Scleroderma: Treatment Options and a Look to the Future - Dr. Macklin

Overview of scleroderma manifestations, organ involvement, brief classifications (limited, diffuse, sine scleroderma). Overview of current treatment options, need for additional therapies. Overview of plan for multi-disciplinary scleroderma center at the University of Chicago. Potential future therapies in the literature at large. Planned trials/future treatment options at the University of Chicago.

For more info about scleroderma and the foundation, head to www.stopscleroderma.org

This talk was presented at the Scleroderma Patient Education Conference on May 4, 2024, hosted by the Scleroderma Foundation of Greater Chicago.

1. Scleroderma: Treatment Options and a Look to the Future Michael Macklin MD, PharmD University of Chicago

2. Objectives Classification and manifestations of scleroderma Overview of treatment options for scleroderma Potential treatments on the horizon at large and at the University of Chicago Multi disciplinary care in scleroderma

3. Etiology Scleroderma is an incompletely understood disease There is clearly an autoimmune basis with vascular dysfunction, and activation of fibroblasts leading to fibrosis

4. Benfaremo D, Svegliati S, Paolini C, Agarbati S, Moroncini G. Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches. Biomedicines. 2022; 10(1):163. https://doi.org/10.3390/biomedicines10010163

5. Classification Limited: Skin involvement that does not go past elbows or knees for limbs, no trunk involvement, face/neck can be involved Diffuse: Skin involvement that does go past elbows or knees for limbs, trunk involvement, face/neck can be involved Sine scleroderma: No skin involvement, still has Raynaud's, antibodies, internal organ involvement

6. Classification Limited and diffuse tend to have different antibody profiles (SCL-70 for diffuse, centromere for limited) Diffuse tends to have an aggressive course initially then becomes less active overtime while limited is more slowly but consistently progressive Diffuse has more direct lung damage (interstitial lung disease) while limited has more lung blood vessel involvement (pulmonary artery hypertension) Diffuse in general is more “fibrotic”, limited in general is more “vascular”

7. Skin Manifestations Scleroderma/sclerodactyly with skin thickening Telangiectasia Calcinosis Salt and pepper appearance

8. Mammino , J. (n.d.). Systemic sclerosis . American Osteopathic College of Dermatology . https://www.aocd.org/page/SystemicSclerosis

9. McMichael , J. (2018, November 7). Prayer sign . Twitter . https://twitter.com/globaldermie

10. July 22, 2021,N Engl J Med 2021; 385:357DOI: 10.1056/NEJMicm2103390

11. Barrett, C. (2017, August 16). Clinical Signs of Systemic Sclerosis. Stanford Medicine 25. https://stanfordmedicine25.stanford.edu/blog/archive/2017/scleroderma.html

12. Yamamoto T. Multiple calcinosis cutis as a result of Köbner phenomenon in a patient with systemic sclerosis. Our Dermatol Online. 2020;11(e):e176.1-e176.2

13. Gastrointestinal manifestations Gastric antral vascular ectasia (GAVE) Esophageal dysmotility with trouble swallowing, reflux (GERD) Intestinal dysmotility Gastroparesis (Delayed gastric emptying) Malnutrition

14. (2014, September 20). GAVE (gastric antral vascular ectasia). UPDATE IN GASTROENTEROLOGY. https://uptodategastro.wordpress.com/2014/09/20/gave-gastric-antral-vascular-ectasia/

15. Lung involvement Interstitial lung disease (Inflammation and fibrosis within the lung tissue) Pulmonary artery hypertension (high blood pressure in the pulmonary artery)

16. Weerakkody , Y. (2023, May 15). Scleroderma (pulmonary manifestations): Radiology reference article. Radiopaedia . https://radiopaedia.org/articles/scleroderma-pulmonary-manifestations-1 Di Muzio B, Normal chest CT. Case study, Radiopaedia.org (Accessed on 09 Feb 2024) https://doi.org/10.53347/rID-41162

17. Phillips, Q. (2022, July 18). What is pulmonary arterial hypertension (PAH)? Symptoms, Causes, Diagnosis, Treatment, and Prevention. EverydayHealth.com. https://www.everydayhealth.com/pulmonary-arterial-hypertension

18. Kidney Scleroderma renal crisis USMLE® Step 2 CK question of the day: Scleroderma renal crisis . Osmosis . (2023, February 22). https://www.osmosis.org/blog/2021/12/15/usmle-step-2-ck-question-of-the-day-scleroderma-renal-crisis

