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Abstract

Cyclophosphamide (CYC), a derivative of mustard gas, has been a cornerstone in treating life-threatening complications of various inflammatory rheumatic and musculoskeletal diseases (I-RMDs) since the mid-twentieth century, despite its well-documented adverse effects. The transformation of CYC from a chemical warfare agent in World War I to a life-saving drug is remarkable and crucial for rheumatologists to understand. This article offers a historical overview of the events and the scientists who were instrumental in this transformation, along with its key role in I-RMDs. Over the ensuing decades, numerous drugs have been developed to address conditions for which CYC was once the sole treatment option. Nevertheless, even in the third decade of the twenty-first century, CYC continues to serve as a dependable option for managing certain complex and challenging complications of I-RMDs. Rheumatologists, however, face a significant challenge when considering the initiation of CYC therapy. They must carefully weigh its proven efficacy against its potential toxicities. Furthermore, practical considerations such as the route of administration, dosage schedule and treatment duration must be guided by the best available evidence. Unfortunately, such information is often dispersed across decades of publications, with recommendations that are sometimes inconsistent and perplexing.

This review delves into two primary aspects of CYC: its historical evolution and the practical considerations for its use in contemporary rheumatology practice.

Keywords

Cyclophosphamide systemic sclerosis systemic lupus erythematosus ANCA-associated vasculitis IgG4-related disease lupus nephritis inflammatory rheumatic and musculoskeletal diseases

Introduction

The devastation of World Wars (WW) I and II showcased both humanity’s capacity for destruction and its resilience in transforming calamity into progress. From the horrors of chemical warfare, particularly mustard gas (whose derivative is cycloph«osphamide (CYC)), emerged groundbreaking medical advancements. The accidental release of mustard gas in WWII’s ‘Little Pearl Harbor’ at Bari (Italy) led to investigations into nitrogen mustard, revealing its potential for cancer treatment.^1,2 Pioneering researchers, including Goodman and Gilman, laid the foundation for using nitrogen mustards in cancer chemotherapy and recognised its ability to suppress white blood cells and shrink lymph nodes, laying the foundation for modern chemotherapy.^3,4 This pivotal discovery eventually led to the development of CYC, a crucial drug in treating cancers and certain inflammatory rheumatic and musculoskeletal diseases: I-RMDs.

Nitrogen Mustard and Its Derivative Cyclophosphamide in the Management of I-RMDs

The use of nitrogen mustard for treating rheumatoid arthritis (RA) was first reported in the 1950s by Spanish physicians Jimenez-Diaz et al. and Robecchi et al.^5,6 However, the credit for integrating chemical immunosuppression into routine rheumatology practice belongs to the rheumatologists at the Cleveland Clinic, Cleveland, Ohio, United States. In a series of landmark articles published in 1957, Scherbel, Schuchter, and Harrison from the Department of Rheumatic Diseases at the Cleveland Clinic successfully transitioned the use of nitrogen mustard (HN2) from a research concept to clinical application in managing I-RMDs.^7–10 The concept proposed by Scherbel et al. at the Cleveland Clinic—using cytotoxic drugs to treat I-RMDs—quickly gained traction among physicians at several centres across the United States, with five significant reports emerging between 1960 and 1976.^11–15 The rheumatologists at the Cleveland Clinic also acknowledged the contributions of several other prominent rheumatologists of that era in the United States, including Daniel McCarthy, Rollins and Shaw. These pioneers reported similar experiences with the use of nitrogen mustard in treating RA and other I-RMDs, such as systemic lupus erythematosus (SLE), polyarteritis nodosa, dermatomyositis (DM) and glomerulonephritis.⁹

The first use of CYC in I-RMDs was in RA and was carried out by Fosdick et al. on 38 patients who had failed other therapies. They concluded that CYC showed promise as a therapeutic option for patients of RA who had failed other therapies.¹⁶ Suarez-Almazor et al. shed more light upon the use of CYC in RA in their systematic review which concluded that CYC is effective for the treatment of RA in patients who have failed other therapies; however, its use is limited by its toxicity.¹⁷ However, with the introduction of highly effective and less toxic therapies, such as low-dose methotrexate, the use of CYC in RA was eventually discontinued.

John Fahey et al. from Presbyterian Hospital, New York, the United States in 1954 did pioneering work in the description of granulomatosis with polyangiitis (GPA, earlier called Wegener’s granulomatosis).¹⁸ The first use of CYC as single-drug therapy for GPA in four patients was reported by Carl Pearson’s group from Los Angeles on 29 April 1971.¹⁹ Within eight months of the first publication (December 1971) Workers at NIH (National Institutes of Health), Bethesda, United States led by Anthoney Fauci, published their landmark article describing high efficacy of CYC in GPA in 9 cases.²⁰ Both the groups showed complete-to-partial remission in most of the patients treated with CYC in GPA. The NIH team published their collective experience with 180 patients with GPA with multiorgan anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) between 1967 and 1991.²¹

The Mode of Action of Nitrogen Mustard and Cyc for the Treatment of Cancer and I-RMDs

The mechanism of action of nitrogen mustard which enables it to eliminate rapidly dividing cells, such as cancer cells and immune system cells, made it popular in both these fields.

Nitrogen mustards are polyfunctional alkylating agents.²² In the body, nitrogen mustards (available in three forms: HN1, HN2, and HN3) react with two guanine bases on opposite strands of a DNA helix, forming interstrand cross-links. This process, known as DNA alkylation, prevents the unwinding of the DNA helix, thereby blocking essential processes such as replication and transcription. The resulting disruption leads to the death of rapidly dividing cells.^22–24

Administering nitrogen mustard in its gaseous form posed significant challenges due to its instability and the need for specialised handling. This made the development of CYC, a more stable and practical derivative of nitrogen mustard, a pivotal advancement. Synthesised by Friedman and Seligman in 1954²⁵ and further developed by Norbert Brock et al.²⁶ CYC became available both in oral and intravenous (IV) form, thus making it as a reliable treatment option.

