Immunosuppression use in early systemic sclerosis may be increasing over time

Abstract

Background:

Immunosuppression remains the main treatment for progressing skin involvement, interstitial lung disease and inflammatory joint or muscle disease in systemic sclerosis. This study investigated the pattern and trends in immunosuppressive agents used in early systemic sclerosis (diagnosed before and after 2007) to determine whether the changes in the preferred type, timing and combination of immunosuppression took place over the past decade.

Methods:

In total, 397 Canadian Scleroderma Research Group database patients (183 diffuse cutaneous systemic sclerosis and 214 limited cutaneous systemic sclerosis) who had baseline and follow-up visits within 3 years (mean: 1.8 ± 0.8) after disease onset were included: 82% females, age at diagnosis 53 ± 13 years. Bivariate, chi-square, analysis of variance and adjusted regression analyses were used.

Results:

In total, 115 diffuse cutaneous systemic sclerosis patients (63%) and 62 limited cutaneous systemic sclerosis (29%) received immunosuppressive drugs, most commonly methotrexate, followed by mycophenolate mofetil and cyclophosphamide. In diffuse cutaneous systemic sclerosis, immunosuppressants were prescribed after 2007 more often (74% vs 50%, p = 0.001), especially methotrexate (p = 0.02) and mycophenolate mofetil (p = 0.04), and earlier (peak at 2 years after onset). Immunosuppressive therapy was associated with male gender, interstitial lung disease, anti-Scl70 positivity, ACA negativity and inflammatory joint disease in limited cutaneous systemic sclerosis and with ACA negativity and a higher modified Rodnan skin score in diffuse cutaneous systemic sclerosis. Multivariate regression analysis showed that the use of immunosuppressants after 2007 was predicted only by ACA negativity in limited cutaneous systemic sclerosis and by younger age in diffuse cutaneous systemic sclerosis.

Conclusion:

Over the past decade, there has been a trend to prescribe immunosuppressants more often and earlier in diffuse cutaneous systemic sclerosis patients, regardless of modified Rodnan skin score. Methotrexate is being more frequently used, and mycophenolate mofetil has gained favour over cyclophosphamide. Autoantibody status was the most consistent predictor of immunosuppressive therapy.

Introduction

Systemic sclerosis (SSc) is a rare connective tissue disease, characterized by the thickening of the skin, vascular injury, antibodies and internal organ involvement.^1,2 SSc is classified into limited and diffuse cutaneous subsets (lcSSc and dcSSc). ³ Patients with dcSSc often comprise a quarter-to-third of SSc, ¹ with higher morbidity and mortality predominantly due to internal organ damage. ⁴ The heterogeneity in disease progression and clinical presentation makes treatment complex, ⁵ but immunosuppressive (IS) drugs remain the standard of care despite inconsistent findings on their efficacy.^6,7

Cyclophosphamide (CYC) is an IS drug commonly used as induction therapy in SSc with associated interstitial lung disease (SSc-ILD). ⁸ Three randomized controlled trials (RCTs) demonstrated the safety and efficacy of oral and pulse CYC with improvement in forced vital capacity (FVC).^9–12 Serious adverse events occur in 14% of SSc patients receiving CYC regardless of the route of administration. ¹³ It appears that mycophenolate mofetil (MMF) treatment was not superior to CYC; however, MMF has less toxicity, so it has displaced CYC as first-line treatment for SSc-ILD.^8,14,15 Usually maintenance therapy is needed after induction treatment with MMF or azathioprine (AZA). AZA may stabilize SSc-ILD.^16–18 As a first-line therapy, however, AZA lacked the efficacy of CYC and MMF.^19,20 Methotrexate (MTX) is recommended as a treatment for skin involvement in early dcSSc. ²¹ MTX studies had borderline statistical significance and showed modest benefit; ²² however, data are generally lacking for MTX use in SSc-ILD.^14,15

There are site differences in the treatment of SSc using data from the Canadian Scleroderma Research Group (CSRG). ²³ In 2009, the European League Against Rheumatism (EULAR) published its first recommendations for the treatment of SSc. ²⁴ Some specific SSc-related organ involvement was not included ²⁴ that may partly explain an overall poor agreement with EULAR recommendations in CSRG centres as well as differences in access and approvals for certain medications. ²⁵

One could expect that the EULAR recommendations have led to a shift in treatment patterns of SSc over time. The CSRG database provides an opportunity to investigate temporal trends by studying patients diagnosed with early SSc before and after 2007. The aims of this study were to explore whether the changes in the preferred type and combination of IS, timing and predictors of administration occurred over the past decade in the incident cohorts of dcSSc and lcSSc patients that were constructed from the CSRG database.