19. Cardiac Myocarditis (inflammation of the heart muscle) Pericarditis (inflammation of the sac around the heart) Heart failure Arrythmias (Abnormal heart rhythms)

20. Muscle Myositis (inflammation in muscles) in overlap Srikantharajah , D., Lloyd, M.E. & Kiely, P.D.W. Rituximab and intravenous immunoglobulin treatment in PM/ Scl antibody-associated disease: case-based review. Rheumatol Int 42, 359–364 (2022). https://doi.org/10.1007/s00296-021-05075-z

21. Raynaud's Wide variety of severity

22. October 24, 2013, N Engl J Med 2013; 369:1638, DOI: 10.1056/NEJMicm1304702

23. Treatment Much progress has been made Treatment generally guided by manifestations present Some organ involvement still has few options available

24. Skin thickening Treatment options include: Methotrexate (anti metabolite) Mycophenolate (anti metabolite) Rituximab? (biologic, anti B-Cell) Tocilizumab? (biologic, anti inflammatory signal molecule, IL-6)

25. Skin thickening Immunoglobulin therapy? (blood product) Cyclophosphamide rarely (DNA disrupting agent) Area of significant need overall

26. telangiectasia Laser therapy, with dermatology

27. telangiectasia Graham Dinsdale, Andrea Murray, Tonia Moore, Janice Ferguson, Jack Wilkinson, Helen Richards, Christopher E. M. Griffiths, Ariane L Herrick, A comparison of intense pulsed light and laser treatment of telangiectases in patients with systemic sclerosis: a within-subject randomized trial, Rheumatology, Volume 53, Issue 8, August 2014, Pages 1422–1430, https://doi.org/10.1093/rheumatology/keu006

28. Calcinosis Area of significant need Injections or compounded sodium thiosulfate cream around area Minocycline (oral, antibiotic/general anti-inflammatory properties) Tofacitinib? (Oral, targeted selective molecule, JAK inhibitor), data from myositis Surgical removal

29. GAVE (Watermelon stomach) Argon plasma coagulation (laser to burn off blood vessels) Therapy used for other manifestations may also help

30. GAVE (Watermelon stomach) Ohira , Tetsuya et al. “Detection of active bleeding from gastric antral vascular ectasia by capsule endoscopy.” World journal of gastrointestinal endoscopy vol. 5,3 (2013): 138-40. doi:10.4253/wjge.v5.i3.138

31. Dysmotility in the gastrointestinal system An area of great unmet need Proton pump inhibitors for reflux (pantoprazole, esomeprazole, etc ) Various promotility drugs (Metoclopramide, erythromycin, pyridostigmine, prucalopride) Immunoglobulin therapy? (blood product) Nassar M, Ghernautan V, Nso N, et al. Gastrointestinal involvement in systemic sclerosis: An updated review. Medicine (Baltimore). 2022;101(45):e31780. doi:10.1097/MD.0000000000031780 Matsuda, Kazuki M et al. “Rapid improvement of systemic sclerosis-associated intestinal pseudo-obstruction with intravenous immunoglobulin administration.” Rheumatology (Oxford, England) vol. 62,9 (2023): 3139-3145. doi:10.1093/rheumatology/kead093

32. Dysmotility in the gastrointestinal system Over the counter laxatives can be helpful in early stages (senna, polyethylene glycol, etc.) Prolonged dysmotility can lead to diarrhea from small intestinal bowel overgrowth, easily treatable with antibiotics Severe dysmotility can lead to malnutrition, need to bypass intestines, total parental nutrition (TPN)

33. Muscle involvement Inflammatory myositis is also undergoing a treatment revolution Immunoglobulin therapy (blood product) now standard of care Other therapies if myositis is a predominant feature

34. Scleroderma renal crisis Prevention is important, association with high prednisone doses, especially in patients who are RNA polymerase III positive Treated with high doses of blood pressure medicine, mainly angiotensin converting enzyme inhibitors (ACEI) such as lisinopril, captopril

35. Interstitial lung disease (Inflammation and fibrosis within the lung tissue) Mycophenolate (anti metabolite) standard of care Azathioprine (anti metabolite), may be inferior to other options Rituximab (biologic, anti B-Cell) Tocilizumab (biologic, anti inflammatory signal molecule, IL-6) Tocilizumab is one of two FDA approved therapies for scleroderma, specifically for ILD (2021) Roofeh , David et al. “Tocilizumab Prevents Progression of Early Systemic Sclerosis-Associated Interstitial Lung Disease.” Arthritis & rheumatology (Hoboken, N.J.) vol. 73,7 (2021): 1301-1310. doi:10.1002/art.41668 Kaufman M. FDA Approves Tocilizumab to Treat Systemic Sclerosis-Associated ILD. The Rheumatologist. Published March 25, 2021. Accessed February 17, 2024. https://www.the-rheumatologist.org/article/fda-approves-tocilizumab-to-treat-systemic-sclerosis-associated-ild/