Route of Administration

CYC is primarily administered through two routes: (a) oral and (b) IV route, each with distinct advantages and limitations. The oral route is convenient to administer and relatively cost-effective. However, it results in a higher cumulative dose compared to the IV route, which, while effective, is associated with increased toxicity. Improper adherence to oral CYC regimens, such as failing to take the medication in the morning or neglecting adequate hydration throughout the day, can lead to serious complications, including haemorrhagic cystitis and other urinary tract side effects.²⁷ Prolonged use of oral CYC beyond the prescribed treatment period, often due to loss to follow-up, can result in catastrophic outcomes, such as the development of secondary malignancies. On the other hand, IV-CYC offers better tolerability, facilitates easier monitoring and typically involves a lower cumulative dose compared to the oral formulation, making it a preferred option in many clinical scenarios.

Following the development of a stable compound-CYC, its use expanded and researchers began exploring CYC in various rheumatologic diseases.

CYC in Lupus Nephritis

Historically, the first formal trial of CYC for lupus nephritis was conducted in 1970 by Cameron, Boulton-Jones, Robinson and Ogg at Guy’s Hospital, London.²⁸ This open-label trial involved six patients with biopsy-confirmed lupus nephritis. The outcome was mixed: Three patients showed a significant reduction in proteinuria; the dose of corticosteroids in two patients could be reduced significantly while maintaining disease control; one patient who had active necrotising renal lesion succumbed.²⁸

Almost simultaneously, in 1971, a controlled trial led by A.D. Steinberg and his team at the National Institutes of Health (NIH), Bethesda, United States, examined the use of CYC in lupus nephritis.²⁹ This trial yielded positive results and was followed by eight additional NIH-led trials, the last of which was published in 1992. A summary of these trials is provided in Table 1.

Table 1.

Summary of National Institutes of Health (NIH) Studies on Cyclophosphamide Use in Lupus Nephritis.

Sr No.	Trial/ First Author (year)	Total Number of Subjects	Dose/Schedule of CYC Used	Adjunct Treatment	Compared with	Trial Duration	Conclusion
1	Steinberg et al. (1971)²⁹	13	Oral CYC (n = 7) Initial dose: 3 mg/kg/day, increased to 4 mg/kg/day after 2 weeks	Prednisone, up to 30 mg/day	Placebo (n = 6)	10 weeks	CYC-treated patients showed statistically significant improvements in proteinuria, serum C3, anti-DNA antibodies, urinary sediments and extra-renal lupus activity compared to placebo
2	Steinberg et al. (1974)³⁰	38	Group 1: Oral CYC (n = 10): 3 mg/kg/day, increased after 4 weeks to 4 mg/kg/day	Prednisone up to 0.5 mg/kg/day in groups 1 and 2	Group 2: AZA (n = 13): 2 to 4 mg/kg/day Group 3: Placebo (n= 15)	10 weeks	CYC was significantly superior to AZA and placebo for renal function, urinary sediment, proteinuria, anti-DNA, C3, and symptoms. AZA showed no significant benefit over placebo
3	Decker et al. (1975)³¹	38	Group 1: Oral CYC (n = 10): 4 mg/kg/day	Prednisone 0.5 mg/kg/day in groups 1 and 2	Group 2: AZA (n = 13): 4 mg/kg/day Group 3: Prednisone only (n = 15): 0.5 m5g/kg/day	Mean follow-up: 27.7 months (range, 1–48 months)	Renal function gradually deteriorated in all groups, most often in the prednisone-only group. Cytotoxic agents offered limited disease control, suggesting a need to evaluate other treatment options
4	Dinant et al. (1983)³²	41	Group 1 (n = 16): Oral CYC and oral AZA: Each drug at a dose of 1 mg/kg/day Group 2 (n = 12): IV CYC: 0.5 to 1.0 gram/meter sq. BSA every 3 months The medications were continued indefinitely		Group 3 (n = 13): Prednisone only: 0.95 mg/kg/day	Mean observation period: 42 months (range: 1–6.5 years)	No significant differences were found among the groups in hypertension, serum creatinine, anti-DNA antibodies, C3 levels, proteinuria, haematuria or extrarenal disease flares
5	Carette et al. (1983)³³	53	Group 1 (n = 18): Oral CYC: 4 mg/kg/day	Prednisone: 0.5 mg/kg body weight day in Groups 1 and 2	Group 2 (n = 20): Oral AZA: 4 mg/kg/day Group 3 (n = 15): Prednisone alone: 1 mg/kg/day	Mean duration: 85 months (range: 0–134 months).	CYC was superior to prednisone and AZA in preventing renal function decline and slightly better at delaying renal failure. Oral immunosuppressants combined with prednisone benefited lupus patients with intermediate chronic changes on biopsy
6	Balow et al. (1984)³⁴	62	Group 1: Oral CYC (n = 7): 4 mg/kg/day Group 2: Oral AZA and CYC (n = 14): Each drug at 1 mg/kg/day Group 3: IV CYC (n = 13): 1 gram/ m² BSA every 3 months	Prednisone: 0.5 mg/kg/day (Except in Group 4)	Group 4: Prednisone alone (n = 16): 1 mg/kg/ day Group 5: Oral AZA (n = 12): 4 mg/kg/day	19–131 months (Median 44 months)	Cytotoxic drug treatment reduced the likelihood of progressive renal scarring in lupus nephritis, as compared to prednisone alone
7	Austin et al. (1986)³⁵	107	Group 1: Oral CYC (n = 18): 4 mg/kg/day Group 2: Oral AZA and CYC (n = 22): Each drug at 1 mg/kg/day Group 3: IV CYC (n = 20): 0.5-1 gram/m² BSA, every 3 months	Prednisone: 0.5 mg/ kg/day. (Except in group 4)	Group 4: Prednisone alone (n = 28): 1 mg/kg/day for 4–8 weeks, followed by gradual tapering Group 5: Oral AZA (n = 19): 4 mg/kg/day	4.3 years	Cytotoxic therapies lowered the risk of end-stage renal disease, but the difference was statistically significant only for IV CYC plus low-dose prednisone, as compared to high-dose prednisone alone
8	Steinberg et al. (1991)³⁶	111	Group 1: Oral CYC (n = 18): 1-4 mg/kg/day Group 2: Oral CYC and oral AZA (n = 23): 1 mg/kg/day of each drug Group 3: IV CYC (n = 20): 0.5-1 gram/ m² BSA, monthly for up to 3 months, and then once every 3 months	Prednisone: 10–20 mg on alternate days. (Except in group 4)	Group 4: Prednisone alone (n = 30): 1 mg/kg of body weight for 4-8 weeks, followed by taper. Group 5: Oral AZA (n = 20): 1-4 mg/kg/day	4.3 years	Progression to end-stage renal disease was found to occur most rapidly in those who received prednisone only. The group receiving IV CYC alone had the least risk of progression to end stage renal disease
9	Boumpas et al. (1992)³⁷	65	Group 1: Short course of IV CYC (n = 20): 0.5-1.0 g/m², monthly for 6 months Group 2: Long course of IV CYC (n = 20): 0.5-1 g/m², monthly for 6 months, followed by single quarterly doses for 2 more years	Prednisone:0.5 mg/kg/day for 4 weeks, then tapered at a rate of 5 mg every other day to the minimum dose for control of extra-renal disease	Group 3: IV pulse Methylprednisolone (MPS) (n = 25): 1 g/m² MPS, three daily doses initially, followed by single monthly doses for 6 months	4 years	Pulse MPS posed a higher risk of doubling serum creatinine than long-course CYC, which better preserved renal function. Adding quarterly pulses to monthly CYC reduced exacerbations. Short-course CYC had a similar risk of doubling creatinine but a higher risk of exacerbations