Methods

The CSRG is a network of 15 Canadian centres with rheumatologists who collect data annually on clinical and demographic information in adult patients with SSc. All but two sites are academic centres. To be enrolled in the registry, patients had to have a diagnosis of SSc confirmed by a rheumatologist, are ⩾18 years of age, provide informed consent and speak English or French. A total of 1580 patients were recruited between 2004 and 2016. Dates of symptom onset, disease duration (time since first non-Raynaud’s phenomenon (RP) symptom), current and past medications, SSc type, modified Rodnan skin score (mRSS), organ parameters, patient assessment of organ function (on a 0–10 scale) and changes in health status, autoantibodies and laboratory parameters are documented. ²⁶ IS therapy included but was not limited to MTX, AZA, CYC, leflunomide, MMF and biologics.

Study design and patients

We included dcSSc and lcSSc patients with disease duration of ⩽3 years from the first non-RP symptom at baseline who met the 2013 ACR/EULAR SSc classification criteria.^27,28 Patients in both of these subsets were further divided into those diagnosed in 2007 and before and those with a diagnosis after 2007; as in the earlier group, the RCTs that informed the EULAR recommendations would not have been as widely known and in the later group, the guidelines may have informed treatment and this cut-point would divide the database roughly in half. Overall, ever use was determined by whether patients had IS drug use prior to baseline visit or at any of the follow-up periods within the first 3 years after disease onset.

Statistical analysis

Continuous variables were expressed with means ± standard deviation. Baseline demographic/disease characteristics were compared using unpaired t test for continuous variables and chi-square test for categorical variables. Chi-square and Fisher’s exact tests were used to compare between cohorts and subsets of early SSc (dcSSc before and after 2007 and lcSSc before and after 2007 diagnosis). Associations between the current use of IS and demographic/disease characteristics at each visit were assessed by Pearson test followed by logistic regression. All statistical analyses were performed with SPSS software v.26.0 (IBM Corp., Armonk, NY, USA); p values less than 0.05 were considered statistically significant.

Results

A total of 397 (183 dcSSc and 214 lcSSc) patients were eligible and had either only baseline (42%) or baseline and follow-up (58%) visits within 3 years after disease onset. Figure 1 shows the CSRG patients included in the study, dividing patients into those diagnosed before and after 2007.

Figure 1.

Flow diagram of patient selection and study design.

Out of 183 dcSSc patients with a mean disease duration of 1.75 ± 0.76 (range: 0.08–3) years at baseline visit, 122 (67%) had follow-up visits: 94 patients were followed up at 1 year and 28 at 2 years. In lcSSc subset, mean (±SD) disease duration was 1.86 ± 0.78 (range: 0.01–3) years and 108 (50.5%) patients had follow-up visits: 84 patients were followed up at 1 year and 24 at 2 years. The follow-up period was 0.66 ± 0.71 years for dcSSc patients and 0.50 ± 0.68 years for lcSSc patients. Baseline characteristics of the patients are given in Table 1. The patients in the two cohorts did not differ in age, but the after 2007 group had slightly shorter disease duration at baseline visit.

Table 1.

Baseline demographic and disease characteristics of the patients with early SSc.

