Disease indication
The most lethal rheumatic disease, and the organ it is named after has no approved treatment at all. Several trials here did work — they worked on the lung, and were scored on the skin.
Disease-modifying: Stop the progressive replacement of skin and organ tissue with collagen, judged on the modified Rodnan skin score — a trained examiner pinching skin at seventeen sites. No drug has ever been approved on it. The only intervention with a demonstrated survival benefit in this disease is not a drug at all.
In four decades. The recent misses on a skin primary are tocilizumab (focuSSced, Phase 3), lenabasum (RESOLVE-1, Phase 3), riociguat (RISE-SSc, Phase 2b) and abatacept (ASSET, Phase 2). Two of those programmes nonetheless produced an approved drug, on a lung endpoint measured in the same trial.
Skin thickening regresses without treatment in a substantial share of patients with early diffuse disease, and modern placebo arms improve accordingly. A trial must beat spontaneous recovery on a score whose measurement error is roughly the size of the effect it is powered to detect.
The highest case-specific mortality of any rheumatic disease. Since renal crisis became treatable, lung fibrosis and pulmonary hypertension account for most of it — which is why the two organs with their own pages here are the two that decide survival.
Autologous haematopoietic stem-cell transplantation, in two randomised trials. It is a procedure rather than a licensable product, it carries treatment-related mortality of a few percent, and no regulator lists it as an approved therapy for this disease.
Systemic sclerosis is four therapeutic problems that happen to occur in the same patient, and holding them side by side explains more about this disease than any single page can. Same autoimmunity, same fibroblasts, same person — and one manifestation was solved with a borrowed blood pressure pill, one has fourteen drugs it can borrow, one has two of its own, and one has nothing at all.
Progressive thickening and tethering of the skin, and the feature the disease is named and classified by. Rarely the direct cause of death, and the best single predictor of who dies of everything else.
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Progressive interstitial fibrosis, present on imaging in most patients and clinically significant in roughly a third. The only manifestation to have produced a drug approval naming this disease.
Obliterative narrowing of the small pulmonary arteries, raising pressures until the right ventricle fails. Fourteen drugs are available to these patients and were licensed for a category rather than for them.
Abrupt malignant hypertension with acute kidney failure, once the most feared complication of this disease and almost uniformly fatal within months. It is now largely survivable, and it was solved by accident.
No page yet
These may be nearer to separate diseases than the shared name implies, and the autoantibody is the clearest evidence for that. Anti-topoisomerase I predicts lung fibrosis, anti-RNA polymerase III predicts renal crisis and rapid skin thickening, and anticentromere predicts pulmonary hypertension with limited skin involvement. The two manifestations that decide survival largely occur in different patients, and a trial enrolling on the diagnosis mixes them all.
The whole page in one table. The skin endpoint is a clinician's fingers, it improves without treatment, and nothing has ever been approved on it. The lung endpoint measured in the same trials is a spirometer, and two drugs have.
| Endpoint | Type | Read at | Standing |
|---|---|---|---|
| Modified Rodnan skin score (mRSS) | Clinician-rated | 12 months | Contested |
| ACR CRISS composite index | Composite | 12 months | Exploratory |
| Forced vital capacity (FVC) decline | Performance | 52 weeks | Accepted |
| Scleroderma HAQ (HAQ-DI with visual analogue scales) | Self-reported | 12 months | Contested |
| Event-free survival | Composite | 2–5 years | Accepted |
This disease is three processes at once — vasculopathy, autoimmunity and fibrosis — and no model has all three. Each isolates one leg, a candidate is selected on the leg it targets, and it then meets patients who have all of them. That is a different failure from the one on the Parkinson's page: not a wrong model, a partial one.
| Model | FaceDoes it look like the disease? | ConstructDoes it arise the same way? | PredictiveHalt or reverse fibrosis |
|---|---|---|---|
Read the outcome column against the endpoint column rather than on its own. Two of these programmes produced an approved drug. Neither was approved on the endpoint it was designed around.
