CYC in Scleroderma

Team: CYC in Scleroderma, aka “CYC’d for SLS”

Region: Get in the Game

Base article: Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655-2666. PMID 16790698.

Authors: Louisiana State University Shreveport Rheumatology Fellowship. Iman Qaiser, MD, second year rheumatology fellow, Smita Maruvada, MD, second year rheumatology fellow, Jasmeen Uppal, MD, first year rheumatology fellow, Mohammad Hassaan Khan, MD, first year rheumatology fellow, Warda Maqsood, MD, first year rheumatology fellow, Sulman Hasan, MD, second year rheumatology fellow, Kinza Muzaffar, MD, Assistant Professor of Internal Medicine, Madiha Tariq, MD, Program Director Rheumatology, Overton Brooks VA Medical Center Shreveport, Sarwat Umer, MD, Professor of Internal Medicine, Louisiana State University Shreveport, Samina Hayat, MD, Professor of Internal Medicine, Louisiana State University Shreveport.

Team Overview

Scleroderma is a complex, multi-systemic disease. Forty percent of scleroderma patients have pulmonary involvement, mostly interstitial lung disease.1 Ventilatory restriction, along with pulmonary hypertension, is responsible for a staggering mortality rate of 42% within 10 years after disease onset! 2, 3 For a disease that has been such an Achilles heel for rheumatologists since the 1700s, management was still not clearly defined by the millennium and rheumatologists were still playing defense.4 In 2006, Tashkin et al went on offense against scleroderma lung disease and produced this slam-dunk of a study, also known as the Scleroderma Lung Study I or SLS-I, which showed the clear effectiveness of cyclophosphamide in improving and maintaining FVC (forced vital capacity) in scleroderma patients. Between the 158 patients who were randomized, the mean difference in FVC at 12 months between the cyclophosphamide and placebo group was 2.53%, favoring cyclophosphamide with P < 0.03. Not only that, cyclophosphamide also showed significant improvement in TLC (total lung capacity), functional ability, health-related quality of life and skin thickness. The study also clearly demonstrated the downside of cyclophosphamide, with adverse effects of cytopenias. 1

Impact on Rheumatology

While RA, gout and vasculitis got their fair share of glory throughout history, scleroderma was benched far too long. Scleroderma patients, often minority ethnic populations, would die young and suffer effects on every organ system. William Osler wrote in 1898 “On Diffuse Scleroderma”, comparing a scleroderma patient to Tithonus, who wished for eternal life, but forgot to ask for eternal youth: “Like Tithonus to ‘wither slowly’ and like him ‘beaten down and marred and wasted’ until one is literally a mummy, encased in an ever-shrinking, slowly-contracting skin of steel, is a fate not pictured in any tragedy, ancient or modern.” 5 Research into treatment for this cruel disease was long overdue by the 2000s, and the SLS-I team was just what the rheumatology league needed at that point in time.

Haters will say cyclophosphamide was already being used for scleroderma before 2006. True, there were some retrospective studies showing the benefit of cyclophosphamide, but we ask you what degree of confidence would these small studies give you when using a drug known to have high toxicity? 2 The SLS-I study changed the entire game. It was a well-strategized, 2-year long, double-blind, placebo-controlled, randomized, multi-center, prospective study  which drew solid conclusions regarding the efficacy, toxicity and risk-benefit ratio of cyclophosphamide in scleroderma. 1 It gave the rheumatologist that much needed alley-oop to score confidently against scleroderma.

The SLS-I study also laid down a game plan for the SLS-II and SLS-III trials. 6, 7 It was the dream team that all other teams aspired to. It’s clear, this team deserves to be named the most important and transformational article ever written in the field of rheumatology!

Chances in the Tournament

The SLS-I study got in the game when it was needed the most! While vasculitis and scleroderma are both devastating diseases, scleroderma did not get the attention it needed from cyclophosphamide until 27 years later! But when it did, SLS-I owned the court like it was their home! The impregnable strategy with which CYC was studied for scleroderma, makes our team a sure shot winner. Our opponents wouldn’t even be able to defend us man-to-man with their sample size of 17 compared to our 158! 8 Additionally, keeping score might be difficult for them, seeing as they did not use many objective measurements. After that easy win, we would be up against a team that discusses the timing of drug initiation of a drug that has been well studied for decades, in a disease that has been well known for centuries. 9 We question if they should even be in the game when they only made it to a conditional recommendation in the American College of Rheumatology guidelines. 10 Eventually, we would like to be able to jump ball with the RAVE trial, as rituximab is the hot, new player on the block. 11 But let’s see how much steam rituximab can handle when facing off with the MVP, the Michael Jordan, the OG of rheumatology: cyclophosphamide.

Though advances have been made in scleroderma research, there is still a lot that needs to be studied for this overwhelming disease. Our team paved the way forward for future players and researchers in how to deal with this systemic disease in an objective and calculated way, and in the process reach out to the crowds of patients rooting for us. SLS-1 is indeed an all-star in rheumatology!

Next scouting report: ULT During Flare

Back to the full list of scouting reports.

See the Q&A on for the Get in the Game region: Are there patients in whom you would avoid initiating of ULT during acute gout flare? 


  1. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in
  2. scleroderma lung disease. N Engl J Med. 2006;354(25):2655-2666.
  3. Steen VD, Conte C, Owens GR, Medsger TA Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994;37(9):1283-1289.
  4. White B, Moore WC, Wigley FM, Xiao HQ, Wise RA. Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000;132: 947-54.
  5. Adigun R, Goyal A, Hariz A. Systemic Sclerosis. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
  6. OSLER W: On diffuse scleroderma; with special reference to diagnosis and to the use of thyroid extract. Jour. Cutan. & Gen. Urinary Dis., XVI: 49 & 127, (Feb. & Mar.), 1898.
  7. Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708-719. doi:10.1016/S2213-2600(16)30152-7
  8. Khanna D, Spino C, Bernstein E, Goldin J, Tashkin D, et al. Combination Therapy of Mycophenolate Mofetil and Pirfenidone vs. Mycophenolate Alone: Results from the Scleroderma Lung Study III. In: ACR Convergence 2022, 10-14 November, 2022, Philadelphia, USA.
  9. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med. 1979;301(5):235-238.
  10. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med. 2012;125(11):1126-1134.e7.
  11. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout [published correction appears in Arthritis Care Res (Hoboken). 2020 Aug;72(8):1187] [published correction appears in Arthritis Care Res (Hoboken). 2021 Mar;73(3):458]. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180
  12. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.

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