Characteristics	Entire cohort (n = 397)	Patients with SSc diagnosed ⩽ 2007 (n = 171)	Patients with SSc diagnosed > 2007 (n = 226)	p value
Female, n (%)	327 (82)	150 (87)	177 (79)	0.03
Age at diagnosis, mean ± SD, years	53.7 ± 13.0	53.8 ± 13.3	53.7 ± 12.7	0.95
Disease duration from RP, mean ± SD, years	5.6 ± 9.1	5.5 ± 9.0	5.7 ± 9.2	0.79
Disease duration from first non-RP manifestation of SSc, mean ± SD, years	1.6 ± 0.8	1.7 ± 0.8	1.5 ± 0.7	0.02
Disease subset, n (%)
lcSSc	214 (54)	88 (51)	126 (56)	0.14
dcSSc	183 (46)	83 (48)	99 (44)
mRSS, mean ± SD, years	12.5 ± 11.6	13.2 ± 11.8	12.1 ± 11.4	0.36
mRSS dcSSc, mean ± SD, years	22.1 ± 10.3	22.4 ± 10.3	21.8 ± 10.3	0.69
mRSS lcSSc, mean ± SD, years	4.3 ± 3.8	4.3 ± 3.3	4.3 ± 3.9	0.96
HAQ-DI, mean ± SD	0.8 ± 0.7	0.9 ± 0.7	0.8 ± 0.7	0.77
Telangiectasia, n (%)	235 (593)	116 (68)	119 (53)	0.003
RP, n (%)	375 (94)	163 (95)	212 (94)	0.91
Pitting scars, n (%)	129 (33)	51 (30)	78 (35)	0.32
Digital ulcers, n (%)	28 (7)	15 (9)	13 (6)	0.25
Gangrene, n (%)	7 (2)	3 (2)	4 (2)	0.10
Interstitial lung disease, n (%)	58 (15)	29 (17)	29 (13)	0.268
FVC (%), mean ± SD	91.5 ± 20.0	90.7 ± 20.7	92.7 ± 19.2	0.42
FVC < 70%	32 (12.3)	15 (11.8)	17 (12.7)	0.83
dcSSc	19 (15.6)	12 (16.2)	7 (14.6)	0.81
lcSSc	13 (9.4)	3 (5.7)	10 (11.6)	0.24
DLCO (%), mean ± SD	75.7 ± 23.7	76.3 ± 24.6	74.8 ± 22.1	0.62
PAH, n (%)	40 (1)	25 (15)	15 (7)	0.01
Renal crisis, n (%)	20 (5)	11 (6)	9 (4)	0.27
Organ involvement, a % of patients:
Peripheral vascular	132 (44.6)	56 (33.9)	76 (57.1)	0.0001
Joint/tendon	113 (42.0)	66 (42.6)	47 (40.9)	0.78
Skin	362 (92.4)	156 (92.9)	206 (92.0)	0.74
Muscle	59 (15.3)	26 (15.5)	33 (15.1)	0.91
Gastrointestinal tract	328 (84.1)	142 (83.0)	186 (85.3)	0.54
Lung	269 (67.8)	98 (67.1)	171 (68.1)	0.84
Heart	84 (23.0)	36 (21.7)	48 (23.2)	0.73
Kidney	20 (5.8)	11 (7.4)	9 (4.6)	0.28
Arthritis	61 (15.8)	27 (18.6)	34 (14.2)	0.25

RP: Raynaud’s phenomenon; dcSSc: diffuse cutaneous systemic sclerosis; lcSSc: limited cutaneous systemic sclerosis; mRSS: modified Rodnan skin score; SD: standard deviation; HAQDI: Health Assessment Questionnaire-Disability Index; FVC: forced vital capacity; DLCO: carbon monoxide diffusing capacity; PAH: pulmonary arterial hypertension.

^aGrade ⩾ 1 on Medsger’s severity scale, except for peripheral vascular system (grade ⩾ 2).

Immunosupressive treatment in early SSc

In total, 115 (63%) early dcSSc patients received IS within the first 3 years after disease onset: 101 received IS at least once during a follow-up period and 14 patients reported taking IS prior to the baseline visit. Sixty-two (29%) early lcSSc patients received IS: 39 patients during a follow-up period and 22 before the baseline visit. IS was most frequently prescribed at years 2 and 3 after the onset of first non-RP manifestation in early dcSSc patients, approximately half of the patients received IS. The proportion of lcSSc patients receiving IS was considerably lower at each year and distributed more equally through the first 3 years (Table 2).