Note: AZA: Azathioprine, BSA: Body surface area, CYC: Cyclophosphamide, MPS: Methyl prednisolone.

Furthermore, six independent trials were conducted at centres outside the NIH, as summarised in Table 2. Buoyed by the success of CYC in lupus nephritis, its use was expanded to other I-RMDs.

CYC in Neuro-psychiatric SLE (NPSLE)

Central nervous system (CNS) involvement is a significant contributor to illness severity and death in patients with SLE. Managing NPSLE is a substantial challenge for clinicians in everyday practice.⁴³ In a randomised trial of 32 patients that compared IV CYC with IV methylprednisolone, IV CYC was found to be significantly better than IV methylprednisolone in treating NPSLE. This study also suggested that to achieve optimal response in NPSLE with no flares, treatment with CYC should be sustained for two years.⁴³ Table 3 summarises selected studies of CYC in NPSLE.

CYC in ANCA-Associated Vasculitis (AAV)

Vasculitis is among the most aggressive and difficult to treat conditions faced by rheumatologists. Before the advent of CYC treatment, mortality of severe AAV was ~80% within one year of diagnosis.⁴⁶ Table 4 gives the list of CYC trials in AAV along with the dose schedule.

The randomised controlled trials of CYC in AAV can be classified into:

Induction trials

The CYCLOPS trial conducted in 2009 was a randomised trial comparing daily oral and monthly IV CYC regimens.⁴⁷ It showed that the rate of induction of remission and the number of patients who achieved remission is almost equivalent in both the regimens. Further details of the CYCLOPS and several other trials are mentioned in Table 4.

Maintenance trials

The CYCAZAREM trial was a randomised control trial evaluating the role of oral CYC as a maintenance therapy for patients with AAV and renal involvement and compared it to AZA. The trial advocated that AZA can be safely used as a substitute to CYC during the remission phase.⁴⁸ Table 4 provides further details on CYC In AAV.

Table 2.

Non-NIH (National Institutes of Health) Trials on the Use of CYC in Lupus Nephritis.