36. Interstitial lung disease (Inflammation and fibrosis within the lung tissue) Cyclophosphamide rarely (DNA disrupting agent) Combination therapy (Mycophenolate + biologic)? Nintedanib in cases of significant fibrosis (anti fibrotic), generally added to immunosuppression Nintedanib is the only other FDA approved therapy, ILD (2019) Putman M. FDA Approves Nintedanib for SSc -ILD, But Temper Your Expectations. The Rheumatologist. Published December 18, 2019. https://www.the-rheumatologist.org/article/fda-approves-nintedanib-for-ssc-ild-but-temper-your-expectations/

37. Pulmonary artery hypertension (high blood pressure in the pulmonary artery) Managed by a pulmonary hypertension specialist (pulmonary and/or cardiology depending on center) Combination therapy generally used Sildenafil, tadalafil (Phosphodiesterase V inhibitor) (vasodilator) Ambrisentan , macitentan , bosentan (endothelin receptor antagonist) (prevents vasoconstriction) Kuwana , Masataka et al. “Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis.” Annals of the rheumatic diseases vol. 79,5 (2020): 626-634. doi:10.1136/annrheumdis-2019-216274

38. Pulmonary artery hypertension (high blood pressure in the pulmonary artery) Epoprostenol , treprostinil , iloprost (prostacyclin analogues) (vasodilator)

39. HEART INVOLVMENT An area of great unmet need Myocarditis (inflammation of the heart muscle) Immunosuppression seems to work, unknown best drug Pericarditis (inflammation of the sac around the heart) Treated like pericarditis outside of scleroderma (Naproxen/ibuprofen, colchicine)

40. HEART INVOLVMENT Heart failure/arrythmia (Abnormal heart rhythms) Treated like causes outside of scleroderma Significant heart failure from scleroderma carries a very poor prognosis

41. Raynaud's Lifestyle modification (gloves, cold avoidance, hand warmers, etc ) Amlodipine, nifedipine (Calcium channel blockers) Sildenafil, tadalafil (Phosphodiesterase V inhibitor) Fluoxetine? (SSRI) Losartan? (ARB) Smoking cessation! Dziadzio , M et al. “Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial.” Arthritis and rheumatism vol. 42,12 (1999): 2646-55. doi:10.1002/1529-0131(199912)42:12<2646::AID-ANR21>3.0.CO;2-T Coleiro , B et al. “Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine.” Rheumatology (Oxford, England) vol. 40,9 (2001): 1038-43. doi:10.1093/rheumatology/40.9.1038

42. Raynaud's Botox? (controversial, may actually worsen) Fat transfer with plastic surgery? Digital sympathectomy? (surgical stripping of sympathetic nervous system) Bosentan (endothelin receptor antagonist) (prevents vasoconstriction) Epoprostenol (prostacyclin analogue) (vasodilator) Peripheral nerve block (temporary) Senet, Patricia et al. “Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.” Arthritis & rheumatology (Hoboken, N.J.) vol. 75,3 (2023): 459-467. doi:10.1002/art.42342

43. Future Treatment Many potential treatment options are in development! Some are specific for ILD, other multiple system involvement

44. FT011 Oral drug, Phase 2 in diffuse scleroderma Is a G protein-coupled receptor 68 protein sensing antagonist, inhibits pro-fibrotic and inflammatory pathways Improved a variety of outcomes including lung function, skin thickening vs placebo GI side effects and photosensitivity seem to be the most common side effects Phase 3 to come Khanna D, Spino C, Bernstein E, Goldin J, Tashkin D, roth M, SLS III Investigators O. Combination Therapy of Mycophenolate Mofetil and Pirfenidone vs. Mycophenolate Alone: Results from the Scleroderma Lung Study III [abstract]. Arthritis Rheumatol . 2022; 74 (suppl 9). https://acrabstracts.org/abstract/combination-therapy-of-mycophenolate-mofetil-and-pirfenidone-vs-mycophenolate-alone-results-from-the-scleroderma-lung-study-iii/. Accessed February 16, 2024