Table 2.

Proportion of early SSc patients receiving IS therapy at each year after disease onset.

Years after the first non-Raynaud’s phenomenon symptom	dcSSc			lcSSc			p value
	Total N	N on IS	% on IS	Total N	N on IS	% on IS
1	63	24	38	60	10	17	0.009
2	116	55	47	106	20	19	<0.0001
3	125	62	50	156	22	14	<0.0001

In addition, we analysed IS treatment received by our patients at FU visits beyond the first 3 years after disease onset. Supplementary Figure 1 shows that the proportion of patients receiving IS remained high ((47%–52%) at years 2 through 5 after disease onset. Later, cross-sectionally, the proportion of patients gradually declined from 41% at year 6 to 24% at year 10. In lcSSc group, IS treatments were used at the highest frequency between 6 and 9 years after the onset of first non-RP manifestation with 20% of patients receiving IS annually, which was slightly higher than the average proportion of lcSSc patients receiving IS within the first 5 years (16% per year) (Supplementary Figure 1B). This was likely due to new or worsening organ complications in the later stages of disease (such as inflammatory arthritis and/or ILD).

IS treatment in patients with SSc diagnosed before and after 2007

In early dcSSc subset, we found a trend to IS being prescribed more often after 2007 (74% vs 50%, p = 0.001). When we analysed the proportions of patients receiving IS at each year after disease onset, the number peaked earlier at 2 years after 2007 (65%), while before 2007, the highest proportion of patients receiving IS fell into ‘3-year’ category (45%) and only quarter of patients received IS at years 1 and 2 before 2007. The number of patients receiving IS within the first year after disease onset increased from 29% before 2007 to 43% after 2007 but due to small numbers this was not significant (Table 3).

Table 3.

Proportion of patients receiving IS treatment in SSc subsets diagnosed before and after 2007.

Years after the first non-RP symptom	Year of diagnosis				p value
	⩽2007		>2007
	Total number of patients seen at each year	% receiving IS	Total number of patients seen at each year	% receiving IS
dcSSc
1	24	29	40	43	0.29
2	51	26	65	65	0.0001
3	62	45	63	54	0.33
lcSSc
1	13	15	47	17	0.99
2	24	21	82	18	0.77
3	49	14	107	14	0.97

In early lcSSc, equal proportion of patients with SSc diagnosed before and after 2007 received IS within 3 years after disease onset (p = 0.990). There was also no difference in the proportion of patients receiving IS at each year after disease onset (Table 3).

The frequency of specific IS drugs used did not differ in patients with early SSc diagnosed before and after 2007, except for MTX and MMF prescribed more often in patients with dcSSc diagnosed after 2007 (Table 4).When the timing of MMF administration was analysed, there was an initial peak in MMF use around 2008–2009 when half of all patients in need of IS treatment (46%, 16 of 35) were started on MMF. Later, the percentage of patients initiating MMF decreased and remained constant at 25% (range: 24%–27%) of all patients receiving IS treatment between 2010 and 2013, following by a rise back to 60% after 2013.

Table 4.

IS medications prescribed in early SSc divided by subsets.

Ever use within 3 years after the first non-RP symptom	dcSSc
	All, n = 183 (%)	⩽2007, n = 84 (%)	>2007, n = 99 (%)	p value
MTX	36	26	43	0.02
CYC	7	10	4	0.14
AZA	4	4	5	0.63
MMF	15	10	20	0.05
Other	8	8	7	0.75
	lcSSc
	All, n = 214 (%)	⩽2007, n = 87 (%)	>2007, n = 127 (%)	p-value
MTX	9	8	9	0.72
CYC	6	7	5	0.49
AZA	2	3	2	0.37
MMF	4	6	3	0.35
Other	5	3	6	0.48

MTX: methotrexate; CYC: cyclophosphamide; AZA: azathioprine; MMF: mofetil mycophenolate.

Frequency of use and the number of different IS medications

In the dcSSc group ever received IS (n = 115), MTX was used most often (83 patients; 72%), followed by MMF (22%), CYC (18%), AZA (10%) and leflunomide (2%). Four patients (3%) received other IS treatment (two - Tocilizumab, one each Imatinib and Etanercept).