Sr No.	Trial or First Author (Year)	No of Subjects	Dose/Schedule of CYC used	Adjunct Treatment	Compared with	Trial Duration	Conclusion
1	Cameron et al. (1970)²⁸	6	Oral CYC (n = 6): Ranging from 250 to 50 mg/day	Prednisolone: Range: 40-2.5 mg/day.	There was no comparison group. All patients were treated with CYC and varying doses of prednisolone	Mean duration 12 months	CYC use resulted in significant reduction in proteinuria and reduction in dose of prednisolone
2	Feng et al. (1973)³⁸	42	IV CYC: 400 mg per week, followed by oral CYC: 100 mg four times a week.	Prednisolone: 15-60 mg per day, depending on the severity of symptoms.	There was no comparison group. All patients were treated with IV CYC and varying doses of prednisolone	6-84 months, average of 34 months	CYC is a useful alternative for patients of SLE intolerant to steroids or with severe side effects, and can also be used with low-dose steroids
3	Donadio et al. (1978)³⁹	50	Group 1: Oral CYC (n = 24): 2 mg/kg/day for 6 months.	Prednisone: 60 mg/day for 1-3 months, tapered to 20 mg/day by 6 months Maintenance therapy in both groups was with prednisone	Group 2: Prednisone alone (n = 26): 60 mg per day for 1-3 months, tapered to 20 mg/day by 6 months	6 years	Most patients in both groups improved after 6 months, but the prednisone-alone group had more renal flares than the combined treatment group
4	Euler et al. (1994)⁴⁰	14	Plasmapheresis: 60 ml/kg on 3 consecutive days; followed by IV CYC: 12 mg/kg/day for 3 consecutive days; followed by oral CYC: 2-5 mg/kg/day for 6 months	Oral prednisone initiated at: 2 mg/kg/day for 2 days then tapered gradually to 0.1 mg/kg/day over 6 months	There was no comparison group	6 months of treatment Observation period of mean 5.6 years	A long-term treatment-free clinical remission is achievable in some patients with severe SLE
5	Houssiau et al. (2002)⁴¹	90	IV CYC- Low dose group (n=44): 6 fortnightly pulses of 500 mg.	IV Methylprednisolone: 750 mg for 3 consecutive days; followed by oral prednisolone: 0.5-1 mg/kg/day for 4 weeks, tapered gradually. Maintenance: prednisolone: 5-7.5 mg/day for 30 months from inclusion (Given in both groups) Maintenance immunosuppression: AZA: 2 mg/kg/day, started 2 weeks after CYC, for 30 months from inclusion (given in both groups)	IV CYC-high-dose group (n = 46): 6 monthly pulses of 500 mg/m² and 2 quarterly pulses	Median follow-up period: 41 months (8-62 months)	In European SLE patients with lupus nephritis, low-dose IV CYC (3 g cumulative) followed by AZA achieves clinical results comparable to high-dose regimens
6	Appel et al. (2009)⁴²	370	Group 1: IV CYC (n=185):6 monthly pulses of 0.5 to 1.0 g/m² BSA	Prednisone tapered from the starting dosage of 60 mg/d. Given to both groups	Group 2: MMF (n = 185): 3 g/day	6 months	The study did not show MMF was superior to IV CYC for lupus nephritis induction. There were no significant differences in adverse events or infections between the groups

Note: AZA: Azathioprine, BSA: Body surface area, CYC: Cyclophosphamide, MMF: Mycophenolate mofetil, SLE: Systemic lupus erythematosus.

Table 3.

Cyclophosphamide in Neuropsychiatric SLE.

Sr. No	Author,Year	No. of Subjects	Dose of CYC	Adjunct Treatment	Compared with	Duration	Conclusion
1	Neuwelt et al. (1995)⁴⁴	31	IV CYC: 500-1000 mg/m²/month	Plasmapheresis: 3 exchanges of 3 L each	There was no comparison group	The specific duration over which the study was conducted is not detailed	IV CYC may be effective for severe NPSLE, especially in patients unresponsive to other treatments
2	Barile-Fabris et al. (2005)⁴³	32	IV CYC (n = 19): 0.75 g/m² /month for 1 year, followed by every 3 months for another year	IV MPS: 1 g/day for 3 consecutive days	IV MPS (n = 13): 1 g/day for 3 days, monthly for 4 months, then bimonthly for 6 months and then every 3 months for 1 year	2 years	CYC is more effective than MPS for severe NPSLE. However, larger studies are needed to confirm this
3	Fanouriakis et al. (2015)⁴⁵	46	Three different dosing regimens were used- 1) NIH regimen: IV CYC: 0.75-1 g/m² BSA/ month for 6 months 2) Euro-Lupus regimen: IV CYC: 500 mg fortnightly, for 6 doses 3) IV CYC: 15 mg/Kg/ month for 6 months	The dose of pulse IV MPS is not specified. Maintenance was with any one of the following- 1) AZA (no. of events: 31) 2) Bimonthly or quarterly pulses of intravenous CYC (no of events: 9) 3) MMF (no. of events: 5) 4) No maintenance treatment (no. of events: 2)	–	Median duration: 46.5 months	CYC combined with glucocorticoids proved to be an effective treatment for severe NPSLE, resulting in sustained clinical responses in a substantial number of cases during long-term follow-up

Note: AZA: Azathioprine, BSA: Body surface area, CYC: Cyclophosphamide, MMF: Mycophenolate mofetil, MPS: Methyl prednisolone, NIH: National Institutes of Health, NPSLE: Neuro-psychiatric SLE.

Table 4.

Cyclophosphamide in ANCA-Associated Vasculitis.

