| Status: Supported for use via the One Wales Medicines process | |
Using the agreed starting and stopping criteria, rituximab can be made available within NHS Wales for the second-line treatment of pemphigus (excluding pemphigus vulgaris) and fourth-line treatment of pemphigoid disease in adults and children whose disease has not responded to previous treatments including steroids and steroid-sparing agents. Rituximab should be prescribed on the basis of lowest acquisition cost. The risks and benefits of the off-label use of rituximab for this indication should be clearly stated and discussed with the patient to allow informed consent. At the latest review of this recommendation in July 2023, the decision by the One Wales Medicines Assessment Group was to retain the current advice with no changes required. This advice will be reviewed after three years or earlier if new evidence becomes available. |
Darllen yn Gymraeg / Read in English
Beth benderfynodd Grŵp Asesu Meddyginiaethau Cymru'n Un?
Gellir rhoi rituximab i drin clefyd pemphigoid a mathau o pemphigus pan nad yw triniaethau eraill, megis steroidau, wedi gweithio. Mae Grŵp Strategaeth Meddyginiaethau Cymru Gyfan (AWMSG) wedi argymell rituximab yn flaenorol i drin pemphigus vulgaris, y math mwyaf cyffredin o pemphigus; felly nid yw trin pemphigus vulgaris yn rhan o'r cyngor hwn gan Cymru'n Un. I weld argymhelliad AWMSG ewch i: awttc.nhs.wales/accessing-medicines/medicine-recommendations/rituximab-mabthera8/.
Mae pemphigus yn gyflwr prin, hirdymor sy'n achosi pothelli a briwiau ar y croen neu bilenni mwcaidd fel y geg neu'r organau cenhedlu. Mae pemphigoid yn anhwylder pothellu prin sy'n achosi darnau coch ar y croen, gyda phothelli ar y corff, dwylo, traed a'r geg.
Gellir rhoi rituximab i drin pemphigus pan nad yw un driniaeth arall wedi gweithio, a gellir ei roi i drin pemphigoid pan nad yw o leiaf 3 thriniaeth arall wedi gweithio.
Bydd rituximab ar gael i gleifion cymwys sydd wedi cofrestru gyda phractis meddyg teulu yng Nghymru, hyd yn oed os oes angen iddynt dderbyn eu triniaeth y tu allan i Gymru.
Mae rituximab wedi'i drwyddedu i drin pemphigus vulgaris a gellir rhoi rituximab i gleifion yng Nghymru â pemphigus vulgaris os ydyn nhw a'u meddyg yn credu ei bod yn driniaeth addas. Ond nid yw rituximab wedi'i drwyddedu i drin mathau eraill o pemphigus nac i drin pemphigoid, felly os caiff ei ddefnyddio i drin y cyflyrau hyn fe’i gelwir yn ddefnydd “all-drwydded”. Pan gaiff meddyginiaeth ei defnyddio yn “all-drwydded”, rhaid i'ch meddyg esbonio'n glir i chi y risgiau a'r manteision o gymryd y feddyginiaeth. Dylai eich meddyg roi gwybodaeth glir i chi, siarad â chi am eich opsiynau a gwrando'n ofalus ar eich barn a'ch pryderon. Darllenwch ein taflen wybodaeth i gleifion am ddefnydd di-drwydded ac all-drwydded o feddyginiaethau.
Mae Grŵp Asesu Meddyginiaethau Cymru'n Un ac AWTTC yn adolygu'r penderfyniad hwn yn rheolaidd i weld a oes unrhyw dystiolaeth newydd a allai effeithio ar y penderfyniad hwn.
I gael rhagor o wybodaeth am pemphigus a pemphigoid ewch i: Help with Pemphigus and Pemphigoid | PemFriendsUK (Saesneg yn unig)
What did the One Wales Medicines Assessment Group decide?
Rituximab can be given to treat pemphigoid disease and types of pemphigus when other treatments, such as steroids, have not worked. The All Wales Medicines Strategy Group (AWMSG) has previously recommended rituximab to treat pemphigus vulgaris, the most common type of pemphigus; so treating pemphigus vulgaris is not part of this One Wales advice. To view AWMSG’s recommendation visit: awttc.nhs.wales/accessing-medicines/medicine-recommendations/rituximab-mabthera8/.
Pemphigus is a rare, long-term condition that causes blisters and sores on the skin or mucous membranes such as the mouth or the genitals. Pemphigoid is a rare, blistering disorder that causes red skin patches with blisters on the body, hands, feet and mouth.
Rituximab can be given to treat pemphigus when one other treatment has not worked, and can be given to treat pemphigoid when at least 3 other treatments have not worked.
Rituximab will be available to eligible patients who are registered with a GP practice in Wales, even if they need to receive their treatment outside Wales.
