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

Study reference	Daoussis D, Liossis SC, Tsamandas AC et al. (2010) Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology 49: 271–80 Daoussis D, Liossis SC, Tsamandas AC et al. (2012) Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clinical and Experimental Rheumatology 30 (Suppl 71): S17–22
Unique identifier	Not reported
Study type	Open-label RCT and 1‑year non-comparative follow-up study
Aim of the study	To investigate the efficacy of rituximab for systemic sclerosis
Study dates	Not reported
Setting	A single centre in Greece
Number of participants	14 participants
Population	People with systemic sclerosis (mean duration 7–8 years). All had diffuse disease
Inclusion criteria	Participants fulfilled the ACR classification criteria for systemic sclerosis. All had ILD and had been on stable treatment in the 12 months before enrolment
Exclusion criteria	Not reported
Intervention(s)	Participants born on an even-numbered date (n=8, median age 53 years, mean mRSS 13.5) received of rituximab 375 mg/m² weekly for 4 weeks at baseline and 6 months in addition to their usual treatment^a
Comparator(s)	Participants born on an odd-numbered date (n=6, median age 56 years, mean mRSS 11.5) received their usual treatment only^a
Length of follow-up	All participants were followed up for 1 year The 8 participants who received rituximab subsequently received a further 2 cycles of rituximab (at 12 months and 18 months) and were followed for a second year in an uncontrolled follow-up study
Outcomes	Primary outcomes: Changes in lung function tests Changes in mRSS
	Secondary outcomes: Changes in skin histology Changes on lung imaging Changes in functional impairment using the 20‑item HAQ‑DI
	Safety outcomes: Adverse effects
Source of funding	The Hellenic Rheumatology Society. Also, Roche Hellas paid the open access publication charges
Overall risk of bias/quality assessment (CASP RCT checklist)	Did the trial address a clearly focused issue?	Yes
	Was the assignment of participants to treatments randomised?	Yes^b
	Were participants, health workers and study personnel blinded?	No^c
	Were the groups similar at the start of the trial?	Yes^d
	Aside from the experimental intervention, were the groups treated equally?	Yes
	Were all of the participants who entered the trial properly accounted for at its conclusion?	Yes
	How large was the treatment effect?	See table 10
	How precise was the estimate of the treatment effect?	See table 10
	Can the results be applied in your context? (or to the local population)	Yes
	Were all clinically important outcomes considered?	Yes
	Are the benefits worth the harms and costs?	See key points
Study limitations	The study included only 14 participants and was not sufficiently powered to reliably detect any differences between the groups The participants in the study were heterogeneous in terms of disease duration, severity and previous treatments Skin thickening often improves during the natural course of scleroderma The participants had longstanding disease and had previously received a variety of immunosuppressants. They were receiving concomitant immunosuppressants and it cannot be excluded that these contributed to any improvement in symptoms
Comments	^a Generally prednisolone and/or other immunosuppressants. No changes in medication were allowed during the study ^b Participants were randomised to treatment; however, the simple method of randomisation used led to unequal numbers in the groups. Allocation concealment was not reported and may not have been adequate ^c The study was open-label. Assessment of mRSS and lung imaging was blinded ^d The method of randomisation may have led to imbalances in between the groups that could affect response to treatment; however, no significant differences were seen in the baseline characteristics that were reported (including mRSS: 13.5 in the rituximab group compared with 11.5 in the placebo group)
Abbreviations	ACR, American College of Rheumatology; HAQ‑DI, Health Assessment Questionnaire Disability Index; ILD, interstitial lung disease; mRSS, modified Rodnan skin score; RCT, randomised controlled trial

Study reference	Daoussis D, Melissaropoulos K, Sakellaropoulos G et al. (2016) A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Seminars in Arthritis and Rheumatism
Unique identifier	Not reported
Study type	Open-label non-randomised comparative study
Aim of the study	To assess the long-term efficacy and safety of rituximab in ILD associated with systemic sclerosis compared with conventional treatment
Study dates	Not reported
Setting	4 centres in Greece
Number of participants	51 participants
Population	People with ILD associated with systemic sclerosis. 86% had diffuse disease
