. HAQ/CHAQ physical function (10 points)
5. Muscle enzymes (creatine kinase) (10 points)
6. Extramuscular disease activity (MDAAT) (15 points)

PRIMARY RESULTS

Safety (Period 1 + Open-label Extension)

• 664 total IVIg infusion cycles administered
• TEAEs possibly/probably related to IVIg: 30/52 patients (57.7%) in Period 1 vs. 11/48 (22.9%) placebo
• Most common IVIg-related adverse events:
  • Headache: 42%
  • Pyrexia: 19%
  • Nausea: 16%
• Serious adverse events related to IVIg: 9 (including 6 thromboembolic events)
• Thromboembolic events (TEE): 6 in 5 patients - possibly/probably related to IVIg
  • Patients with TEEs had 2.4-15.2× more baseline TEE risk factors than those without
  • TEE rate reduced by slower infusion rate and lower dose (1 g/kg in stable patients)
  • No TEEs occurred at the lower dose in extension phase
• 8 patients discontinued due to IVIg-related TEAEs
• No haemolytic reactions; no deaths

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ProDERM Response Predictors (2025)

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IVIg Meta-analyses

Meta-analysis 1: Goswami RP et al., Autoimmun Rev. 2022 [PMID: 34800685]

• 29 studies, n=576 (544 adult IIM + 32 JDM)
• Studies from 2010-2020; IMACS core set outcomes used

• Dysphagia: significant treatment response
• Cutaneous disease activity: significant improvement
• SCIg shows higher response than IVIg (but smaller dataset)
• IVIg as first-line therapy effective (77%); evidence on extramuscular disease in new-onset IIM remains uncertain

Meta-analysis 2: Xiong A et al., Mod Rheumatol. 2023 [PMID: 35660927]

• 17 papers (PubMed, Embase, CNKI; July 1919 - May 2021)
• Focused on DM and PM

• CK improvements seen in both DM (SMD -0.73, p=0.0002) and PM (SMD -3.29, p=0.0001)
• No significant difference in response rate between <2 courses vs. ≥2 courses (0.80% vs 0.80%)
• Adverse events mostly mild and transient; only 7 serious adverse events total

Cochrane Review: Gordon PA et al., Cochrane Database Syst Rev. 2012 [PMID: 22895935]

• Included the Dalakas 1993 trial as the primary high-quality RCT
• Concluded IVIg has evidence of benefit in DM
• Called for larger RCTs - since fulfilled by ProDERM

Cochrane Review (2025): Raaphorst J et al. [PMID: 40787733]

• Non-targeted immunosuppressive and immunomodulatory therapies for IIM
• Highest-quality and most recent synthesis available

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IVIg Dosing in Myositis

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IVIg in Specific Subtypes

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PART 3 - Head-to-Head Comparison

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PART 4 - Treatment Algorithm

STEP 1 - ALL IIM SUBTYPES (except IBM):
  High-dose prednisone (0.75-1.5 mg/kg/day)
  ± Early DMARD (MTX 7.5-20 mg/week or AZA 2-3 mg/kg/day)
  ↓ Insufficient response at 2-4 months, OR severe/high-risk features

STEP 2 - ADD IVIg:
  2 g/kg induction, then 1 g/kg q4-8 weeks
  Prioritize for:
    - IMNM (anti-HMGCR: IVIg alone; anti-SRP: triple therapy)
    - Acute severe DM
    - Dysphagia
    - Steroid complications

STEP 3 - ADD/SWITCH TO RITUXIMAB:
  1g IV × 2 (days 0 and 15) or 375 mg/m² × 4 weekly
  Prioritize for:
    - Anti-Jo-1 / anti-Mi-2 positive
    - Myositis-ILD (esp. antisynthetase, anti-MDA5)
    - Refractory skin DM
    - JDM refractory to step 2

SPECIAL SITUATIONS:
  Anti-MDA5 RP-ILD: Consider early RTX ± IV CYC + IVIg combination
  Anti-HMGCR IMNM: IVIg monotherapy as initial approach
  IMNM refractory to triple therapy: Add RTX

IBM: No immunotherapy - PT/OT/swallowing therapy only

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Summary Table of All Key Trials

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