Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vascular damage and fibrosis that affects multiple organ systems and the skin.1 Depending on the extent of skin involvement, SSc can be classified as diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc).2 In dcSSc, patients experience a rapidly progressive thickening of the skin and severe internal organ impact, with high morbidity and mortality.2 Current therapeutic options cannot stop the progression of the disease; they only minimize disease involvement and offer a degree of symptom relief.1,2

In recent years, the development of targeted therapies for SSc has progressed, and several clinical trials with innovative treatments are currently ongoing. Typical clinical trial outcome measures used in SSc clinical trials include the modified Rodnan skin score (mRSS), which represents a primary outcome measure of skin thickness. In clinical trials involving patients with SSc who present with interstitial lung disease (ILD), the predicted percentage of forced vital capacity (FVC%) has also been used as the primary or secondary endpoint.2

Benlysta and Rituximab Adjunctive to CellCept

A phase 2 randomized, double-blind, placebo-controlled clinical trial is currently recruiting participants to determine if a combination therapy of rituximab, Benlysta® (belimumab), and CellCept® (mycophenolate mofetil) is safe and tolerable, as well as more effective than the combination of placebo and CellCept (NCT03844061). The primary efficacy outcome will be measured by change in Composite Response Index in Systemic Sclerosis (CRISS). This 52-week study is expected to be completed in June 2024.3

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Adcetris® (brentuximab vedotin) is an experimental drug-antibody conjugate that targets the protein CD30. CD30 is expressed on activated immune cells such as lymphocytes and is found in elevated levels in patients with dcSSc.1,4

There are currently ongoing phase 1/2 (NCT03222492) and phase 2 (NCT03198689) clinical trials to determine the therapeutic efficacy of Adcetris in patients with dcSSc.4,5 The BRAVOS phase 1/2 clinical trial is a multicenter, prospective, double-blind, placebo-controlled, dose-escalation, safety and tolerability trial of Adcetris in patients with SSc. This trial has an expected completion date of August 2023.4

The phase 2 trial is a pilot study to determine both the safety and preliminary efficacy of this experimental treatment, and it aims to treat 11 patients with dcSSc. The primary outcome of this trial is the mean change in mRSS. Exploratory outcomes include the Health Assessment Questionnaire Disability Index (HAQ), patient and physician global scores, inflammatory markers (erythrocyte sedimentation rate, C-reactive protein), and CRISS. The trial is expected to be completed by October 2023.5

Read more about SSc experimental therapies


A phase 1 clinical trial on Siliq® (brodalumab, KHK4827), a biological therapy that targets the subunit A of the interleukin-17 (IL-17) receptor, is currently ongoing (NCT04368403).1,6 This is an exploratory evaluation of the pharmacokinetics and safety of the drug in 8 patients with SSc. The completion of this study is expected in February 2024. The primary outcome of this trial is the serum concentration of the drug, while the change in mRSS from baseline represents a secondary outcome measure.6

Read more about SSc clinical features


A randomized, double-blind, placebo-controlled, repeat-dose, multicenter trial (NCT04781543) is currently recruiting approximately 300 participants to determine the pharmacokinetics, efficacy, safety, and tolerability of HZN-825, a lysophosphatidic acid receptor 1 (LPAR1) antagonist.7,8 This phase 2 clinical trial includes a 4-week screening period and a 52-week double-blind treatment period. Participants who reach week 52 will be able to enter a 52-week extension study (NCT05626751).9

Read more about SSc prognosis

Observational Studies in Systemic Sclerosis

SCLEROJAKI (NCT05177471) is an observational study designed to evaluate both the safety and efficacy of Janus kinase (JAK) inhibitors in patients with SSc who present with ILD. JAK inhibitors have anti-inflammatory and antifibrotic activities and are approved for the treatment of rheumatoid arthritis. This study is currently recruiting participants. The primary outcome measure is the relative change in FVC% predicted after 12 months of JAK inhibitor treatment.10

Read more about SSc comorbidities


  1. Bohdziewicz A, Pawlik KK, Maciejewska M, et al. Future treatment options in systemic sclerosis—potential targets and ongoing clinical trials. J Clin Med. 2022;11(5):1310. doi:10.3390/jcm11051310
  2. Chung MP, Chung L. Drugs in phase I and phase II clinical trials for systemic sclerosis. Expert Opin Investig Drugs. 2020;29(4):349-362. doi:10.1080/13543784.2020.1743973
  3. Belimumab and rituximab combination therapy for the treatment of diffuse cutaneous systemic sclerosis. February 18, 2019. Updated September 10, 2022. Accessed April 24, 2023.
  4. Brentuximab vedotin for systemic sclerosis (BRAVOS). July 19, 2017. Updated February 13, 2023. Accessed April 24, 2023.
  5. Brentuximab vedotin in early diffuse cutaneous systemic sclerosis. June 26, 2017. Updated March 9, 2023. Accessed April 24, 2023.
  6. A study of KHK4827 in patients with systemic sclerosis. April 29, 2020. Updated February 14, 2023. Accessed April 24, 2023.
  7. A multicenter trial to evaluate the efficacy, safety, tolerability and pharmacokinetics of HZN-825 in patients with diffuse cutaneous systemic sclerosis. March 4, 2021. Updated March 1, 2023. Accessed April 24, 2023.
  8. Horizon Therapeutics plc announces first patient enrolled in phase 2b pivotal trial evaluating HZN-825 for the treatment of diffuse cutaneous systemic sclerosis. News release. Horizon Therapeutics plc; November 9, 2021.
  9. An open-label extension trial of HZNP-HZN-825-301 in adult participants with diffuse cutaneous systemic sclerosis (diffuse cutaneous SSc). November 25, 2022. Updated February 22, 2023. Accessed April 24, 2023.
  10. Efficacy and safety of JAK inhibitors in systemic sclerosis-associated interstitial lung disease (SCLEROJAKI). January 4, 2022. Updated January 20, 2022. Accessed April 24, 2023.

Reviewed by Kyle Habet, MD, on 4/30/2023.