Results tables | Skin involvement in systemic sclerosis: rituximab | Advice

	Rituximab	Usual treatment	Analysis
n=14	n=8	n=6
Primary outcome
Mean change (±SD) in mRSS from baseline to 1 year	Baseline 13.50 (±6.84) 1 year 8.37 (±6.45 Difference −5.13^a	Baseline 11.50 (±2.16) 1 year 9.66 (±3.38 Difference −1.84	Statistically significant improvement from baseline with rituximab (p=0.0003) No statistically significant improvement from baseline with usual care (p=0.16)
Median % change (upper and lower quartiles) in mRSS from baseline to 1 year	−39.25% (−27.33% to −64.95%)	−20.80% (−10.78% to −39.28%)	No statistically significant difference in improvement between the groups (p=0.06)
Selected secondary outcomes
Median change (upper and lower quartiles) in HAQ‑DI from baseline to 1 year	Baseline 0.69 (0.28 to 1.25) 1 year 0.31 (0.13–0.69 Difference −0.38^b	Baseline 0.31 (0.09 to 0.90) 1 year 0.13 (0.09 to 0.40 Difference −0.18	Statistically significant improvement from baseline with rituximab (p=0.03) No statistically significant improvement from baseline with usual care (p=0.130)
Improvement in HAQ‑DI of more than 0.2^b	6/8 participants (2 participants saw no change)	3/6 participants (1 participant worsened and 2 participants saw no change)	No statistical analysis
Outcomes reported in follow-up study
Mean change (±SEM) in mRSS from baseline to 2 years	Baseline 13.50 (±2.42) 2 years 4.87 (±0.83 Difference −8.63^a	Not studied past 1 year	Statistically significant improvement from baseline (p<0.0001)
Median % change (upper and lower quartiles) in mRSS from baseline to 2 years	−64.58% (−51.79% to −73.74%)	Not studied past 1 year	No statistical analysis
Median change (upper and lower quartiles) in HAQ‑DI from baseline to 2 years	Baseline 0.69 (0.28 to 1.25) 2 years 0.25 (0.13 to 0.44 Difference −0.44^b	Not studied past 1 year	Statistically significant improvement from baseline (p<0.0001)
Safety and tolerability outcomes
n=14	n=8	n=6
Number of participants hospitalised	2/8 (25%) (2 with RTI, 1 with associated leukopenia)	None reported	No statistical analysis
Adverse events reported	1 mild infusion reaction	None reported	No statistical analysis
^a This is within or above the range considered to include the minimum clinically important change in mRSS (3 to 7.5) ^b This is within or above the range considered to include the minimum clinically important change in HAQ‑DI (0.2 to 0.25)
Abbreviations: HAQ‑DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score; RTI, respiratory tract infection; SD, standard deviation; SEM, standard error of mean

	Rituximab	Usual treatment	Analysis
n=51	n=33	n=18
Primary outcome
Mean changes (±SD) in mRSS from baseline to 4 years	Baseline 14.72 (±10.52) 1 year 8.83 (±7.83) Difference −5.89^a 2 years 5.93 (±5.15) Difference −8.79^a 3 years 4.53 (±5.29) Difference −10.19^a 4 years 5.37 (±8.34) Difference −9.35^a	Baseline 17.78 (±9.48) 1 year 15.78 (±9.89) Difference −2.00 2 years 13.72 (±9.67) Difference −4.06^a 3 years 15.53 (±9.53) Difference −2.25 4 years 13.64 (±8.56) Difference −4.14^a	Statistically significant improvements from baseline with rituximab at all time points (all p<0.01) Statistically significant improvements from baseline with usual care at 2, 3 and 4 years, but not 1 year (p=0.030, p=0.041, p=0.023 and p=0.064 respectively) Rituximab was statistically significantly better than usual care at 1, 2 and 3 years but not 4 years 1-year difference 3.89^a (p= 0.002) 2-year difference 4.88^a (p=0.015) 3-year difference 7.94^a (p=0.002) 4-year difference 5.21^a (p=0.053)
Safety and tolerability outcomes
N=51	n=33	n=18
Number of deaths	5/33 (15%) (3 with end-stage lung fibrosis, 1 with lung cancer, and 1 with sudden death of unknown cause)	2/18 (11%) (both RTI)	No statistically significant difference between the groups (p=0.68)
Number of participants hospitalised	3/33 (9%) (2 with RTI and 1 with UTI)	10/18 (56%) (5 with RTI, 4 with UTI and 1 with digital ulcers)	No statistical analysis
Other adverse effects reported	1 HBV reactivation 2 mild infusion reactions		No statistical analysis
^a This is within or above the range considered to include the minimum clinically important change in mRSS (3 to 7.5)
Abbreviations: HBV, hepatitis B virus; mRSS, modified Rodnan skin score; RTI, respiratory tract infection; SD, standard deviation; UTI, urinary tract infection

