RARE DISEASE
Diffuse cutaneous systemic sclerosis
Diffuse cutaneous systemic sclerosis
Diffuse cutaneous systemic sclerosis
Synonyms: Diffuse cutaneous systemic scleroderma, Progressive cutaneous systemic scleroderma, Progressive cutaneous systemic sclerosis
Synonyms: Diffuse cutaneous systemic scleroderma, Progressive cutaneous systemic scleroderma, Progressive cutaneous systemic sclerosis
Synonyms: Diffuse cutaneous systemic scleroderma, Progressive cutaneous systemic scleroderma, Progressive cutaneous systemic sclerosis
Drug discovery
8
drugs
With orphan designations
Overview
Diffuse cutaneous systemic sclerosis (dcSSc) is a severe subtype of systemic sclerosis characterized by rapid, widespread skin fibrosis (typically affecting arms, trunk, and face) and early multi-organ involvement, including interstitial lung disease, renal crisis, gastrointestinal dysmotility, and cardiac complications. Associated with anti-Scl-70 antibodies, it progresses faster than limited forms, with a 10-year survival rate of 60–80% due to life-threatening organ damage [1][4][6].
Population
Prevalence: ~1/25,000 adults, predominantly affecting women (4:1 female-to-male ratio) [1][12].
Demographics: Higher incidence in African American individuals, who often present younger with more aggressive organ involvement [2][12].
Autoantibodies: Anti-topoisomerase I (Scl-70) positivity in 30–40% of cases [1][7].
Burden
Mortality: Leading causes include pulmonary fibrosis (60% of cases), renal crisis (15–20%), and cardiac complications [1][4][15].
Treatment burden: Average 10 tablets/day, frequent discontinuations due to side effects [5][9].
Quality of life: Profound impact from skin tightening, pain, fatigue, and loss of independence; 27% report fecal incontinence [5][16].
Therapies
Immunosuppressants: Methotrexate, mycophenolate mofetil, or cyclophosphamide for skin fibrosis and lung involvement [8][13][17].
Organ-specific therapies: Calcium channel blockers (Raynaud’s), proton pump inhibitors (gastroesophageal reflux), and pulmonary vasodilators (pulmonary hypertension) [1][6].
Emerging options: Autologous stem cell transplantation for rapidly progressive cases [13].
Categories: rare cardiac diseases, rare renal diseases, rare respiratory diseases, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
1,090 drug discovery papers about Diffuse cutaneous systemic sclerosis, with 1 first-in-class and 36 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,090 drug discovery papers about Diffuse cutaneous systemic sclerosis, with 1 first-in-class and 36 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-07 | Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis.
Systemic sclerosis is an autoimmune fibrotic skin disease characterised by immune activation and fibrosis. Fibroblasts are at the core of this fibrotic process, differentiating into effector myofibroblasts; however, the drivers of this process remain obscure. Recently, metabolic changes in cells in fibrotic diseases have been uncovered, with changes in the TCA cycle and glycolysis being observed. The objective of this work was to elucidate the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in systemic sclerosis. Serum from early diffuse systemic sclerosis (SSc) patients and healthy controls (HC) was collected for PKM2 analysis by ELISA. Fibroblasts were isolated from HC and SSc biopsies and treated with transforming growth factor-beta 1 (TGF-β1) to assess PKM2 expression. PKM2 was pharmacologically modulated, and collagen and Extracellular Matrix (ECM) regulators were evaluated. Metabolic activity was assessed using Seahorse assays, and lactate transport was chemically inhibited. Chromatin immunoprecipitation was performed using a histone lactylation-specific or isotype antibody, and lactate or acetate supplementation experiments were conducted. We found significantly elevated circulating and fibroblast PKM2 in SSc patients. Fibroblast PKM2 could be induced in healthy fibroblasts by TGF-β1 exposure. Furthermore, PKM2 drives a metabolic shift to glycolysis that can be blocked by forced tetramerisation of PKM2 from its dimeric form; this resulted in reduced ECM and matrix regulators. Mechanistically, PKM2-mediated glycolysis results in elevated lactate, which drives collagen via epigenetic regulation by histone H3K18 lactylation. Blockade of PKM2 dimerisation reduced Histone H3 at Lysine 18 (H3K18) lactylation at the collagen promoter, which could be restored with lactate but not acetate. We further demonstrated that lactate-induced collagen is partially mediated by HIF-1α. PKM2 drives activation of fibroblasts in SSc via metabolic changes such as glycolysis. Taking advantage of PKM2 tetramerisation or blockade of lactate generation could be a possible therapeutic option in a disease with few treatment options.