In the lcSSc group (n = 62), MTX was also the most commonly prescribed IS medication; however, the proportion of patients receiving MTX was significantly lower than in dcSSc (52% vs 72%, p < 0.006). CYC replaced MMF as the second choice IS. CYC and AZA were chosen more often as IS treatment in lcSSc compared to dcSSc (37% vs 18%, p < 0.006% and 24% vs 10%, p < 0.015, respectively). Neither Leflunomide nor MMF use was statistically different in lcSSc and dcSSc (7% vs 2%, p = 0.098% and 29% vs 22%, p = 0.280, respectively). Two lcSSc patients (3%) received other IS treatment (Rituximab).

In both subsets, we found similar distribution of patients receiving one and more IS medications subsequently during the follow-up with the majority of patients receiving only one IS drug within the first 3 years of disease (Supplementary Figure 2). None received combination therapies with biological agents or ⩾ 2 IS medications at the same time.

Predictors of IS administration in early SSc

In entire early SSc cohort, associations between IS administration and the following baseline parameters were found by bivariate analysis: ILD (r = 0.145, p = 0.004), mRSS (r = 0.299, p = 0.0001), arthritis using the DAS28-ESR (r = 0.303, p = 0.007), ACA negativity (r = −0.184, p = 0.003), anti-Scl70 positivity (r = 0.155, p = 0.028), as well as a reverse correlation with disease duration (r = −0.109, p = 0.030) and age (r = −0.136, p = 0.007). Those positive for anti-RNAPIII were prescribed more IS treatment (r = 0.127, p = 0.051). Using multiple regression analysis adjusted for SSc subtype, the best predictors of IS use were ILD (Exp(B): 11.7, 95% confidence interval (CI): 1.9–70.9, p = 0.007) and DAS28-ESR (Exp(B): 1.9, 95% CI: 1.1–3.4, p = 0.024), while mRSS showed only a slight association with IS use (Exp(B): 1.1, 95% CI: 1.0–1.2, p = 0.066). When divided by the year of diagnosis, only patients with SSc diagnosed before 2007 had ILD (p = 0.016), arthritis (DAS(ESR), p = 0.020) and, to a lesser degree, mRSS (p = 0.064) as predictors of IS use.

In lcSSc patients, IS treatment was associated with male gender, ILD, anti-Scl70 positivity and ACA negativity, as well as with inflammatory arthritis in patients with lcSSc diagnosed before 2007 (Table 5). ACA negativity was the only variable associated with IS treatment in dcSSc patients. When the disease was diagnosed before 2007, a higher mRSS was associated with IS administration.

Table 5.

Associations between IS therapy and the patient-specific factors by bivariate analysis.

dcSSc
Variables at baseline	Entire cohort (n = 183)		Patients with SSc diagnosed ⩽ 2007 (n = 84)		Patients with SSc diagnosed > 2007 (n = 99)
	Pearson r	p value	Pearson r	p value	Pearson r	p value
mRSS	0.06	0.43	0.24	0.03	−0.10	0.34
ILD	−0.01	0.85	0.08	0.46	−0.08	0.46
IA	0.01	0.86	0.00	1.00	0.06	0.56
IA b	−0.05	0.48	0.00	1.00	−0.08	0.46
Anti-RNAPIII	−0.06	0.58	−0.03	0.83	a
ACA	−0.21	0.02	−0.23	0.05	−0.19	0.63
Anti-Scl70	0.14	0.23	0.16	0.19	a
Age	−0.12	0.12	−0.20	0.07	−0.06	0.57
Male gender	−0.05	0.47	0.03	0.79	−0.17	0.10
Disease duration	−0.050	0.51	0.15	0.19	−0.19	0.07
Follow-up period	0.20	0.008	0.23	0.04	0.17	0.08
lcSSc
Variables at baseline	Entire cohort (n = 214)		Patients with SSc diagnosed ⩽ 2007 (n = 62)		Patients with SSc diagnosed > 2007 (n = 152)
	Pearson r	p value	Pearson r	p value	Pearson r	p value
mRSS	0.06	0.43	0.05	0.73	0.06	0.48
ILD	0.14	0.05	0.20	0.11	0.11	0.18
IA	0.05	0.43	0.21	0.11	−0.01	0.90
IA b	0.04	0.52	0.30	0.02	−0.06	0.43
Anti-RNAPIII	0.07	0.53	−0.06	0.65	0.33	0.06
ACA	−0.32	0.0001	−0.05	0.74	−0.52	0.0001
Anti-Scl70	0.20	0.03	−0.03	0.81	0.36	0.003
Age	−0.07	0.28	0.06	0.64	−0.13	0.10
Male gender	0.19	0.007	0.22	0.08	0.18	0.03
Disease duration	−0.08	0.23	−0.08	0.56	−0.09	0.30
Follow-up period	0.08	0.24	0.13	0.31	0.07	0.42

