Key points

Advice

The content of this evidence summary was up-to-date in March 2017. See summaries of product characteristics (SPC), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Regulatory status: Rituximab (MabThera, Roche Products Limited) is a monoclonal antibody. Rituximab is licensed in adults for treating non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis. It is administered as an intravenous infusion. Rituximab is not licensed for treating systemic sclerosis (or localised scleroderma) and use for this indication is off‑label.

Overview

This evidence summary includes 7 studies that investigated rituximab (usually 375 mg/m² weekly for 4 weeks at 0 and 6 months, or 1,000 mg at 0 and 2 weeks) for treating skin involvement in systemic sclerosis (mainly diffuse). Most were open-label observational studies without a comparator. In 6 of the 7 studies, compared with baseline, statistically significant improvements were seen with rituximab at follow-ups of 6 months to 4 years in:

skin thickening (modified Rodnan skin scores [mRSS])
functional impairment (Health Assessment Questionnaire Disability Index [HAQ-DI] scores)
disease activity and severity (European Scleroderma Study Group [EScSG] index scores).

The improvements in skin thickening and functional impairment often reached the level considered to be the minimum clinically important amount. In the 2 studies that compared rituximab and usual care directly, rituximab was better than usual care at improving skin thickening, with a statistically significant difference between the groups at most time points. No statistically significant improvement in skin thickening was seen in the seventh study.

Although the studies included in this evidence summary suggest that rituximab may be effective for treating skin involvement in some people with diffuse systemic sclerosis, the evidence is of low quality and has many limitations, and it is difficult to draw any firm conclusions from it. The studies included small numbers of participants (total n=177) and most were open-label, observational studies without a comparator, making it difficult to determine whether any improvements seen with rituximab were related to the treatment or not. In the majority of the studies, there was no blinding of treatment or outcome assessment. Also, participants in many studies were receiving concomitant immunosuppressants and it cannot be excluded that these contributed to any improvement in symptoms. The study populations varied and it is unclear which people might benefit most from treatment, which dosage is optimal and how often treatment cycles need to be repeated.

The adverse effects seen in the studies reflect those listed in the SPC for rituximab. Several deaths and hospitalisations were reported with rituximab (and usual care): not all were considered related to the study medication.

Specialists involved in producing this evidence summary considered that rituximab should be used only for treating skin involvement in diffuse systemic sclerosis that is refractory to standard treatments, after all other options (such as autologous stem cell transplantation), have been explored, and taking into account the risk of serious adverse effects.

A summary to inform local decision-making is shown in table 1.

Table 1 Summary of the evidence on effectiveness, safety, patient factors and resource implications

Effectiveness

Statistically significant improvements in skin thickening (mRSS) from baseline were seen with rituximab in 5 studies (Daoussis et al. 2010, Daoussis et al. 2016, Jordan et al. 2015, Bosello et al. 2015 and Melsens et al. 2016) and 1 follow-up study (Daoussis et al. 2012) at follow-ups of 6 months to 4 years: no significant improvement was seen in the 7^th study (Lafyatis et al. 2009).
At follow-ups of 6 months to 4 years, in the 3 studies with a comparator, no statistically significant improvements in skin thickening from baseline were seen with usual care in Daoussis et al. (2010) or Jordan et al. (2015), but a significant improvement was seen with usual care in Daoussis et al. (2016).
Rituximab was statistically significantly better than usual care at improving skin thickening at 1, 2 and 3 years, but not at 4 years in Daoussis et al. (2016) and at 6 months in Jordan et al. (2015).
Daoussis et al. (2010) found a statistically significant improvement in functional impairment (HAQ‑DI) from baseline to 1 year with rituximab, but not with usual care. The improvement with rituximab continued at 2 years in Daoussis et al. (2012). Improvements were also found from baseline to 1–4 years with rituximab in Bosello et al. (2015), (statistically significant) and Lafyatis et al. (2009) (no statistical analysis).
Bosello et al. (2015) found statistically significant improvements in disease activity and severity (EScSG indices) from baseline to 4 years with rituximab, and Melsens et al. (2016) found a statistically significant improvement in disease activity from baseline to 12 months.

Safety

Noting that not all studies had a usual care group, 7 deaths occurred in people receiving rituximab, of which at least 2 were considered unrelated to study treatment, and 2 deaths occurred in people receiving usual care. Five people receiving rituximab were reportedly hospitalised, compared with 10 people receiving usual care, although the number is likely to be higher because only 2 studies provided this information.
Overall, the adverse effects seen in the studies reflect those listed in the SPC for rituximab. The most commonly reported adverse effects were respiratory tract, urinary tract and other infections, infusion-related reactions, fatigue, rigors and nausea.
Serious adverse events reported in 1 or 2 participants included hepatitis B virus reactivation, and cardiac and renal adverse events.

Patient factors

Rituximab is administered by intravenous infusion.
It is generally given in addition to other treatments for scleroderma, including other immunosuppressants.
Premedication with paracetamol, an antihistamine and methylprednisolone is required to reduce the risk of adverse effects.
Skin thickening may improve spontaneously, without treatment.

Resource implications

Rituximab 10 mg/ml concentrate for solution for intravenous infusion costs £349.25 for 2×10 ml vials and £873.15 for 1×50 ml vial (MIMS, January 2017).
A cycle of rituximab 375 mg/m² weekly for 4 weeks at 0 and 6 months costs £9,779.20 (for a dose of 700 mg) assuming body surface area is 1.86 m².
A cycle of rituximab 1,000 mg at 0 and 2 weeks costs £3,492.60.
These costs are for the medicine only and do not include VAT, any local procurement discounts or other costs incurred, such as dilution and administration or standard supportive therapy.