2026-08-02 | Treating skin involvement in diffuse cutaneous systemic sclerosis: results from an international scleroderma specialist survey.
To evaluate contemporary global treatment of diffuse cutaneous systemic sclerosis (dcSSc) skin by SSc specialists. An anonymous survey was distributed via the Scleroderma Clinical Trials Consortium, European Scleroderma Trials and Research Group (EUSTAR), and Collaborative National Quality and Efficacy Registry (CONQUER) distribution lists between June and September 2025. The survey comprised four sections: Demographics, Treatment of dcSSc Skin, Impact of Recent Guidelines, and Clinical Trials. Responses included 103 physicians (93 completed): 43% North America, 31% Europe, 15% South America and 12% elsewhere. The majority practice within an SSc centre (80%) and participate in clinical trials (84%). Mycophenolate mofetil (MMF) was preferred first-line treatment (71%) for dcSSc without ILD, rising to 92% for dcSSc with mild/non-progressive ILD. For active skin involvement despite MMF, trial referral was preferred as next step irrespective of ILD (59% without ILD and 58% with ILD). Treatment preferences have evolved, with 40% increasing MMF use and 47% decreasing methotrexate use, over the previous 2-3 years. Biologic use has increased, with 56% and 37% reporting increasing rituximab and tocilizumab use, respectively. For dcSSc without ILD, 85% have prescribed rituximab, and 65% have prescribed tocilizumab. Biologic availability has impacted trial enrolment (73% agreement). Treatment decision-making for dcSSc skin involvement has been materially influenced by recent BSR and/or EULAR guidelines (43% agreement). MMF is preferred first-line for dcSSc. In the absence of compelling scientific justification for combination or step-up immunomodulatory approaches, trial referral is currently the preferred next treatment option. Biologic use is increasing, which impacts trial enrolment.
2026-08-01 | Systemic Sclerosis Induced by Immune Checkpoint Inhibitors from the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO): A Case Series
Objectives Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, improving outcomes in multiple advanced malignancies. Their use is often limited by immune-related adverse events (irAEs), including rare rheumatic irAEs, such as ICI-induced systemic sclerosis (ICI-SSc). Compared to idiopathic SSc, ICI-SSc typically presents with fewer extra-cutaneous manifestations and negative serologies, but data remains limited.[1] This case series describes the clinical presentation, management, and outcomes of patients with ICI-SSc to guide clinicians in balancing autoimmune toxicities with cancer control. Methods A retrospective chart review was conducted on 7 adults diagnosed with systemic sclerosis following ICI exposure between March 2021 and August 2025. All patients were referred to a Canadian academic rheumatology clinic specializing in Immuno-Oncology during ICI therapy. Clinical data was abstracted from medical records, including patient demographics, malignancy type and stage, ICI type and duration, clinical features, serologies, treatment, and outcomes. Results Of the 7 patients identified, 5 (71.4%) were female and 2 (28.6%) were male, with a mean age (SD) of 63 (10.9) years. Malignancies included: metastatic melanoma (n=4), metastatic squamous cell carcinoma (n=1), breast cancer Stage IIA/IIB (n=1), and metastatic endometrial adenocarcinoma (n=1). ICIs used included: pembrolizumab (n=2), nivolumab (n=1), cemiplimab (n=1), and ipilimumab/nivolumab combination followed by nivolumab monotherapy (n=2), which were discontinued due to SSc symptoms within 1-13 months of initiation. Serologies showed ANA positivity in 4 patients (57.1%), with SSc-specific antibodies (anti-Scl-70) detected in 1 patient. Other antibodies detected included anti-RP-11, anti-RP-155, anti-Ro-52, anti-chromatin, and anti-OJ. 2 patients had negative serologies, 1 with elevated inflammatory