Sr No	Trial or First Author (Year)	No. of Subjects	Dose/Schedule of CYC Used	Adjunct Treatment	Compared with	Trial Duration	Conclusion
1	CYCZAREM (2002)⁴⁸	155	Induction of remission: Oral CYC (n = 155): 2 mg/kg/day for 3 months	Prednisone: 1mg/kg/day, tapered to 0.25 mg/kg/day by 3 months After 3 months: Prednisone: 10 mg/day. Followed by prednisolone: 7.5 mg/kg/day	Maintenance of remission: (After induction of 3 months) Group 1: Oral CYC (n = 73): 1.75 mg/kg/day for 9 months. Group 2: AZA (n = 71): 2 mg/kg/day, for 9 months After this, all patients were given AZA: 1.5 mg/kg/day, for 6 more months	18 months (induction: 3 months, maintenance: 9 months, post maintenance: 6 months)	In patients with generalised vasculitis, the withdrawal of CYC and the substitution of AZA after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced
2	MEPEX (2007)⁵⁰	137	Oral CYC (n = 137): 2.5 mg/kg per day for 3 months followed by 1.5 mg/kg/day for 3 months (Total 6 months) Followed by: AZA: 2 mg/kg per day for 6 months	Oral prednisolone: 1 mg/kg/day at entry, tapered to 15 mg/day at 3 months, and 10 mg/day from 5th to 12th month	Oral CYC was combined with either- Group 1: IV MPS (n = 67): 1 000 mg IV monthly for 3 consecutive months OR Group 2: Plasma Exchange (n = 70): Seven plasma exchanges of 60 mL/kg each, over 14 days of study entry	12 months	Plasma exchange improved renal recovery in ANCA-associated vasculitis with renal failure, compared to IV methylprednisolone, with similar survival and adverse event rates in both groups
3	CYCLOPS (2009)⁴⁷	149	Group 1: IV CYC (n = 76): 15 mg/kg every 2 weeks for 3 doses, followed by every 3 weeks until remission, and then for 3 more months	Prednisolone: 1 mg/kg/day, tapered to 5 mg/day over 18 months Maintenance therapy: AZA: 2 mg/kg/day until month 18	Group 2: Oral CYC (n = 73): 2 mg/kg per day until remission, then 1.5 mg/kg/day for 3 more months	18 months	IV CYC regimen induced remission of ANCA-associated vasculitis as well as the oral CYC regimen, but the IV CYC regimen had a lower cumulative CYC dose and fewer cases of leukopenia
4	RAVE (2010)⁵¹	197	The remission induction period was 6 months- Group 1 (n = 98): Oral CYC: 2 mg/kg/day combined with IV placebo—rituximab (RTX) (placebo disguised as RTX)	MPS pulses: 1000 mg, followed by prednisone: 1 mg/kg/day, tapered and discontinued by 5 months Maintenance treatment: For patients in the CYC group who achieved remission: AZA: 2mg/kg/day Patients in the RTX group who achieved remission were given placebo-AZA in the maintenance phase	Group 2 (n = 99): IV RTX: 375 mg/sq. m. once a week for 4 weeks, combined with placebo-CYC (placebo disguised as CYC)	6 months	RTX therapy was not inferior to oral CYC for the induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease
5	RITUXVAS (2010)⁵²	44	CYC group (n = 11): IV CYC 15 mg/kg every 2 weeks for 3 doses, followed by every 3 weeks until remission (6-10 doses). Maintenance treatment: AZA: 2 mg/kg/day	IV Methylprednisolone 1 gram, followed by oral prednisolone: 1mg/kg/day, tapered to 5 mg/day over 6 months	RTX group (n = 33): IV 375 mg/m² BSA/week for 4 consecutive weeks; combined with IV CYC: 15 mg/kg, with the first and third RTX doses No maintenance therapy.	12 months	RTX was not superior to IV CYC for severe ANCA-associated vasculitis, with both showing high remission rates and similar early severe adverse events
6	MYCYC (2019)⁵³	140	IV CYC (n = 70): 15 mg/kg every 2-3 weeks (6-10 doses)	Both groups: Prednisolone:1 mg/kg/day, tapered to 5 mg/day by 6 months, continued for 18 months Maintenance (Both groups): AZA: 2 mg/kg/day after remission, continued for 18 months	MMF (n = 70): 2-3 g/day for 3-6 months	18 months	MMF was non-inferior to CYC for remission induction in AAV, but resulted in higher relapse rate
7	J Tuin et al. (2019)⁵⁴	84	Oral CYC (n = 43): 2 mg/kg/day for 6 months	All patients received prednisolone in tapering doses. Maintenance therapy: (both groups) AZA: 1.5 mg/kg/day, tapered after 12 months and stopped completely after 2 years	MMF (n = 41): 2 g/day for 6 months	4 years	The trial did not show MMF to be as effective as CYC in inducing remission of relapsed ANCA-associated vasculitis. However, MMF may be a treatment option for patients with non-life-threatening relapses

Note: ANCA: Anti-neutrophil cytoplasmic antibody, AZA: Azathioprine, BSA: Body surface area, CYC: Cyclophosphamide, MMF: Mycophenolate mofetil, MPS: Methyl prednisolone, RTX: Rituximab.

Since these important early reports, major advances in the treatment of AAV have improved five-year survival to 74%–91% and 45%–76% for GPA and MPA respectively.⁴⁹

CYC in Systemic Sclerosis-related Interstitial Lung Disease (SSc-ILD)

As such, immunosuppressive drugs have been used mainly for SSc-ILD. There have been several uncontrolled studies performed with CYC that revealed a positive effect on pulmonary functions in patients with SSc-ILD.⁵⁵ These led to the first randomised controlled trial with CYC for SSc-ILD, the Scleroderma Lung Study I (SLS I)⁵⁶ which was followed by the ‘Scleroderma Lung Study II’ (SLS II),⁵⁷ detailed in Table 5.

Table 5.

Cyclophosphamide in Other I-RMDs.