	Rituximab	Matched controls	Analysis
n=63	Whole mRSS cohort ^a : n=46	None
	Diffuse disease: n=35	None
	Severe, diffuse disease ^b n=25	n=25	Nested case-control analysis
Primary outcome
Severe, diffuse disease ^b
Mean change (±SEM) in mRSS from baseline to 6 months (IQR 5 to 9 months)	Baseline 26.6 (±1.4) 6 months 20.3 (±1.8) Difference −6.3^c (±1.4)	Baseline 25.0 (±1.2) 6 months 23.1 (±1.5) Difference −1.9 (±1.0)	Statistically significant improvement from baseline with rituximab (p=0.0001) No statistically significant improvement from baseline with control (p=0.1) Rituximab was statistically significantly better than control (difference 4.4^c, p=0.02)
Median % change (IQR) in mRSS from baseline to 6 months (IQR 5 to 9 months)	−24.0% (±5.2%)	−7.7% (±4.3%)	Statistically significant improvement from baseline with rituximab (p=0.0001) Statistical significance of improvement from baseline with control not reported Rituximab was statistically significantly better than control (difference 16.3%, p=0.03)
Selected secondary outcomes
Diffuse disease
Mean change (±SEM) in mRSS from baseline to 6 months (IQR 3 to 9 months)	Baseline 22.1 (±1.6) 6 months 17.7 (±1.6 Difference −4.4^c	Not applicable	Statistically significant improvement from baseline (p=0.0005)
Median % change (IQR) in mRSS from baseline to 6 months (IQR 3 to 9 months)	−16.7% (±5.5%)	Not applicable	Statistically significant improvement from baseline (p=0.005)
Whole cohort
Mean change (±SEM) in mRSS from baseline to 7 months (IQR 5 to 9 months)	Baseline 18.1 (±1.6) 7 months 14.4 (±1.5 Difference −3.7^c	Not applicable	Statistically significant improvement from baseline (p=0.0002)
Median % change (IQR) in mRSS from baseline to 7 months (IQR 5 to 9 months)	−15.0% (±5.3%)	Not applicable	Statistically significant improvement from baseline (p=0.008)
Safety and tolerability outcomes
n=63 ^d (data on adverse events were not reported for the control group)
Serious adverse events	None reported
Adverse events reported	1 cardiac/renal involvement 1 arrhythmia 14 fatigue 11 infections 2 nausea 3 rigor 2 serum sickness/hypersensitivity reactions
^a Participants with limited or diffuse systemic sclerosis, with mRSS reported at baseline and follow‑up ^b The nested case-control analysis was undertaken in the subgroup of participants with mRSS ≥16/51 ^c This is within or above the range considered to include the minimum clinically important change in mRSS (3 to 7.5) ^d The numbers of participants in the analyses for individual adverse effects varied between 48 and 56: the reason for this is unclear
Abbreviations: IQR, inter quartile range; mRSS, modified Rodnan skin score; SEM, standard error of mean