markers. All patients had scleordactyl (diffuse 57.1%, limited 42.9%) and extra-cutaneous features, most commonly Raynaud’s phenomenon (71.4%). Other manifestations included inflammatory arthritis (42.9%), nailfold capillary changes (42.9%), esophageal dysmotility (28.6%), telangiectasia (14.3%), and sicca symptoms (14.3%). No patients developed interstitial lung disease, pulmonary arterial hypertension, or scleroderma renal crisis. Management included ICI cessation for all patients, prednisone (85.7%), disease-modifying antirheumatic drugs (mycophenolate mofetil 57.1%, methotrexate 28.6%, hydroxychloroquine 28.6%), infliximab and intravenous immunoglobulins, and vasodilatory therapies. All malignancies were stable at 6 months post-ICI therapy. Conclusion ICI-SSc is a significant irAE primarily characterized by cutaneous manifestations but, in contrast to previous reports, this case series demonstrates that extra-cutaneous manifestations and seropositivity can occur. Along with ICI-cessation, immunosuppressive therapy was effective in symptom control without compromising cancer stability. This work may assist those involved in caring of patients with ICI-SSc to initiate immunosuppressive therapy and minimize the risk of end-organ complications. References [1.] Cho LK. Rheum Dis Clin North Am 2024;50:301-12.
2026-08-01 | Isolated Neck Extensor Myositis and Chest Wall Skin Thickening: Case Report of a Rare Initial Presentation of Systemic Sclerosis and Overlap Myositis
Background Systemic sclerosis is a multisystemic connective tissue characterized by immune dysregulation, fibrosis and vasculopathy. Skin thickening, a cardinal feature of this disease process, characteristically progresses in a centripetal pattern.[1] Overlap disease with idiopathic inflammatory myositis can be seen, classically involving weakness of the proximal muscle groups of the upper and lower limbs.[2] Case Report We report the case of a 46-year-old female referred for assessment of possible systemic sclerosis with a several month history of neck extensor weakness, Raynaud’s phenomenon, moderate skin thickening isolated to the chest, positive ANA 1:640 nucleolar, and elevated CK of 436. Over the next few months, she developed rapidly progressive and severe skin thickening of the proximal and distal extremities, face and hands with associated sclerodactyly. Advanced serological testing was negative for myositis or systemic sclerosis associated with autoantibodies. Baseline investigations including echocardiogram, pulmonary function test and high-resolution CT scan of the lungs were normal. MRI of the extremities and neck demonstrated mild edema to the posterior neck paraspinal muscles, EMG of the neck extensors was positive for irritable myopathy, and subsequent muscle biopsy of the cervical paraspinal muscles demonstrated marked fibrosis with end-stage muscle atrophy in keeping with partially treated myositis. Punch biopsies of the skin demonstrated sclerosing dermatitis. A diagnosis of diffuse cutaneous systemic sclerosis with overlap myositis was made. She was treated initially with methotrexate followed by mycophenolate, however due to rapidly progressive cutaneous disease she underwent autologous hematopoietic stem cell transplant approximately 8 months after initial presentation. With ongoing follow-up 6 months post-transplant, the patients’ skin thickening had significantly improved, her myositis and Raynaud’s phenomenon had resolved, and she remained in remission off all immunosuppressive therapies. Conclusion Isolated neck extensor myositis and initial skin thickening of the chest is a rare presentation of early diffuse cutaneous systemic sclerosis. This case highlights the importance of close follow up of patients with atypical disease manifestations and seeking histopathological correlation to assist in making a definitive diagnosis. References [1.] Volkmann E. Lancet 2022;401:304-18. [2.] Bhansing K. Arthritis Res Ther 2014;16:R111.