Inclusion criteria	Participants fulfilled the ACR classification criteria for systemic sclerosis. All had ILD (according to imaging, lung function tests or both) and had been on stable treatment in the 12 months before enrolment
Exclusion criteria	Not reported
Intervention(s)	33 participants (mean age 54 years, mean disease duration 5.7 years, mean mRSS 14.7) chose to receive rituximab 375 mg/m² weekly for 4 weeks at baseline, repeated 6 monthly for at least 2 cycles (with or without conventional treatment^a) 19 participants received at least 4 cycles of rituximab and completed a 2‑year follow‑up
Comparator(s)	18 participants (mean age 52 years, mean disease duration 2.6 years, mean mRSS 17.8) declined rituximab and received conventional treatment only^a
Length of follow-up	Maximum follow-up was 7 years. Median follow-up was 4 years
Outcomes	Primary outcomes: Changes in lung function tests Changes in mRSS
Outcomes	Safety outcomes: Adverse effects
Source of funding	Partially funded by a 'Karathodori' grant
Overall risk of bias/quality assessment (CASP RCT checklist)	Did the trial address a clearly focused issue?	Yes
	Was the assignment of participants to treatments randomised?	No
	Were participants, health workers and study personnel blinded?	No^b
	Were the groups similar at the start of the trial?	No^c
	Aside from the experimental intervention, were the groups treated equally?	Yes
	Were all of the participants who entered the trial properly accounted for at its conclusion?	Yes
	How large was the treatment effect?	See table 11
	How precise was the estimate of the treatment effect?	See table 11
	Can the results be applied in your context? (or to the local population)	Yes
	Were all clinically important outcomes considered?	Yes
	Are the benefits worth the harms and costs?	See key points
Study limitations	The study was not designed to reliably detect any differences between the groups The treatment and control groups were heterogeneous in terms of disease duration Participants were receiving concomitant immunosuppressants and it cannot be excluded that these contributed to any improvement in symptoms
Comments	^a Prednisolone and/or other immunosuppressants ^b The study was open-label. It is not reported whether outcome assessors were blind or not, but this is probably unlikely ^c Baseline characteristics were usually similar between the groups, but disease duration was statistically significantly shorter in the control group (2.6 years compared with 5.7 years in the rituximab group, p=0.012). It is unclear how this difference might affect the results. The difference in baseline mRSS between the groups was 3, although this was not statistically significant
Abbreviations	ACR, American College of Rheumatology; FVC, forced vital capacity; ILD, interstitial lung disease; mRSS, modified Rodnan skin score

Study reference	Jordan S, Distler JHW, Maurer B et al. (2015) Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Annals of the Rheumatic Diseases 74: 1188–94
Unique identifier	Not reported
Study type	A prospective observational study including a retrospective nested case-control study
Aim of the study	To analyse the effects of rituximab on skin and lung fibrosis and safety in people in the EUSTAR cohort
Study dates	Not reported
Setting	42 centres in Europe
Number of participants	63 participants (mean age 51 years) treated with rituximab 25 participants with severe diffuse systemic sclerosis (mRSS ≥16/51) were matched with controls
Population	People with systemic sclerosis (median duration 6 years, 35/63 with diffuse disease, average mRSS 18.1) who were prospectively included in the EUSTAR database and treated with rituximab at the discretion of their doctor
Inclusion criteria	Inclusion criteria were fulfilment of ACR classification criteria for systemic sclerosis, treatment with rituximab, and at least 1 follow‑up
Exclusion criteria	People were excluded if they had autologous stem cell transplantation between baseline and follow‑up
Intervention(s)	47 participants received 2 infusions of rituximab 1,000 mg 2 weeks apart 13 participants received 1 infusion of rituximab 1,000 mg 3 participants received other dosage regimens 31 participants also received concomitant methylprednisolone 100 mg with rituximab 41 participants also received conventional treatment with 1 or more immunosuppressants (including prednisolone) or colchicine
Comparator(s)	The control group included people in the EUSTAR database with systemic sclerosis (according to the same criteria) who were not treated with rituximab, and had at least 1 follow‑up Matching criteria included mRSS, FVC, follow-up duration, scleroderma subtype, disease duration and concomitant immunosuppressant treatment
Length of follow-up	Data were collected over a 6‑month period. Median follow up was 7 months (IQR 4 to 9 months)