45. Guselkumab IL-23 inhibitor (biologic) Used in psoriatic arthritis, psoriasis, data in Crohn’s Phase 2 trial in Japan Primary outcome is skin thickening https://clinicaltrials.gov/study/NCT04683029

46.   Anifrolumab Type 1 interferon blocker (biologic) Used in Lupus, especially for skin involvement Phase 3 study Evaluating effect on lung function and skin thickening mainly Chicago site is planned, not yet recruiting https://clinicaltrials.gov/study/NCT05925803

47. Ixazomib Ixazomib is an oral proteosome inhibitor Currently used in multiple myeloma Phase 2 study Recruiting at Mayo Clinic Arizona Evaluating effect on ILD and skin thickening https://www.clinicaltrials.gov/study/NCT04837131

48. Baricitinib A JAK inhibitor used in COVID-19, RA Phase 4 trial in China evaluating use in ILD and skin thickening compared with cyclophosphamide https://clinicaltrials.gov/study/NCT05300932

49. RO7303509 RO7303509 is a biologic that targets TGF- β 3 (antifibrotic) Phase 1A already done, recruiting for Phase 1B Sites include DC, Boston, Rochester MN, NYC Han L, Jamalian S, Pan L, et alPOS1266 A PHASE IA, RANDOMIZED STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF SINGLE ASCENDING DOSES OF RO7303509, AN ANTI-TGF Β3 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS Annals of the Rheumatic Diseases 2023;82:976-977. https://clinicaltrials.gov/study/NCT05462522

50. inebilizumab Anti CD19 biologic (B cell targeting) Phase 3 placebo-controlled study Evaluating skin thickening Taking place in Japan Already approved for Neuromyelitis Optica (NMO) https://clinicaltrials.gov/study/NCT05198557

51. Belimumab and Rituximab Belimumab is an anti B-lymphocyte stimulator ( BLyS ) biologic Currently used in Lupus Combination of belimumab and rituximab vs placebo Phase 2, recruiting in NYC Evaluating ILD and skin thickening https://clinicaltrials.gov/study/NCT03844061

52. Belimumab Primary outcome is lung function Phase 3 study, placebo controlled Northwestern is a site-recruiting per clinicaltrials.gov https://clinicaltrials.gov/study/NCT05878717

53. Ifetroban Thromboxane receptor antagonist Oral drug, phase 2 study, placebo controlled Looking specifically at both diffuse scleroderma and at patients with confirmed pulmonary artery hypertension Secondary endpoints include skin thickening, lung function Closest sites include NYC, Philadelphia, Omaha, Boston, Baltimore https://clinicaltrials.gov/study/NCT02682511

54. HZN-825 HZN-825 is a lysophosphatidic acid receptor blocker, lysophosphatidic acid is thought to be involved in fibrosis Phase 2 placebo-controlled study in diffuse scleroderma Evaluating lung function, skin thickening Sites include Ann Arbor, NYC, Boston, Philadelphia, Rochester MN https://clinicaltrials.gov/study/NCT04781543

55. Tulisokibart Tulisokibart is biologic targeting tumor necrosis factor (TNF)-like cytokine 1A Also being evaluated in IBD Placebo controlled phase 2 in patients with diffuse disease with ILD Mainly looking at lung function Recruiting centers include DC, Baltimore, Boston, Ann Arbor, Cleveland, Toledo, Milwaukee, Pittsburgh, NYC https://clinicaltrials.gov/study/NCT05270668

56. Vixarelimab Vixarelimab blocks the oncostatin M receprot , blocking signaling of oncostatin M and interleukin 31 Oncostatin M/IL-31 are thought to be involved in itch, inflammation and fibrosis Primarily evaluating lung function in ILD Sites include Northwestern-Glenview, Muncie IN Sofen , Howard et al. “Efficacy and safety of vixarelimab , a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomised , double-blind, placebo-controlled, phase 2a study.” EClinicalMedicine vol. 57 101826. 3 Feb. 2023, doi:10.1016/j.eclinm.2023.101826 https://clinicaltrials.gov/study/NCT05785624

57. Autologous stem cell transplant Chatterjee S, Majhail N. Autologous Hematopoietic Cell Transplantation: Way of the Future in Severe Systemic Sclerosis? Cleveland Clinic. Published November 30, 2018. Accessed February 17, 2024. https://consultqd.clevelandclinic.org/autologous-hematopoietic-cell-transplantation-way-of-the-future-in-severe-systemic-sclerosis