2026-06-27 | High-intensity immunosuppression versus modern standard care in poor-prognosis diffuse cutaneous systemic sclerosis: A propensity-matched study.
Purpose: The 2023 EULAR update recommends autologous hematopoietic stem-cell transplantation preceded by high-intensity immunosuppression (HI-IS/HSCT) for selected poor-prognosis early diffuse cutaneous systemic sclerosis (dcSSc). As real-world data remain scarce, we compared 5-year outcomes of HI-IS/HSCT recipients with propensity-matched controls receiving standard care. Because undergoing HI-IS/HSCT identifies poor-prognosis systemic sclerosis (SSc), we compared their 5-year outcomes with those of propensity-matched dcSSc controls receiving standard care. This retrospective multicenter study analyzed ACR/EULAR-2013 dcSSc patients treated after 2013 from the Greater Paris University Hospitals and French national registry. Patients had poor-prognosis SSc defined by early disease and rapid skin progression or organ involvement. HI-IS/HSCT recipients were matched 1:1 with conventional immunosuppression controls using nearest-neighbor 20-variable propensity scores (covering demographics, antibodies, organ involvement, and prior treatments). Outcomes included overall survival (OS), event-free survival (EFS), progression-free survival (PFS), and toxicities at 60 months. Exploratory multivariable logistic regression identified predictors of EFS. We analyzed 100 patients, equally divided between the HI-IS/HSCT and control groups. Five-year OS was similar (90%) in both groups. However, HI-IS/HSCT was associated with significantly improved 5-year event-free survival (76% vs 46%, p = 0.021) and progression-free survival (82% vs 40%, p = 0.001), a more favorable Global Rank Composite Score (p = 0.001), greater skin improvement (p < 0.001), and stabilization of FVC (p = 0.034) compared with controls. Prior DMARD burden was significantly lower in the transplant group (median 1 vs 2, p < 0.0001). Conditioning containing fludarabine/rituximab showed a non-significant trend towards higher EFS compared to CYC + ATG alone (82.6% vs 66.7%, p = 0.33). HI-IS/HSCT caused higher grade ≥4 toxicities (36% vs 8%, p < 0.001), with a 2% procedure-related mortality. Older age and pre-existing cardiac involvement were independently associated with worse EFS after transplant. In patients with poor-prognosis dcSSc, 5-year overall survival was high and similar between HI-IS/HSCT and modern conventional care. However, HI-IS/HSCT provided significantly superior event-free and progression-free survival, skin improvement, and pulmonary stabilization. These findings support early HSCT as a highly effective disease-stabilizing therapy in carefully selected patients, provided they undergo rigorous cardiac screening.
2026-08-07 | Pyruvate kinase M2 is elevated in systemic sclerosis and plays a role in its pathogenesis.
Systemic sclerosis is an autoimmune fibrotic skin disease characterised by immune activation and fibrosis. Fibroblasts are at the core of this fibrotic process, differentiating into effector myofibroblasts; however, the drivers of this process remain obscure. Recently, metabolic changes in cells in fibrotic diseases have been uncovered, with changes in the TCA cycle and glycolysis being observed. The objective of this work was to elucidate the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in systemic sclerosis. Serum from early diffuse systemic sclerosis (SSc) patients and healthy controls (HC) was collected for PKM2 analysis by ELISA. Fibroblasts were isolated from HC and SSc biopsies and treated with transforming growth factor-beta 1 (TGF-β1) to assess PKM2 expression. PKM2 was pharmacologically modulated, and collagen and Extracellular Matrix (ECM) regulators were evaluated. Metabolic activity was assessed using Seahorse assays, and lactate transport was chemically inhibited. Chromatin immunoprecipitation was performed using a histone lactylation-specific or isotype antibody, and lactate or acetate supplementation experiments were conducted. We found significantly elevated circulating and fibroblast PKM2 in SSc patients. Fibroblast PKM2 could be induced in healthy fibroblasts by TGF-β1 exposure. Furthermore, PKM2 drives a metabolic shift to glycolysis that can be blocked by forced tetramerisation of PKM2 from its dimeric form; this resulted in reduced ECM and matrix regulators. Mechanistically, PKM2-mediated glycolysis results in elevated lactate, which drives collagen via epigenetic regulation by histone H3K18 lactylation. Blockade of PKM2 dimerisation reduced Histone H3 at Lysine 18 (H3K18) lactylation at the collagen promoter, which could be restored with lactate but not acetate. We further demonstrated that lactate-induced collagen is partially mediated by HIF-1α. PKM2 drives activation of fibroblasts in SSc via metabolic changes such as glycolysis. Taking advantage of PKM2 tetramerisation or blockade of lactate generation could be a possible therapeutic option in a disease with few treatment options.