Sr No	Disease	Trial or First Author (Year)	Type of Study	No. of Subjects	Dose/Schedule of CYC Used	Adjunct Treatment	Compared with	Trial Duration	Conclusion
1	Scleroderma ILD	SLS-1 (2006)⁵⁶	RCT	158	Oral CYC (n = 79): 2 mg/kg/day for 1 year. Followed up for 1 more year after stopping CYC	None	Placebo (n = 79)	24 months	One year of oral CYC in scleroderma-related ILD led to modest improvements in lung function, dyspnoea, skin thickening and function. However, the benefits were not sustained after stopping therapy
2	Scleroderma ILD	SLS 2 (2016)⁵⁷	RCT	142	Oral CYC (n = 73): 2 mg/kg/day for 1 year, followed by placebo for 1 year		MMF (n = 69): 1.5 g twice a day for 2 years	24 months	MMF was better tolerated and associated with less toxicity as compared to CYC; but the hypothesis that MMF would have greater efficacy at 24 months than CYC was not confirmed
3	Scleroderma ILD	Hombergh et al. (2018)⁵⁵	Retrospective, open-label study	75	IV CYC (n = 75): 750 mg/m²/month for 12 months	Maintenance therapy after CYC: MMF (n = 51): 2-3 g/day	There was no comparison group	3 years	High-dose CYC leads to a sustained stabilisation of pulmonary function in SSc-ILD. Lung functions remained stable for 3 years after treatment with CYC
4	Diffuse cutaneous scleroderma	Herrick et al. (2017)⁵⁹	Prospective observational study	326	CYC (n = 87) IV CYC: 500 mg/ sq.m/month for 6-12 months. Oral CYC: 1-2 mg/kg/day for 12 months	Maintenance treatment after CYC: Methotrexate: 15-25 mg/week Or MMF: 1-2 gram/day	Methotrexate (n = 65): 20-25 mg/week MMF (n = 118): 2 g/day No immunosuppression (n = 56)	24 months	No significant outcome differences were seen across methotrexate, MMF, CYC or no immunosuppressant, though early diffuse cutaneous SSc patients may benefit from immunosuppression. Skin scores improved across all groups, but least in the no-treatment group. CYC is relatively effective in pulmonary fibrosis
5	Idiopathic inflammatory myositis	Bae et al. (2018)⁶⁷	Retrospective observational study.	14 (dermatomyositis: 9; polymyositis: 3; immune-mediated necrotising myopathy: 2)	Oral CYC (n = 14): 150 mg/day for 12 months	Prednisone: 20-80 mg/day initially, tapered to 15 mg/day	There was no comparison group	Mean duration: 12.4 months (range: 0.5–43 months)	CYC may be effective for patients with treatment-refractory IIM. Significant improvements in disease activity measures and reduction in daily prednisone dose following CYC, were noted
6	Idiopathic inflammatory myositis	Shahin et al. (2021)⁶⁸	Retrospective cohort study.	22 (Dermatomyositis: n = 14; Polymyositis: n = 8)	IV CYC (n = 17): 0.5-0.75 g/sq. m) per month for 6 months, followed by every 3 months for 6 more cycles (18 months)	IV methylprednisolone, followed by oral prednisone: 0.5 mg/kg/day, tapered gradually.	RTX (n = 5): 1 gram every 6 months, for 3 cycles. (RTX was given to patients who were refractory to CYC)	7.7 ± 4.3 years	CYC can be effective for treating muscle involvement in IIM, while RTX shows promise for refractory cases, especially with cardiac or bulbar symptoms, and may benefit from early use in these patients
7	CTD ILD	RECITAL Trial (2022)⁶¹	RCT	101	IV CYC (n = 50): 600 mg/m² BSA every 4 weeks for six doses	Hydrocortisone: 42·9 mg/day (mean dose) in the CYC group. Hydrocortisone: 37·6 mg/day (mean dose) in the RTX group	RTX (n = 51): 2 doses of 1 g each, 2 weeks apart.	48 weeks	RTX and CYC were equally effective in improving lung function in CTD-ILD. However, RTX had fewer side effects and allowed for lower steroid use, making it a suitable alternative
8	Cryoglobulinemic vasculitis	Lamprecht et al. (2000)⁶⁹	Case report	1	Oral CYC (2 mg/kg/day)	Prednisolone: 1 g IV on 3 consecutive days, followed by 2 mg/kg/day orally, tapered to 0.1 mg/kg/day Plasmapheresis: 6 sessions in 2 weeks	Oral CYC was given after the patient continued to deteriorate on IV CYC: 15 mg/kg/month		The patient’s condition improved with regression of livedo reticularis, polyarthritis, paraesthesia and paresis
9	IgG4-related disease	Yunyun et al. (2017)⁷⁰	Prospective comparative clinical trial.	102	Oral CYC (n = 50): 50-100 mg/day for 3 months, tapered to 50 mg/day or every other day, up to 12 months	Prednisone: 0.5-1.0 mg/kg/day for 1 month, tapered to 5-10 mg/day, up to 12 months	Prednisone only (n = 52): 0.5-1.0 mg/kg/day for 1 month, tapered to 5-10 mg/day, up to 12 months	12 months	Adding CYC to glucocorticoids improves treatment effectiveness and reduces relapse in IgG4-related disease compared to glucocorticoids alone
10	Behçet’s disease	Davatchi et al. (2004)⁷¹	RCT	35	Group 1: IV CYC (n = 17): 1 g/sq. m/ month for 3 months	Prednisolone: 0.5mg/kg/day, given to both groups	Group 2: Placebo (n = 18). After 3 months, the two groups were swapped	6 months	IV CYC with prednisolone significantly improved ocular lesions compared to prednisolone alone, though these were not statistically significant. IV CYC combined with prednisolone is more effective than prednisolone alone
11	Neuromyelitis optica spectrum disorder	Yaguchi (2013)⁷²	Retrospective observational study	4	IV CYC: 500-774 mg/sq. m/month (mean = 12 doses)	IV MPS: 1 g/day for 3 days, followed by 5-10 mg/day. Plasmapheresis (n = 2) AZA (n = 1): 100 mg/day	None	1 year	IV CYC may be effective in treating acute and chronic phases of NMOSD. IV CYC, when combined with IV MPS and plasmapheresis, could be a valuable therapeutic option for NMOSD patients with severe disabilities

Note: AZA: Azathioprine, BSA: Body surface area, CTD: Connective tissue disease, CYC: Cyclophosphamide, ILD: Interstitial lung disease, MMF: Mycophenolate mofetil, MPS: Methyl prednisolone, NMOSD: Neuromyelitis optica spectrum disorder, RCT: Randomised, controlled trial; RTX: Rituximab.

