TMJ 'dysfunction' - Health implications

A fundamental critique of the disease-modifying paradigm in multiple sclerosis: efficacy, endpoints, cost, and lived clinical experience

The case discussed on Prof. Giovannoni’s forum exemplifies a broader assumption that now dominates multiple sclerosis (MS) care: that escalation or sequencing of increasingly potent disease-modifying therapies (DMTs) meaningfully alters the long-term trajectory of the disease. This assumption warrants far more sceptical scrutiny than it typically receives.

Despite more than three decades of therapeutic development, no licensed MS therapy has cured the disease, nor has any convincingly demonstrated prevention of late-stage disability or progressive neurological decline when examined over sufficiently long time horizons. What has been repeatedly shown is suppression of relapses and MRI lesion activity outcomes that serve primarily as surrogate endpoints rather than direct measures of irreversible neurodegeneration or sustained functional preservation.

Surrogate outcomes and diminishing clinical meaning

Modern MS trials are overwhelmingly designed around short-term inflammatory outcomes: annualised relapse rates, new or enlarging T2 lesions, and gadolinium enhancement. While these measures are measurable and regulator-friendly, their relationship to meaningful long-term disability outcomes is weak and inconsistent, particularly beyond the early relapsing phase.

Long-term natural history studies have repeatedly demonstrated a clinico-radiological dissociation, in which inflammatory activity may be well controlled. At the same time, disability, cortical atrophy, cognitive decline, and fatigue continue to accrue. The repeated inference that improved MRI metrics equate to genuine disease modification is therefore not strongly supported by longitudinal evidence.

Peripheral immunosuppression and progressive pathology

The immune-mediated model of MS explains early relapsing disease reasonably well, but becomes increasingly strained when applied to later stages characterised by compartmentalised CNS inflammation, microglial activation, mitochondrial dysfunction, and axonal loss.

Most contemporary DMTs—anti-CD20 monoclonal antibodies, natalizumab, and so-called immune-reconstitution therapies—act predominantly on peripheral immune mechanisms. Their capacity to meaningfully influence chronic CNS-resident pathology remains largely inferential, based on biomarker changes rather than direct demonstrations of neuroprotection.

In this context, repeated escalation from one high-efficacy immunotherapy to another risks becoming biologically impressive but clinically inconclusive.

EBV and the inflation of mechanistic expectations

The Epstein–Barr virus (EBV) hypothesis has added further momentum to B-cell–targeted strategies, but its therapeutic implications remain speculative. While EBV infection is strongly associated with MS risk, there is currently no clinical evidence that any licensed DMT eradicates EBV-infected B cells within the CNS or meaningfully alters EBV-driven pathology in vivo.

Invoking EBV clearance as a differentiator between existing therapies, therefore risks extending an epidemiological association into a therapeutic claim that the evidence does not yet support.

Cost, opportunity cost, and the NHS perspective

These evidentiary limitations become more consequential when considered alongside the extraordinary cost of modern MS therapies. Drugs commonly discussed in escalation pathways-ofatumumab, ublituximab, ocrelizumab, natalizumab, and cladribine carry annual or course costs that, at US list prices, typically range from approximately $60,000 to $100,000 per patient.

Even allowing for confidential NHS discounts and negotiated pricing, the lifetime cost of sequential "high-efficacy" DMT use readily runs into the millions of pounds per patient when treatment spans decades. This is before accounting for infusion services, safety monitoring, management of adverse effects, hospital admissions, and complications of long-term immunosuppression.

Crucially, these costs are justified on the assumption of durable disease modification-an assumption that remains unproven. From a health-economics perspective, this raises a serious question of opportunity cost within a publicly funded system: substantial resources are committed to suppressing surrogate inflammatory markers, while evidence that this strategy prevents severe disability, preserves independence, or reduces long-term care needs remains limited.

The gap between trial outcomes and clinical observation

Beyond formal trial data, there remains a striking disconnect between controlled study outcomes and lived clinical experience. Senior clinicians with long exposure to advanced MS care have privately expressed concern that aggressive immunotherapy, while effective at suppressing measurable inflammation, may in some patients coincide with functional decline, increased fatigue, infections, or reduced resilience over time.

As one senior hospital authority remarked to the author after observing outcomes in a non-pharmacological clinical setting, “They only make them worse. I wish these people had seen what I saw in your office.” While anecdotal, such observations highlight an under-acknowledged reality: improvements seen outside the pharmacological paradigm through lifestyle, symmetry treatment, or systems-based interventions are often discounted because they fall outside the dominant therapeutic framework, not because they lack clinical relevance.

These observations do not invalidate the role of inflammation in MS, but they do challenge the assumption that escalating immunosuppression necessarily translates into better long-term outcomes for all patients.

Conclusion

The case under discussion illustrates not a failure of individual drugs, but a deeper structural issue within MS therapeutics. The field has increasingly equated biological activity with clinical progress and short-term inflammatory suppression with long-term neuroprotection.

Given the absence of curative therapies, the weak linkage between surrogate endpoints and late-stage outcomes, the immense cumulative cost to systems such as the NHS, and the growing gap between trial metrics and real-world clinical experience, it is reasonable to question whether continual escalation within the current immunological paradigm is delivering value commensurate with its claims.

This is not an argument that inflammation is irrelevant, but that expectations placed on disease-modifying therapies now exceed what the evidence can robustly sustain. Until therapies demonstrate durable prevention of disability and progression over decades, both their clinical promise and their economic justification warrant continued sceptical evaluation.

Below are well-recognised weaknesses in the MS evidence base, with indicative citations:

1. Long-term disability outcomes
Confavreux & Vukusic (2006) – Natural history studies showing disability progression often decoupled from relapse activity
Scalfari et al. (2010, 2014) – Relapse frequency poorly predicts long-term disability accumulation

2. Clinico-radiological dissociation
Barkhof (2002) – MRI lesion burden correlates weakly with clinical outcomes
Filippi et al. (2012) – Cortical pathology and atrophy are better predictors of progression than focal lesions

3. Limited impact on progression
Weinshenker et al. (1989–2000s) – Early cohorts demonstrating inexorable progression despite relapse suppression
Kappos et al. (SPMS trials) – Modest or absent effects of immunotherapies on established progression

4. EBV hypothesis limitations
Bjornevik et al. (2022, Science) – Strong epidemiological association, no therapeutic implication demonstrated
Lünemann et al. (2010s) – EBV persistence in CNS not shown to be eradicated by DMTs

5. Surrogate endpoints and regulatory capture
Sormani & Bruzzi (2013) – Questioning relapse rate as a valid surrogate for disability
Ioannidis (2005; general methodology) – Why surrogate endpoints often fail to predict meaningful outcomes

Source: paraphrased and critically analysed from a forum case discussion on Prof. Gavin Giovannoni’s MS Blogs, used for the purpose of criticism and review.