	Rituximab	Analysis
n=20	n=20
Primary outcome
Mean changes (±SD) in mRSS from baseline to last available follow‑up	Baseline 22.3 (±9.5) 6 months 14.4 (±8.4) Difference −7.9^a Median improvement 30.9% (11.1% to 69.2%) 12 months 11.2 (±7.5) Difference −11.1^a 24 months 10.0 (±6.9) Difference −12.3^a 36 months 8.1 (±5.2) Difference −14.2^a 48 months 9.8 (±7.2) Difference −12.5^a Final follow-up^b 10.8 (±7.2) Difference −11.5^a	Statistically significant improvement from baseline at all time points (all p<0.0001 except 6 months, p=0.001)
Selected secondary outcomes
Mean changes (±SD) in HAQ‑DI from baseline to last available follow‑up	Baseline 1.2 (±0.8) 6 months 0.7 (±0.8) Difference −0.5^c 12 months 0.6 (±0.7) Difference −0.6^c Final follow-up^b 0.6 (±0.9) Difference −0.6^c	Statistically significant improvement from baseline at all time points (all p<0.0001)
Mean changes (±SD) in EScSG disease activity index from baseline to last available follow‑up	Baseline 5.8 (±1.7) 6 months 1.6 (±1.0) Difference −4.2 12 months 1.5 (±1.0) Difference −4.3 Final follow-up^b 1.8 (±1.7) Difference −4.0	Statistically significant improvement from baseline at all time points (all p<0.0001)
Mean changes (±SD) in EScSG disease severity index from baseline to last available follow‑up	Baseline 10.9 (±3.0) 6 months 8.0 (±3.0) Difference −2.9 12 months 7.7 (±3.0) Difference −3.2 Final follow-up^b 7.5 (±3.2) Difference −3.4	Statistically significant improvement from baseline at all time points (all p<0.0001)
Safety and tolerability outcomes
n=20
Number of deaths	1 heart failure and 1 arrhythmia (probably unrelated to study medication)
Number of serious adverse events	1 breast cancer (thought to be unrelated to study medication) and 1 herpes zoster infection
Adverse events reported	2 ulcer infections 3 URTIs
^a This is within or above the range considered to include the minimum clinically important change in mRSS (3 to 7.5) ^b Final follow-up for each participant; mean follow-up 48.5 months ^c This is above the range considered to include the minimum clinically important change in HAQ‑DI (0.2 to 0.25)
Abbreviations: EScSG, European Scleroderma Study Group (disease activity and severity indices); HAQ‑DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score; SD, standard deviation; URTI, upper respiratory tract infection

	Rituximab	Analysis
n=15	n=15
Primary outcome
Mean changes (±95% CI) in mRSS^a from baseline to 12 months	Baseline 20.6 (±4.4) 6 months 20.2 (±5.5) Difference −0.4 (p=0.82) 12 months 21.1 (±5.2) Difference +0.5 (p=0.83)	No statistically significant changes from baseline at 6 or 12 months (p=0.82 and p=0.83)
Selected secondary outcomes
Mean changes (±95% CI) in HAQ‑DI^b from baseline to 12 months	Baseline 0.67 (±0.32) 6 months 0.64 (±0.36) Difference −0.03 12 months 0.55 (±0.33) Difference −0.12	No statistical analysis
Safety and tolerability outcomes
n=15
Number of serious adverse events	1 prostate cancer (thought to be unrelated to study medication)
Adverse events reported	7 infusion reactions 2 mild hypotension 1 each of flushing, fatigue, nausea and abdominal cramping, rigors and hand tingling 1 UTI 1 dental abscess
^a The minimum clinically important change in mRSS is considered to range from 3 to 7.5 ^b The range considered to include the minimum clinically important change in HAQ‑DI is 0.2 to 0.25
Abbreviations: CI, confidence interval; HAQ‑DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score; UTI, urinary tract infection

	Rituximab	Analysis
n=14	n=14 ^a
Primary outcome
Mean changes (±SD) in EScSG disease activity index from baseline to last available follow‑up	Baseline 4.3 (±1.8) 3 months 2.0 (±1.4) Difference −2.3 6 months 1.1 (±0.7) Difference −3.2 12 months 0.7 (±0.8) Difference −3.6 (95% CI −4.9 to −2.4)	Statistically significant improvement from baseline at all time points (all p<0.001)
Selected secondary outcomes
Mean changes (±SD) in mRSS from baseline to 12 months	Baseline 24.8 (±4.4) 3 months 18.9 (±6.3) Difference −5.9^b 6 months 14.1 (±4.2) Difference −10.7^b 12 months 10.4 (±3.1) Difference −14.4^b (95% CI −17.3 to −11.6)	Statistically significant improvement from baseline at all time points (all p<0.001)
Safety and tolerability outcomes
n=14
Number of deaths	1 sepsis (probably unrelated to study medication)
Number of serious adverse events	1 CABG, 1 non-infectious subfebrility and 1 renal crisis (all probably unrelated to study medication)
^a The 3‑ and 6‑month analyses include only 13 participants because 1 participant died ^b This is within or above the range considered to include the minimum clinically important change in mRSS (3 to 7.5)
Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; EScSG, European Scleroderma Study Group (disease activity and severity indices); mRSS, modified Rodnan skin score; SD, standard deviation