The 2023 guidelines by American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST), for the treatment of CTD-ILD state that in SSc-ILD, CYC may be used as an additional drug, after the recommended first-line agents for SSc-ILD (MMF, tocilizumab and RTX) have shown inadequate response.⁵⁸ In such a scenario, CYC may be administered either IV or orally, but the use of intermittent IV pulses is preferred because it is less toxic. The recommended dose of IV CYC is 500–750 mg/m² of BSA (maximum dose of 1200 mg), given monthly for 6 months to be followed by maintenance with a less toxic agent, for example, MMF (2–3 g/day).⁵⁸

CYC in Skin Involvement in Systemic Sclerosis (SSc)

Skin involvement in SSc has been a challenge to treat. Initiation of treatment is done with CYC at a dose of 500 mg/m² for 6–12 months. Maintenance agents commonly used after 6 to 12 months of CYC include methotrexate, MMF or AZA (Table 5).⁵⁹

CYC in Idiopathic Inflammatory Myopathy (IIM)

In a systematic review on IIM patients with progressive ILD, IV-CYC was administered at the dose of 300–800 mg/m² given once in four weeks for six cycles. This was combined with oral prednisolone at a dose between 30 and 60 mg/day for the first two weeks and gradually tapered in all patients. It was shown that IV-CYC improved symptoms, pulmonary function tests and high-resolution computerised tomography (HRCT). The same review also showed improvement both in muscle strength as also in creatine kinase levels.⁶⁰

The RECITAL trial compared RTX versus IV-CYC in patients with ILD in various CTDs, including IIM. It concluded that RTX was not superior to CYC for treating CTD-ILD. However, RTX was associated with fewer adverse events (Table 5).⁶¹

CYC in Catastrophic Antiphospholipid Syndrome (CAPS)

In rare cases, CYC is a part of combination therapy to manage CAPS, especially if secondary to lupus or other autoimmune diseases.⁶²

In SLE-associated CAPS, CYC has been used at a dose of 500–750 mg/m² BSA, as has been administered in other organ or life-threatening manifestations of SLE.⁶³

CYC in Mixed Connective Tissue Disease (MCTD)

For cases with severe systemic involvement, including ILD or renal crisis, CYC has been employed.⁶¹

In a review of 495 participants (most with systemic sclerosis), two separate comparisons were done—CYC versus placebo and CYC versus mycophenolate. The data demonstrated significant improvement in lung function with CYC compared with placebo with regard to FVC%, but no significant impact on lung function when CYC was compared with mycophenolate, at 12 months. CYC had more adverse events as compared to mycophenolate, in particular, leukopenia and thrombocytopenia.⁶⁴

CYC in Sarcoidosis

For refractory cases with extensive pulmonary or extrapulmonary involvement, CYC has been explored as a treatment option. It has been found to be an effective treatment in corticosteroid-resistant disease in both neuro-sarcoidosis and cardiac sarcoidosis, and has been associated with a lower relapse rate for patients with neuro-sarcoidosis.⁶⁵

CYC in Relapsing Polychondritis

In patients with life- or organ-threatening relapsing polychondritis, such as involvement of laryngotracheal and bronchial cartilage, cardiovascular, renal, neurologic disease, ocular or inner ear involvement, a combination of prednisolone (usually 1 mg/kg daily) with oral CYC at a dose of 2mg/kg/day has been used. There are no fixed guidelines about maintenance therapy, but usually it is continued for at least 6 months of disease remission. Once the patient is stable, any of the agents among AZA, Methotrexate (MTX) or IV-pulsed-CYC every one to two months may be considered.⁶⁶

Use of CYC in various other I-RMDs has been described in Table 5.

CYC in Autologous Haematopoietic Stem Cell Transplant

In patients with scleroderma, autologous haematopoietic stem cell therapy (HSCT) has emerged as a potential treatment option. In this context, CYC has a dual role to play:^73–75

Stem cell Mobilisation (Mobilisation phase): CYC facilitates the release of haematopoietic stem cells into the peripheral bloodstream, making them more accessible for collection in autologous stem cell transplantation procedures.

Immune System Reset (Conditioning phase): Prior to reinfusion of stem cells, CYC is administered for its immunoablative effects and this eliminates autoreactive immune cells, thus leading to long term disease remission.

The trials comparing HSCT and CYC in SSc are included in Table 6.

Table 6.

Cyclophosphamide Versus Haematopoietic Stem Cell Transplant in Systemic Sclerosis.

Sr. No.	Trial Name	CYC Regimen	Duration of CYC Treatment	CYC: HSCT Mobilisation Phase Regimen	CYC: HSCT Conditioning Phase Regimen	Conclusion
1	ASSIST (2011)⁷⁶	1,000 mg/m² BSA IV monthly × 6 months	6 months	2 g/m² IV on a single day, along with G-CSF	200 mg/kg CYC + 6.5 mg/kg rabbit ATG + IV MPS 5,000 mg	HSCT significantly improved skin and lung function compared to monthly CYC therapy. All patients in the HSCT group showed improvement, while the majority in the CYC group showed disease progression
2	ASTIS (2012)⁷⁷	750 mg/m² BSA IV monthly × 12 months	12 months	2 g/m² IV, 2 doses (total 4 g/m²) along with G-CSF	200 mg/kg CYC + 7.5 mg/kg rabbit ATG	HSCT showed improved long-term event-free survival and overall survival compared to CYC, despite higher treatment-related mortality in the first-year post-transplant
3	SCOT (2018) ⁷⁸	750 mg/m² BSA IV monthly × 12 months	12 months	Only G-CSF was used.	120 mg/kg CYC + 90 mg/kg horse ATG + total body irradiation (800 cGy)	HSCT led to significant improvements in a composite measure of clinical outcomes compared to CYC, with acceptable long-term safety profiles

Note: ATG: Antithymocyte globulin, BSA: Body surface area, CYC: Cyclophosphamide, MPS: Methyl prednisolone, G-CSF: Granulocyte-colony stimulating factor, HSCT: Haematopoietic stem cell transplant.