| Intervention | Rested on | Primary endpoint | Reached | Outcome |
|---|---|---|---|---|
Lenabasum Corbus Pharmaceuticals · Selective cannabinoid receptor type 2 agonist, intended to resolve inflammation without immunosuppression | Bleomycin skinPatient fibroblasts | ACR CRISS composite index at 52 weeks | Phase 3 RESOLVE-1 · 2021 | Failed |
Tocilizumab Roche / Genentech · Monoclonal antibody blocking the interleukin-6 receptor | Bleomycin skinPatient fibroblasts | Change from baseline in modified Rodnan skin score at 48 weeks | Approved (for the lung manifestation) focuSSced · 2020 | Missed primary |
Abatacept Bristol Myers Squibb / academic · CTLA4-Ig fusion protein blocking the co-stimulatory signal T cells need to be activated | sclGVHDBleomycin skin | Change from baseline in modified Rodnan skin score at 12 months | Phase 2 ASSET · 2020 | Missed primary |
Nintedanib Boehringer Ingelheim · Intracellular inhibition of multiple tyrosine kinases, including PDGF, FGF and VEGF receptors | Bleomycin skinFra-2 | Annual rate of decline in forced vital capacity, in millilitres per year, over 52 weeks | Approved (for the lung manifestation) SENSCIS · 2019 | Approved |
Riociguat Bayer · Soluble guanylate cyclase stimulator, raising cyclic GMP independently of nitric oxide | Bleomycin skinFra-2 | Change from baseline in modified Rodnan skin score at 52 weeks | Phase 2b RISE-SSc · 2019 | Missed primary |
Autologous haematopoietic stem-cell transplantation Academic consortia (EBMT/EULAR; NIAID) · Ablation of the autoreactive immune repertoire, followed by reconstitution from the patient's own stem cells | sclGVHD | Event-free survival: time to death or irreversible major organ failure | Phase 3 (randomised, two trials) ASTIS; SCOT · 2018 | Benefit, no approval |
Mycophenolate mofetil Academic (NHLBI) · Inhibition of inosine monophosphate dehydrogenase, selectively suppressing lymphocyte proliferation | sclGVHD | Course of percent-predicted forced vital capacity over 24 months | Phase 3 Scleroderma Lung Study II · 2016 | Benefit, no approval |
Imatinib Novartis / investigator-initiated · Tyrosine kinase inhibitor blocking PDGF receptor and c-Abl, two nodes downstream of TGF-β | Bleomycin skinTsk-1Patient fibroblasts | Change from baseline in modified Rodnan skin score at 6 to 12 months | Phase 2 Multiple small randomised and open-label studies · 2011 | Failed |
Oral cyclophosphamide Academic (NHLBI) · Alkylating agent producing broad, non-selective immunosuppression | sclGVHDBleomycin skin | Percent-predicted forced vital capacity at 12 months | Phase 3 Scleroderma Lung Study I · 2006 | Benefit, no approval |
How thick and tethered the skin feels to a trained examiner, summed across seventeen body sites
The endpoint the disease is named around, and no drug has ever been approved on it. Two problems compound: examiner-dependent measurement, and a placebo arm that improves because early diffuse skin disease often regresses on its own.
Among the most expensive per success on this site, for an unusual reason. The trials are not large by the standards of common disease. What makes them expensive is that almost none of them work, and the endpoint is a substantial part of why.
A full year on the skin score, twice. Modest enrolment by the standards of common disease and expensive anyway, because the endpoint cannot be read faster and a single trial will not carry a claim on a measure this contested.
718 patient-years against 189 for a symptomatic programme. Cost grows more slowly than exposure because the fixed enrolment cost of each participant — screening, baseline imaging — is paid once however long they are then followed. The goal, not the molecule, still sets the budget.
Citedenrolment, duration and study counts, from named trials.Assumptionthe two cost parameters below.Computedeverything else.