Outcomes	Primary outcome: difference between the groups in change in mRSS from baseline to follow-up in the nested case-control cohort
	Secondary outcomes: difference between the groups in change in FVC from baseline to follow-up in participants with evidence of ILD changes from baseline in mRSS in the whole cohort and in participants with diffuse disease
	Safety outcomes: Adverse effects
Source of funding	None
Overall risk of bias/quality assessment (CASP case-control study checklist)	Did the study address a clearly focused issue?	Yes
	Did the authors use an appropriate method to answer their question?	Yes^a
	Were the cases recruited in an acceptable way?	Yes^b
	Were the controls selected in an acceptable way?	Yes
	Was the exposure accurately measured to minimise bias?	Unclear^c
	What confounding factors have the authors accounted for?	See comments^d
	Have the authors taken account of the potential confounding factors in the design and/or in their analysis?	Yes
	What are the results of this study?	See table 12
	How precise are the results? (How precise is the estimate of risk?)	See table 12
	Do you believe the results?	Yes
	Can the results be applied to the local population?	Yes
	Do the results of this study fit with other available evidence?	Yes
Study limitations	Observational studies are prone to bias, confounding and other methodological problems, and can only show association, not causation The nested analysis included a relatively small number of participants and it is unclear if it was sufficiently powered It is unclear whether all potential confounders were considered There may be differences in rating of mRSS across investigators and centres Most data were collected prospectively, but some were collected retrospectively, which could lead to recall bias Skin thickening often improves during the natural course of scleroderma Many participants received concomitant treatment with methylprednisolone, which may have affected symptoms. Similarly, most also received other immunosuppressants
Comments	^a An RCT would have been preferable; however, a nested case-control study is a suitable option to test a hypothesis in a rare condition ^b As is usual for this type of study, there may be selection bias because doctors chose which participants were treated with rituximab ^c EUSTAR investigators are trained to assess mRSS, and consistent and appropriate outcomes are recorded across the EUSTAR cohort; however, investigators were not blinded ^d The cases and controls in the nested analysis were matched for potential confounders relating to severity and duration of disease, and concomitant treatment. Baseline characteristics were generally similar between the groups, although there was a statistically significant difference in baseline mRSS between the groups in the nested case-control analysis (rituximab 26.6 compared with control 25.0, p=0.03)
Abbreviations: ACR, American College of Rheumatology; EUSTAR, European Scleroderma Trial and Research; FVC, forced vital capacity; ILD, interstitial lung disease; IQR, inter quartile range; mRSS, modified Rodnan skin score; RCT, randomised controlled trial

Study reference	Bosello SL, De Luca G, Rucco M et al. (2015) Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Seminars in Arthritis and Rheumatism 44: 428–36
Unique identifier	Not reported
Study type	Open-label, prospective non-comparative study
Aim of the study	To evaluate the safety and efficacy of long-term rituximab in people with diffuse systemic sclerosis
Study dates	Not reported
Setting	A single centre in Italy
Number of participants	20 participants (mean age 23 years)
Population	People with progressive, diffuse systemic sclerosis (mean duration 30 months, mean mRSS 22.3)^a
Inclusion criteria	Participants fulfilled the ACR classification criteria for systemic sclerosis
Exclusion criteria	Exclusion criteria were rest dyspnoea or signs and symptoms of heart failure, infections, immunodeficiency or a history of tuberculosis contact, or cancer
Intervention(s)	All participants received 2 infusions of rituximab 1,000 mg 2 weeks apart. Methylprednisolone 100 mg was co-administered with each infusion^b. Only 1 participant also received a conventional immunosuppressant
Comparator(s)	None
Length of follow-up	Mean follow-up was 48.5 months
Outcomes	Primary outcomes: Changes in mRSS Changes in lung function tests and lung imaging
	Secondary outcomes: Changes in functional impairment using the HAQ‑DI Changes in EScSG disease activity and severity indices
	Safety outcomes: Adverse effects
Source of funding	The ASRALES Foundation and GILS
Overall risk of bias/quality assessment	Quality assessment checklist not completed. See evidence strengths and limitations for more information.