dcSSc: diffuse cutaneous systemic sclerosis; lcSSc: limited cutaneous systemic sclerosis; IA: inflammatory arthritis (tender and swollen joints); mRSS: modified Rodnan skin score; ILD: interstitial lung disease; ACA: anti-centromere antibodies; anti-RNAPIII: antibodies to RNA polymerase III; anti-Scl70: antibodies to Scl-70.

^aNot enough cases for statistical analysis. ^bOnly swollen joints.

Multivariate logistic regression analysis showed that IS treatment was related to ACA negativity in lcSSc patients (95% CI: 0.1–0.8, p = 0.012) and younger age in dcSSc patients (95% CI: 0.9–0.98, p = 0.002). In patients with lcSSc diagnosed before 2007, ILD (95% CI: 1.0–21.6, p = 0.044) and inflammatory arthritis (95% CI: 1.5–21.8, p = 0.010) were related to IS use.

Regardless of the date of diagnosis, MTX administration was associated with higher mRSS (p = 0.0001), dcSSc (p = 0.0001), anti-RNAPIII (p = 0.039), anti-Scl70 (p = 0.003) positivity and ACA negativity (p = 0.0001). However, in multivariate regression analysis, mRSS was the only significant predictor of MTX used before 2007 (p = 0.017), while Scl70 (p = 0.041) and anti-RNAPIII (p = 0.038) were associated with MTX treatment after 2007.

CYC administration was associated with ILD (p = 0.001), especially low FVC% (p = 0.003) and ACA negativity (p = 0.034) by bivariate analysis. Multivariate regression analysis with adjustment for disease subtype showed that FVC% and negative ACA predicted CYC treatment overall (p = 0.001 and p = 0.045, respectively), before (p = 0.001, p = 0.009) and after 2007 (p = 0.002, p > 0.5).

Discussion

The use of IS increased among patients with dcSSc diagnosed after 2007. The most consistent difference in use was noted with MTX. For all years of follow-up MTX use was greater in the after 2007 dcSSc cohort. A similar pattern was found with MMF. The difference in its use was greatest at 3 years of follow-up with a higher proportion of patients with dcSSc diagnosed after 2007 receiving MMF and then diminished slightly at 5 and 10 years of follow-up as more patients were being prescribed MMF in both cohorts. Relative to MTX and MMF, overall, CYC use was lower with more prescriptions in the earlier cohort. IS drug use in lcSSc patients was similar in both cohorts and there were no notable trends for specific drugs. Due to the low number of patients on each IS drug for lcSSc, differences could have been missed.