2026-08-02 | Treating skin involvement in diffuse cutaneous systemic sclerosis: results from an international scleroderma specialist survey.
To evaluate contemporary global treatment of diffuse cutaneous systemic sclerosis (dcSSc) skin by SSc specialists. An anonymous survey was distributed via the Scleroderma Clinical Trials Consortium, European Scleroderma Trials and Research Group (EUSTAR), and Collaborative National Quality and Efficacy Registry (CONQUER) distribution lists between June and September 2025. The survey comprised four sections: Demographics, Treatment of dcSSc Skin, Impact of Recent Guidelines, and Clinical Trials. Responses included 103 physicians (93 completed): 43% North America, 31% Europe, 15% South America and 12% elsewhere. The majority practice within an SSc centre (80%) and participate in clinical trials (84%). Mycophenolate mofetil (MMF) was preferred first-line treatment (71%) for dcSSc without ILD, rising to 92% for dcSSc with mild/non-progressive ILD. For active skin involvement despite MMF, trial referral was preferred as next step irrespective of ILD (59% without ILD and 58% with ILD). Treatment preferences have evolved, with 40% increasing MMF use and 47% decreasing methotrexate use, over the previous 2-3 years. Biologic use has increased, with 56% and 37% reporting increasing rituximab and tocilizumab use, respectively. For dcSSc without ILD, 85% have prescribed rituximab, and 65% have prescribed tocilizumab. Biologic availability has impacted trial enrolment (73% agreement). Treatment decision-making for dcSSc skin involvement has been materially influenced by recent BSR and/or EULAR guidelines (43% agreement). MMF is preferred first-line for dcSSc. In the absence of compelling scientific justification for combination or step-up immunomodulatory approaches, trial referral is currently the preferred next treatment option. Biologic use is increasing, which impacts trial enrolment.
2026-08-01 | Systemic Sclerosis Induced by Immune Checkpoint Inhibitors from the Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO): A Case Series
Objectives Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, improving outcomes in multiple advanced malignancies. Their use is often limited by immune-related adverse events (irAEs), including rare rheumatic irAEs, such as ICI-induced systemic sclerosis (ICI-SSc). Compared to idiopathic SSc, ICI-SSc typically presents with fewer extra-cutaneous manifestations and negative serologies, but data remains limited.[1] This case series describes the clinical presentation, management, and outcomes of patients with ICI-SSc to guide clinicians in balancing autoimmune toxicities with cancer control. Methods A retrospective chart review was conducted on 7 adults diagnosed with systemic sclerosis following ICI exposure between March 2021 and August 2025. All patients were referred to a Canadian academic rheumatology clinic specializing in Immuno-Oncology during ICI therapy. Clinical data was abstracted from medical records, including patient demographics, malignancy type and stage, ICI type and duration, clinical features, serologies, treatment, and outcomes. Results Of the 7 patients identified, 5 (71.4%) were female and 2 (28.6%) were male, with a mean age (SD) of 63 (10.9) years. Malignancies included: metastatic melanoma (n=4), metastatic squamous cell carcinoma (n=1), breast cancer Stage IIA/IIB (n=1), and metastatic endometrial adenocarcinoma (n=1). ICIs used included: pembrolizumab (n=2), nivolumab (n=1), cemiplimab (n=1), and ipilimumab/nivolumab combination followed by nivolumab monotherapy (n=2), which were discontinued due to SSc symptoms within 1-13 months of initiation. Serologies showed ANA positivity in 4 patients (57.1%), with SSc-specific antibodies (anti-Scl-70) detected in 1 patient. Other antibodies detected included anti-RP-11, anti-RP-155, anti-Ro-52, anti-chromatin, and anti-OJ. 2 patients had negative serologies, 1 with elevated inflammatory