| Phase | Design | N × studies | Duration | Patient-years | Modelled cost |
|---|---|---|---|---|---|
| Phase 1 | SAD / MAD, healthy volunteers Reads: Safety, tolerability and pharmacokinetics Antifibrotics and immunomodulators both carry tolerability questions that shape later dosing, so first-in-human work is not abbreviated. Conventional first-in-human designmoderate confidence | 50 | 9 mo | 38 | $1.4M–$2.2M |
| Phase 2 | Dose-ranging on the skin score, with lung function as a key secondary Reads: Change from baseline in modified Rodnan skin score at 12 months A full year even at Phase 2, because the score moves slowly and a shorter read cannot separate treatment from the spontaneous improvement seen in early diffuse disease. Sized after ASSET and faSScinate. Khanna et al., Arthritis Rheumatol 2020 (ASSET); Khanna et al., Lancet 2016 (faSScinate)high confidence | 120 | 1 yr | 120 | $3.8M–$6.4M |
| Phase 3 | Two pivotals, 48 to 52 weeks, placebo-controlled on background therapy Reads: Change from baseline in modified Rodnan skin score, or the CRISS composite, at 48 to 52 weeks Sized between focuSSced and RESOLVE-1. Two pivotals is the honest assumption for an endpoint on which no drug has ever been approved: the first sponsor to succeed on the skin score should expect to be asked to do it again. Khanna et al., Lancet Respir Med 2020 (focuSSced); Spiera et al., Arthritis Rheumatol 2023 (RESOLVE-1)moderate confidence | 280 × 2 | 1 yr | 560 | $18M–$30M |
| Total | 2.8 yr of clinical development, treating phases as sequential | 718 | $23M–$38M |
Model assumptions, not citations — the only free parameters here. The fixed component covers screening, baseline imaging and randomisation, incurred once per participant; the running component covers visits, monitoring and site fees for each year on study. Splitting them matters: a single rate per patient-year would price short symptomatic trials far below what pivotal trials actually cost.
Calibration: priced this way a single pivotal trial in this programme comes to $3.6M–$5.8M, against published pivotal trial costs of $12–33M (median $19M) across all indications. A rare disease with trials in the low hundreds, so a single pivotal here lands below the published all-indication interquartile range. The unusual feature is duration: the skin endpoint needs a full year regardless of trial size, because the score moves slowly and noisily, so this programme costs more than its enrolment alone would suggest. Moore et al., JAMA Internal Medicine 2018.
Programme cost divided by a 4% likelihood of approval from Phase 1 in skin fibrosis in systemic sclerosis — what one success costs once the failures are paid for. BIO / Informa / QLS, Clinical Development Success Rates — autoimmune disease sits near the all-indication average, and fibrosis sits far below it.
Read this one carefully: The lowest rate on this site, and the one resting on the plainest arithmetic: four decades of randomised trials against skin fibrosis and no approvals at all. Read it as a statement about the endpoint rather than about the biology. Two of the programmes counted as failures here produced approved drugs — on a lung endpoint measured in the same trial — so the 4% describes the odds of winning the argument a skin trial is set up to have, not the odds that a compound does something.
These are portfolio figures spanning all of R&D and already carry the cost of failure, so they are not comparable with the per-programme clinical costs above — they are the order of magnitude those costs roll up into.
Three shifts, and two of them are about who is enrolled and what is measured rather than about new mechanisms.
The composite index was designed to fix the skin score by borrowing strength from lung function, patient report and physician judgement. It then failed as the primary endpoint of a Phase 3 trial, because its components drift in the same favourable direction in untreated patients — the composite inherited the problem instead of averaging it away. The current direction is different in kind: skin biopsy transcriptomic scores and high-frequency ultrasound aim to replace a human judgement with an instrument reading, on the argument that what is wrong with the skin score is not its weighting but that it is measured by hand.
Khanna et al., Arthritis Rheumatol 2016 (CRISS); Spiera et al., Arthritis Rheumatol 2023 (RESOLVE-1)
Three antibodies carve this population into groups with different natural histories: anti-topoisomerase I predicts lung fibrosis, anti-RNA polymerase III predicts rapid skin thickening and renal crisis, and anticentromere predicts pulmonary hypertension with limited skin disease. A trial enrolling diffuse cutaneous disease mixes them, and a pre-specified analysis in one Phase 2 found the response confined to a single skin gene-expression subset. Enriching by serotype or expression subset is the obvious response and remains largely undone, because the disease is rare enough that any enrichment criterion makes an already difficult trial harder to fill.
Steen, Semin Arthritis Rheum 2005 (autoantibody-defined subsets); Khanna et al., Arthritis Rheumatol 2020 (ASSET subset analysis)
Small uncontrolled case series of CD19-directed CAR-T cell therapy in severe autoimmune disease, systemic sclerosis included, report skin score falls and organ improvement that outstrip anything in the randomised record, with autoantibodies disappearing and B cells returning naive. The numbers are single-digit, there is no control arm, and follow-up is short — this is the weakest evidence on the page and the most interesting. It also carries an implicit claim worth stating: if depleting B cells this deeply reverses established fibrosis, the fibroblast is not as autonomous as the culture data suggest.
Müller et al., NEJM 2024 (CD19 CAR-T in autoimmune disease); early single-centre case series