Rituximab is licensed to treat pemphigus vulgaris and patients in Wales with pemphigus vulgaris can be given rituximab if they and their doctor think it is a suitable treatment. But rituximab is not licensed to treat other types of pemphigus or to treat pemphigoid, so using it to treat these conditions is called “off-label” use. When a medicine is used “off-label”, your doctor must clearly explain to you the risks and benefits of taking the medicine. Your doctor should give you clear information, talk with you about your options and listen carefully to your views and concerns. Read our patient information leaflet about unlicensed and off-label use of medicines.
The One Wales Medicines Assessment Group and AWTTC review this decision regularly to see if there is any new evidence that may affect this decision.
For more information on pemphigus and pemphigoid visit: Help with Pemphigus and Pemphigoid | PemFriendsUK
These criteria have been adapted from the NHS England Clinical Commissioning Policy document and the British Association of Dermatologists’ (BAD) guidelines for the management of pemphigus vulgaris1,2.
Starting criteria (pemphigus variants excluding vulgaris): Rituximab may be considered after treatment failure with systemic corticosteroids and topical care. Systemic corticosteroid treatment failure is defined as continued disease activity or failure to heal despite three weeks of prednisolone (1.5 mg/kg/day).
Starting criteria (pemphigoid): Rituximab is a fourth-line option alongside topical care and systemic corticosteroids. Systemic corticosteroids are a well‑established and effective treatment for pemphigoid and should be used as first‑line therapy, alongside topical care. In the event of corticosteroid treatment failure (defined as above), addition of a steroid-sparing immunosuppressant, either azathioprine or mycophenolate mofetil, may be considered as second line treatment, switching to the alternate as third-line treatment.
Patients who satisfy the eligibility criteria will be prescribed rituximab following consultation with the patient and/or carer taking into account potential adverse effects, cautions and contraindications. This is particularly relevant when considering the use of rituximab in frailer elderly patients and its side effects profile. This consultation should be recorded in the patient’s notes.
Rituximab must only be used for treatment in specialised centres, or in collaboration with a specialised centre under the supervision of an expert multidisciplinary team.
The recommended rituximab treatment dose regimen for adults with variants of pemphigus or with pemphigoid is 1,000 mg rituximab followed by a second 1,000 mg dose two weeks later administered by intravenous infusion. Repeat courses may be given at up to six monthly intervals.
Continuing and stopping criteria: Stopping criteria are based on the literature which suggests that it can take up to six months (but more often one to three months) for rituximab to induce complete remission, broadly defined as the absence of new blisters and healing of the majority (> 75%) of lesions (skin and mucosal) for at least two months, with continued remission. If disease control is achieved, further cycles of rituximab should not be given.
Relapse following a period of response to rituximab: Benefit from a single cycle of rituximab may last 9–18 months or more. A second cycle may be considered in the case of relapse.
Treatment failure: Treatment failure is defined as continued disease activity or failure to heal, measured up to six months after a cycle of rituximab. Subsequent treatment options may be considered by the team, both in the event of rituximab failing to achieve disease control and also based on assessment of individual patient need.
References:
Health boards will take responsibility for implementing One Wales Medicines Assessment Group decisions and ensuring that a process is in place for monitoring clinical outcomes.
This report was prepared by the All Wales Therapeutics and Toxicology Centre in July 2023. It summarises any new evidence available since the last review in May 2022 and patient outcome data collected in the last 12 months.
Background: Pemphigus is a group of rare autoimmune conditions in which painful, fragile blisters occur on the skin and mucous membranes. Types of pemphigus include pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. Bullous pemphigoid (BP) is a similar blistering skin disease that tends to affect older people. An NHS England Clinical Commissioning Policy recommends rituximab for use in adults and children as an option to treat pemphigus or pemphigoid that has not responded to steroids and steroid‑sparing agents. Based on unmet need to treat this cohort of patient’s rituximab was considered suitable for assessment through the One Wales process.
Current One Wales decision: Supported
Licence status: Off-label use for this licensed medicine.
Rituximab is licensed for treatment of pemphigus vulgaris, and is approved in Wales on recommendation of the All Wales Medicines Strategy Group (AWMSG 1622, September 2022). The off-label indication under consideration is for the treatment of all forms of pemphigoid and pemphigus disease, except for the licensed and AWMSG-approved, indication of pemphigus vulgaris.
Guidelines: There have been no relevant updates to existing guidelines identified.
Licensed alternative medicines or Health Technology Assessment advice for alternative medicines: No new medicines or HTA advice reported.
Effectiveness: A repeat literature search conducted by AWTTC identified three papers which analysed the clinical effectiveness of rituximab pertinent to the recommendation (see Appendix). These included two quality of life studies and one retrospective efficacy study.