markers. All patients had scleordactyl (diffuse 57.1%, limited 42.9%) and extra-cutaneous features, most commonly Raynaud’s phenomenon (71.4%). Other manifestations included inflammatory arthritis (42.9%), nailfold capillary changes (42.9%), esophageal dysmotility (28.6%), telangiectasia (14.3%), and sicca symptoms (14.3%). No patients developed interstitial lung disease, pulmonary arterial hypertension, or scleroderma renal crisis. Management included ICI cessation for all patients, prednisone (85.7%), disease-modifying antirheumatic drugs (mycophenolate mofetil 57.1%, methotrexate 28.6%, hydroxychloroquine 28.6%), infliximab and intravenous immunoglobulins, and vasodilatory therapies. All malignancies were stable at 6 months post-ICI therapy. Conclusion ICI-SSc is a significant irAE primarily characterized by cutaneous manifestations but, in contrast to previous reports, this case series demonstrates that extra-cutaneous manifestations and seropositivity can occur. Along with ICI-cessation, immunosuppressive therapy was effective in symptom control without compromising cancer stability. This work may assist those involved in caring of patients with ICI-SSc to initiate immunosuppressive therapy and minimize the risk of end-organ complications. References [1.] Cho LK. Rheum Dis Clin North Am 2024;50:301-12.
2026-08-01 | Isolated Neck Extensor Myositis and Chest Wall Skin Thickening: Case Report of a Rare Initial Presentation of Systemic Sclerosis and Overlap Myositis
Background Systemic sclerosis is a multisystemic connective tissue characterized by immune dysregulation, fibrosis and vasculopathy. Skin thickening, a cardinal feature of this disease process, characteristically progresses in a centripetal pattern.[1] Overlap disease with idiopathic inflammatory myositis can be seen, classically involving weakness of the proximal muscle groups of the upper and lower limbs.[2] Case Report We report the case of a 46-year-old female referred for assessment of possible systemic sclerosis with a several month history of neck extensor weakness, Raynaud’s phenomenon, moderate skin thickening isolated to the chest, positive ANA 1:640 nucleolar, and elevated CK of 436. Over the next few months, she developed rapidly progressive and severe skin thickening of the proximal and distal extremities, face and hands with associated sclerodactyly. Advanced serological testing was negative for myositis or systemic sclerosis associated with autoantibodies. Baseline investigations including echocardiogram, pulmonary function test and high-resolution CT scan of the lungs were normal. MRI of the extremities and neck demonstrated mild edema to the posterior neck paraspinal muscles, EMG of the neck extensors was positive for irritable myopathy, and subsequent muscle biopsy of the cervical paraspinal muscles demonstrated marked fibrosis with end-stage muscle atrophy in keeping with partially treated myositis. Punch biopsies of the skin demonstrated sclerosing dermatitis. A diagnosis of diffuse cutaneous systemic sclerosis with overlap myositis was made. She was treated initially with methotrexate followed by mycophenolate, however due to rapidly progressive cutaneous disease she underwent autologous hematopoietic stem cell transplant approximately 8 months after initial presentation. With ongoing follow-up 6 months post-transplant, the patients’ skin thickening had significantly improved, her myositis and Raynaud’s phenomenon had resolved, and she remained in remission off all immunosuppressive therapies. Conclusion Isolated neck extensor myositis and initial skin thickening of the chest is a rare presentation of early diffuse cutaneous systemic sclerosis. This case highlights the importance of close follow up of patients with atypical disease manifestations and seeking histopathological correlation to assist in making a definitive diagnosis. References [1.] Volkmann E. Lancet 2022;401:304-18. [2.] Bhansing K. Arthritis Res Ther 2014;16:R111.