58. Autologous stem cell transplant Has shown benefit for a variety of manifestations in scleroderma May be reasonable in rapidly progressive cases Exact patient selection evolving George Georges, MD at Northwestern is running a trial through heme/ onc University of Chicago will be referring to him as appropriate Bruera , Sebastian et al. “Stem cell transplantation for systemic sclerosis.” The Cochrane database of systematic reviews vol. 7,7 CD011819. 29 Jul. 2022, doi:10.1002/14651858.CD011819.pub2 Sullivan KM, Majhail NS, Bredeson C, et al. Systemic Sclerosis as an Indication for Autologous Hematopoietic Cell Transplantation: Position Statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018;24(10):1961-1964. doi:10.1016/j.bbmt.2018.06.025 Sullivan KM, Shah A, Sarantopoulos S, Furst DE. Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement. Arthritis Rheumatol . 2016;68(10):2361-2371. doi:10.1002/art.39748 Panopoulos , Stylianos T et al. “Outcomes of conventionally-treated systemic sclerosis patients eligible for autologous haematopoietic stem cell transplantation.” Clinical and experimental rheumatology vol. 39 Suppl 131,4 (2021): 29-33. doi:10.55563/ clinexprheumatol /dhn3mb

59. Use of spinal stimulators for refractory Raynaud’s in connective tissue disease Planned study in collaboration with pain management at the University of Chicago Planned for patient's intolerant to, or refractory to drugs such as sildenafil/amlodipine

60. Use of spinal stimulators for refractory Raynaud’s in connective tissue disease Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci . 2008;138(1-2):9-23. doi:10.1016/j.autneu.2007.11.001 Fiks V. Spinal cord stimulation can treat Peripheral Vascular Disease. www.apmconline.org. Accessed February 17, 2024. https://www.apmconline.org/blog/spinal-cord-stimulation-can-treat-peripheral-vascular-disease

61. CAR T therapy University of Chicago will be a site in partnership with Cabaletta Bio Inc for scleroderma, myositis, lupus Klebanoff , C., Yamamoto, T. & Restifo , N. Treatment of aggressive lymphomas with anti-CD19 CAR T cells. Nat Rev Clin Oncol 11, 685–686 (2014). https://doi.org/10.1038/nrclinonc.2014.190

62. CAR T therapy CAR T therapy may be superior to antibody targeted therapies at CD19 (B cells) given ability of CAR T cells to move throughout body Skin involvement, and ILD will be main manifestations evaluated, along with cardiac and/or renal involvement Significant pulmonary artery hypertension is a major exclusion criteria

63. Car t therapy Four patients with scleroderma described All 4 were able to discontinue other immunosuppression Müller, Fabian et al. “CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up.” The New England journal of medicine vol. 390,8 (2024): 687-700. doi:10.1056/NEJMoa2308917

64. CONQUEST University of Chicago will be a site in partnership with the Scleroderma Research Foundation for COUNQUEST Multi arm study, 2 arms at UChicago, placebo controlled Evaluating ILD Background mycophenolate allowed

65. CONQUEST One arm will include Amlitelimab , a biologic that targets OX40L which is involved in cytokine release and T-cell activation Another arm will include BI 1015550, an oral PDE4B inhibitor, which helps downregulate a variety of proinflammatory cytokines BI 1015550 is similar to a drug used for psoriatic arthritis called apremilast, though is more selective which is thought to make it have less gastrointestinal side effects

66. Multidisciplinary scleroderma care Scleroderma is clearly a complex disorder, effecting nearly every organ in the body Multiple fields are needed to work together, with rheumatology often being the primary specialty involved University of Chicago will be forming a multidisciplinary scleroderma program to help improve care for scleroderma patients, and improve access in Chicago

67. Multidisciplinary scleroderma care Rheumatology: Myself GI: Dejan Micic , MD Pain Medicine: Tariq Malik, MD; Dalia Elmofty , MD Renal: Marco Bonilla, MD; Zainab Obaidi , MD Pulmonary hypertension: Stanley Swat, MD Plastic Surgery: Jignesh Unadkat, MD; Summer Hanson, MD, PhD Dermatology: Mark Hoffman, MD Pulmonary: Mary Strek, MD; Cathryn Lee, MD; Ayodeji Adegunsoye , MD

68. Multidisciplinary scleroderma care Overtime will involve dedicated time in Hyde Park on Mondays with coordination of other fields as needed I will also be in Crown Point, IN and River East Need for other fields will be coordinated at Hyde Park

69. Thank you for your attention Any questions?