Toxicities of CYC

CYC is associated with a considerable number of toxicities,^79,80 some of which are enlisted in Table 7. Due to its toxicity profile, CYC is increasingly being replaced by relatively safer alternatives such as MMF and RTX. This shift likely explains the decline in its use in recent years.

Table 7.

Toxicities of CYC.

Sr No	Toxicity	Description	Management Strategies
1	Haemorrhagic cystitis	Bladder inflammation and bleeding caused by the toxic metabolite acrolein (12%-41% of patients and risk increases with the cumulative dose)⁸¹	Adequate hydration Mesna: Administer mesna, which binds to acrolein, reducing bladder toxicity.
2	Nausea and vomiting	Common side effects post-infusion	Antiemetics: Use of ondansetron or prochlorperazine.
3	Bone marrow suppression	Increased susceptibility to opportunistic infections due to reduced white blood cell counts	Monitor complete blood counts (The nadir of white blood cell and platelet counts occurs between 7 and 14 days after CYC) Prophylactic antibiotics for infections like pneumocystis carinii pneumonia (800 mg sulfamethoxazole / 160 mg trimethoprim 1 tablet on alternate days)
4	Infertility	Risk of premature menopause in females and infertility in both sexes (33% risk in women aged 21-25 years, 50%-60% in women aged >30 years)⁸²	Fertility preservation: Discuss options prior to treatment. Hormonal therapies: Leuprorelin (3.75mg monthly, 2 weeks before starting CYC therapy) to protect ovarian function⁸³
5	Secondary malignancies	Increased risk of cancers such as leukaemia and bladder cancer (Risk of bladder cancer doubles for every 10 g increment in CYC dose)⁸⁴	Monitoring: Regular follow-ups and screenings. Lifestyle modifications: Avoid smoking and other carcinogenic exposures
6	Pulmonary toxicity	Rare but can manifest as pneumonitis or pulmonary fibrosis.	Monitoring: Regular pulmonary function tests. Intervention: Discontinue CYC if symptoms develop
7	Cardiotoxicity	Cardiomyopathy, pericarditis and arrythmias, especially at high doses	Monitoring: Regular cardiac evaluations. Dose adjustment: Modify dosage based on cardiac function
8	SIADH	Hyponatremia	Monitoring: Regular electrolyte checks. Fluid management

Note: CYC: Cyclophosphamide; Mesna: sodium 2-mercapto ethane sulfonate; SIADH: Syndrome of inappropriate antidiuretic hormone secretion.

Conclusion

In conclusion, the evolution of CYC from a lethal nitrogen mustard gas to a life-saving therapeutic agent highlights the remarkable potential of scientific innovation in transforming harmful substances into invaluable medical tools. In current practice,

While newer therapies have emerged for the treatment of I-RMDs, CYC remains a cost effective and time-tested drug in life-saving situations, despite its toxicities.

CYC is one of the first-line drugs in the management of proliferative classes of lupus nephritis and AAV.

CYC is highly efficacious in the management of severe forms of SSc, NPSLE and IIM.

The emerging role of CYC in HSCT for SSc in both the mobilisation and conditioning phases is noteworthy.

The toxicities of CYC, particularly infertility, bone marrow suppression and bladder cancer should be borne in mind when using CYC.

Monitoring the total white cell count, specifically between day 7 to 14 after administering CYC, and monitoring the renal function of a patient on CYC is crucial to prevent its life-threatening complications. A constant vigilance for development of infections and malignancies is a must.

Continued research into optimising its use and minimising its adverse effects will further solidify its legacy as a cornerstone in the history of modern medicine.

Footnotes

Authors Contribution

NYK and ANM contributed to literature search and writing of the manuscript.

Data Availability

All relevant data is presented in the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Permission to Reproduce Material from Other Sources

The authors have noted that no third-party content was reproduced in the article.

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The Cyclophosphamide Story: From Killer Gas to Life-saving Drug for Cancers and Inflammatory Rheumatic and Musculoskeletal Diseases (I-RMDs)

Abstract

Keywords

Introduction

Nitrogen Mustard and Its Derivative Cyclophosphamide in the Management of I-RMDs

The Mode of Action of Nitrogen Mustard and Cyc for the Treatment of Cancer and I-RMDs

Route of Administration

CYC in Lupus Nephritis

CYC in Neuro-psychiatric SLE (NPSLE)

CYC in ANCA-Associated Vasculitis (AAV)

CYC in Systemic Sclerosis-related Interstitial Lung Disease (SSc-ILD)

CYC in Skin Involvement in Systemic Sclerosis (SSc)

CYC in Idiopathic Inflammatory Myopathy (IIM)

CYC in Catastrophic Antiphospholipid Syndrome (CAPS)

CYC in Mixed Connective Tissue Disease (MCTD)

CYC in Sarcoidosis

CYC in Relapsing Polychondritis

CYC in Autologous Haematopoietic Stem Cell Transplant

Toxicities of CYC

Conclusion

Footnotes

Authors Contribution

Data Availability

Declaration of Conflicting Interests

Funding

Permission to Reproduce Material from Other Sources

References