2026-06-27 | High-intensity immunosuppression versus modern standard care in poor-prognosis diffuse cutaneous systemic sclerosis: A propensity-matched study.
Purpose: The 2023 EULAR update recommends autologous hematopoietic stem-cell transplantation preceded by high-intensity immunosuppression (HI-IS/HSCT) for selected poor-prognosis early diffuse cutaneous systemic sclerosis (dcSSc). As real-world data remain scarce, we compared 5-year outcomes of HI-IS/HSCT recipients with propensity-matched controls receiving standard care. Because undergoing HI-IS/HSCT identifies poor-prognosis systemic sclerosis (SSc), we compared their 5-year outcomes with those of propensity-matched dcSSc controls receiving standard care. This retrospective multicenter study analyzed ACR/EULAR-2013 dcSSc patients treated after 2013 from the Greater Paris University Hospitals and French national registry. Patients had poor-prognosis SSc defined by early disease and rapid skin progression or organ involvement. HI-IS/HSCT recipients were matched 1:1 with conventional immunosuppression controls using nearest-neighbor 20-variable propensity scores (covering demographics, antibodies, organ involvement, and prior treatments). Outcomes included overall survival (OS), event-free survival (EFS), progression-free survival (PFS), and toxicities at 60 months. Exploratory multivariable logistic regression identified predictors of EFS. We analyzed 100 patients, equally divided between the HI-IS/HSCT and control groups. Five-year OS was similar (90%) in both groups. However, HI-IS/HSCT was associated with significantly improved 5-year event-free survival (76% vs 46%, p = 0.021) and progression-free survival (82% vs 40%, p = 0.001), a more favorable Global Rank Composite Score (p = 0.001), greater skin improvement (p < 0.001), and stabilization of FVC (p = 0.034) compared with controls. Prior DMARD burden was significantly lower in the transplant group (median 1 vs 2, p < 0.0001). Conditioning containing fludarabine/rituximab showed a non-significant trend towards higher EFS compared to CYC + ATG alone (82.6% vs 66.7%, p = 0.33). HI-IS/HSCT caused higher grade ≥4 toxicities (36% vs 8%, p < 0.001), with a 2% procedure-related mortality. Older age and pre-existing cardiac involvement were independently associated with worse EFS after transplant. In patients with poor-prognosis dcSSc, 5-year overall survival was high and similar between HI-IS/HSCT and modern conventional care. However, HI-IS/HSCT provided significantly superior event-free and progression-free survival, skin improvement, and pulmonary stabilization. These findings support early HSCT as a highly effective disease-stabilizing therapy in carefully selected patients, provided they undergo rigorous cardiac screening.
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Drug Discovery Landscape
8 orphan drug designations for Diffuse cutaneous systemic sclerosis.
8 orphan drug designations for Diffuse cutaneous systemic sclerosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
botulinum toxin type A | proteins | FDA | 2026-08-17 | — | ARCK Biologics, LLC |
(2R)-3-(4-{[4-Chloro-2-(difluoromethoxy)phenyl]carbamoyl}-4-[5-(propan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl)-2-(oxan-4-yl)propanoic acid hydrochloride, upadacitinib | small molecules | EMA | 2026-04-20 | — | AbbVie Deutschland GmbH & Co. KG |
nerandomilast | small molecules | FDA | 2026-03-09 | — | Boehringer Ingelheim Pharmaceuticals, Inc, (BIPI) |
nemolizumab | antibodies | FDA | 2026-01-13 | — | Galderma Research and Development, LLC |
autologous CD3+ T cells expressing CD19 chimeric antigen receptor | cell therapies | FDA | 2025-12-19 | — | Juno Therapeutics, Inc., a subsidiary of Bristol Myers Squibb |
Resecabtagene autoleucel | cell therapies | EMA | 2025-11-21 | — | Cabaletta Bio (Germany) GmbH |
blinatumomab | antibodies | FDA | 2025-10-16 | — | Amgen Inc. |
8-methoxsalen | small molecules | FDA | 1993-06-22 | — | Therakos Development Limited |
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