Study limitations	Observational study subject to bias and confounding Small number of participants No comparator No blinding of treatment or outcome assessment, although mRSS was assessed by 2 independent observers It is unclear if the EScSG indices have been validated
Comments	^a 13 participants (65%) had early disease (<3 years since Raynaud's phenomenon occurred). In 18 participants (80%), skin scores had worsened by >10% after cyclophosphamide treatment ^b During follow-up, 8 participants were retreated with further cycles of rituximab because skin scores worsened by >10% (n=4) or arthritis flares occurred (n=4)
Abbreviations	ACR, American College of Rheumatology; EScSG, European Scleroderma Study Group (disease activity and severity indices); HAQ‑DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score

Study reference	Lafyatis R, Kissin E, York M et al. (2009) B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis and Rheumatism 60: 578–83
Unique identifier	Not reported
Study type	Open-label, prospective non-comparative study
Aim of the study	To assess the efficacy of rituximab in diffuse cutaneous systemic sclerosis, examine potential mechanisms of action, and investigate supplementary outcome measures for trials in systemic sclerosis
Study dates	Not reported
Setting	A single centre in the USA
Number of participants	15 participants (mean age 46 years)
Population	People with early^a, diffuse cutaneous systemic sclerosis (mean duration 14.5 months, mean mRSS 20.6)
Inclusion criteria	Participants fulfilled the ACR classification criteria for systemic sclerosis
Exclusion criteria	People were usually excluded if they were receiving conventional immunosuppressants (including prednisolone 10 mg daily or more). However, 1 participant had methotrexate. Other exclusion criteria were FVC or diffusion capacity <50% of the predicted, significant cardiac arrhythmia or ejection fraction <40%
Intervention(s)	All participants received 2 infusions of rituximab 1,000 mg 2 weeks apart
Comparator(s)	None
Length of follow-up	Outcomes were assessed at 6 and 12 months
Outcomes	Primary outcome: Changes in mRSS
	Secondary outcomes: Changes in lung function tests and lung imaging Changes in functional impairment using the HAQ‑DI Changes in various pathological skin outcomes
	Safety outcomes: Adverse effects
Source of funding	Genentech and Biogen Idec, and NIH grants
Overall risk of bias/quality assessment	Quality assessment checklist not completed. See evidence strengths and limitations for more information.
Study limitations	Observational study subject to bias and confounding Small number of participants No comparator No blinding of treatment or outcome assessment, although mRSS was assessed by 2 trained doctors
Comments	^a Early disease was defined as non-Raynaud's phenomenon occurring with 18 months of trial entry
Abbreviations	ACR, American College of Rheumatology; FVC, forced vital capacity; HAQ‑DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score

Study reference	Melsens K, De Keyser F, Decuman S et al. (2016) Assessment of sensitivity to change of the European Scleroderma Study Group activity index. Clinical and Experimental Rheumatology 34 (Suppl 100): 148–51
Unique identifier	NCT00379431
Study type	Open-label, prospective non-comparative study
Aim of the study	To assess sensitivity to change of the EScSG disease activity index in people with early, severe diffuse cutaneous systemic sclerosis treated with rituximab
Study dates	Not reported
Setting	A single centre in Belgium
Number of participants	14 participants (median age 52 years)
Population	People with early^a, diffuse cutaneous systemic sclerosis (mean duration 10 months, mean mRSS 24.8)
Inclusion criteria	Participants fulfilled the ACR classification criteria for systemic sclerosis. Other inclusion criteria were age >18 years, early^a disease, mRSS ≥14, and EScSG activity score ≥3
Exclusion criteria	Exclusion criteria were FVC ≤ 50% of predicted, diffusion capacity ≤40% of the predicted value, left ventricular ejection fraction ≤40%, serious or uncontrolled co-existing diseases, infection, immunodeficiency and a history of cancer
Intervention(s)	All participants received 2 infusions of rituximab 1,000 mg 2 weeks apart, with methylprednisolone 100 mg Prednisolone ≤10mg/day was allowed. Other immunosuppressants were replaced with methotrexate 15 mg weekly (unless contraindicated)
Comparator(s)	None
Length of follow-up	Follow-up was 12 months
Outcomes	Primary outcome: Changes in EScSG disease activity index
	Secondary outcomes: Changes in mRSS Changes in lung function tests and echocardiography
	Safety outcomes: Adverse effects
Source of funding	Research Foundation, Flanders
Overall risk of bias/quality assessment	Quality assessment checklist not completed. See evidence strengths and limitations for more information.
Study limitations	Observational study subject to bias and confounding Small number of participants No comparator No blinding of treatment or outcome assessment It is unclear if the EScSG indices have been validated
Comments	^a Early disease was defined as disease duration ≤4 years since the occurrence of non-Raynaud's phenomenon
Abbreviations	ACR, American College of Rheumatology; EScSG, European Scleroderma Study Group (disease activity and severity indices); FVC, forced vital capacity; mRSS, modified Rodnan skin score