It is not surprising that patients with dcSSc are prescribed IS drugs more often than lcSSc patients given the greater extent of skin thickening and a higher frequency of lung complications in dcSSc, particularly during the first 3–5 years of the disease. ²⁹ Evolving treatment standards in dcSSc likely contributed to the IS prescriptions over the decade of 2007–2017. ³⁰ EULAR recommended the use of MTX and CYC for skin manifestations in early dcSSc and SSc-ILD, respectively, whereas MMF was placed on a research agenda. This may explain the greater use of MTX in the later cohort and the overall low CYC use in early dcSSc patients. In 2011, 65% of surveyed SSc experts agreed SSc-ILD should be treated with CYC but there was not a strong consensus. ²¹ Several studies before and after 2011 have demonstrated the safety and efficacy of MMF.^{14,15,31–33} In 2016–2017, MMF was selected as the preferable induction therapy for SSc-ILD according to the SSc experts’ opinion. ⁸ Increased MMF use in the after 2007 cohort reflected this. Recent literature^34,35 demonstrated that CYC has lost its lead in SSc-ILD to MMF because of the equal efficacy and better safety of MMF. Studies reporting safety of MMF and efficacy in SSc-ILD^31,32,36,37 seemed related to a peak in MMF administration, where approximately half of the CSRG patients who received IS were prescribed MMF in 2008–2009, regardless of SSc subtype. Later, the percentage of patients on MMF went slightly down from half to quarter of all patients receiving IS treatment between 2010 and 2013. The studies published during this time were observational, single-centred and unpowered^15,38,39 with inconclusive results. Some studies showed FVC improvement, ³⁹ while others reported no FVC changes ³⁸ or a deterioration of lung high-resolution computed tomography (HRCT) images at 2 years after MMF treatment but not with CYC in patients matched 1:1. ¹⁵ MMF was generally used as a maintenance treatment after CYC. ²¹ In 2012, a meta-analysis clearly demonstrated that MMF was linked with disease stabilization in patients with SSc-ILD. ⁴⁰ The benefits of MMF shown in meta-analyses^40,41 and the Scleroderma Lung Study II ¹⁴ may account for an increase in MMF administration starting 2014–2015 in the CSRG cohort.

Our study showed some associations between disease-specific factors and IS treatment. ACA positivity and increased age were both negative predictors of IS therapy in dcSSc patients overall and in and before 2007 cohort. Increased age may have been a negative predictor of IS use because it is typically associated with comorbidities and contraindications for IS therapy. Autoantibody status can be subset-specific and predict disease severity.^42–44 ACA are frequently found in those with milder disease course and lcSSc subset, whereas Scl70 antibodies are more frequent in dcSSc with ILD and cardiac involvement, predicting the lowest survival.^42,44 ACA are rarely found in dcSSc patients and appear to be protective for pulmonary fibrosis and scleroderma renal crisis.^45,46 Autoantibodies are often better predictors of organ complications than disease classification.^42,46

It is unclear why antibody profile became such a strong predictor for IS drug use in lcSSc patients after 2007. Studies have shown a clinical heterogeneity in lcSSc, supporting a predictive role of SSc-related autoantibodies for organ damage and mortality.^42–46 The lcSSc patients in 2007 and before may have been treated more according to their clinical sub-classification, whereas after 2007, the autoantibody status was taken into consideration to tailor the treatment. This trend was not noted in dcSSc patients, where the extent of skin involvement may be a reliable marker of disease severity and progression.^47,48

This study has limitations. It was difficult to determine why IS was used (such as for skin, lung, inflammatory arthritis, myositis or combinations of reasons). There may be a lack of generalizability as reimbursement for several expensive IS medications is not available in most provinces in Canada, so we expect that patients from other countries may have had more biologics and a different pattern of IS therapy. Generalizability may be also affected by the fact that the sites had an interest in SSc, and patients may not be reflective of those seen in other centres. Since the focus on early SSc reduced the number of patients eligible for our study, we might not capture all the therapeutic approaches and strategies used for SSc treatment, that is, the use of combination therapies with two or more IS agents (CYC with AZA/MTX, MTX with AZA/MMF) that had been reported previously in less than 1% of the patients in other cohorts. ⁴⁹ The strengths of this study are a well-characterized large incident cohort of early dcSSc patients reflecting contemporary treatment trends, data from multiple sites increased power and generalizability and there was very little missing data.

Conclusion

Our results suggest that the frequency and pattern of major IS therapies for SSc has changed since 2007. Generally, more IS use occurred in dcSSc, particularly with MTX and MMF, whereas CYC was used less over time. Possibly, RCTs during this time shaped the way clinicians used IS in SSc patients. ACA and Scl70 antibody status was closely associated with differences in IS drug use in lcSSc patients over the past decade. Subsetting SSc based on the antibody profile may impact future IS use.