Aryanian et al (2023) conducted a single centre cross-sectional study including 96 pemphigus patients (12 with pemphigus foliaceus) who received rituximab either 3 months (3M group) prior or within the previous two weeks (R group) of enrolment. The objective of the study was to evaluate the effect of rituximab on health-related quality of life (HRQoL) in pemphigus patients and assess the clinical relevance of the patient-reported outcomes. Generally, the 36-Item Short Form Survey (SF-36) scores were improved with rituximab treatment in all dimensions except for mental health, though these differences were not statistically significant. The mean Dermatology Life Quality Index (DLQI) in the 3M group was significantly lower than the R group (6.96 versus 12.31), (p = 0.005) and demonstrated a clinically meaningful improvement in Quality of Life (QoL) for patients in the 3M group. However, this score indicated only a moderate effect on HRQoL which might suggest that the short duration of treatment in the 3M group was a limitation of this study. The patient general assessment (PGA) scores indicated that patients in the 3M group were significantly more likely to report less severe disease versus the R group (p = 0.008). Patients on lower-dose prednisolone had higher QoL measures, suggesting some quality benefit of being able to lower the corticosteroid dose. However, patients were assessed at only one time point, there was no blinding of treatment and the effect of adverse events on QoL was not considered. Results are also not broken down by pemphigus type.
Rashid et al (2022) conducted a single centre observational study which investigated the impact of rituximab on the general and treatment-specific QoL in pemphigus. The study included 47 patients, 18 (38.3%) of which with pemphigus foliaceus, treated with rituximab. Patient reported outcome measurements were collected using DLQI, visual analog scale in pain, Hospital Anxiety and Depression Scale (HADS), and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL). Rashid et al reported that an improvement in DLQI and TABQOL was observed after 6 and 12 months and suggest that this demonstrates the short-term and long-term effects of the first 2 infusions. They observed a decline in the anxiety scores during treatment stating this may contribute to the positive effect of rituximab treatment. Although no improvement in depression was observed, Rashid et al considers that this may be explained by long‑term non-disease-related factors and disease burden. The authors note that a limitation of this study is the absence of the assessment of patient-reported outcome measurements in patients with pemphigus treated with other systemic therapies. Similar to the Aryanian et al study there was no blinding of treatment and results are not broken down by pemphigus type.
The retrospective single centre study by Bohelay et al (2022) assessed efficacy of rituximab treatment in refractory and severe mucous membrane pemphigoid (MMP) in 109 patients with a median follow-up period of 51.4 months. The majority of patients were refractory to immunomodulatory drugs (82.6%) or immunosuppressant agents (66.1%). At baseline 78.0% were receiving an immunomodulator, 4.6% systemic corticosteroids and 15.6% topical corticosteroids. Non-immunosuppressive treatments, such as dapsone and/or salazopyrine (67.9%), had failed in 80.7% of patients, and 66.1% had been administered one or more conventional immunosuppressants, notably cyclophosphamide (50.5%).
Disease control (DC) and clinical response (CR) was achieved in the majority of cases after two cycles of rituximab. These results are similar to efficacy values obtained with rituximab in other autoimmune bullous diseases such as pemphigus. The cumulative proportion of CR (85.3%) was higher than that reported in the systematic review by Lytvyn et al (70.5%), included in the last evidence review in 2022, whereas the proportion of non-responders was similar (5.4%). Fewer patients had been treated with systemic corticosteroids in this study (11.0%) in comparison with the pooled population from the systematic review (25.1%), however, the proportion of patients receiving immunomodulatory drugs was much higher (78.0% versus 15.1%) so the use of concomitant immunomodulatory drugs might have contributed to the difference in CR between this study and the previous review.
Safety: No relevant safety analyses were identified in the repeat literature search.
Cost-effectiveness: No relevant cost-effectiveness analyses were identified in the repeat literature search.
Budget impact: There were no patients treated in Cardiff and Vale University Health Board in the past 12 months. No information on patient numbers has been provided for the other regions.
Impact on health and social care services: Minimal.
Patient outcome data: No patient outcome data have been received.
Evaluation of evidence: No significant new evidence has been published that challenges the previous evidence presented. AWTTC recommends to continue access to rituximab in NHS Wales to treat pemphigoid disease and to treat pemphigus (except pemphigus vulgaris).
Next review date: July 2026
References: a full reference list is available on request.
Appendix
|
Reference: Aryanian et al (2023) Study details: A cross-sectional study including 96 pemphigus patients (12 with pemphigus foliaceus) who received rituximab either 3 months (3M group) prior or within the previous two weeks (R group) of enrolment. Of 96 patients whose data were included, 55 (57.29%) patients had received rituximab 3 months earlier and 41 (42.71%) in the last 2 weeks. Main results: The SF-36 scores were improved with rituximab treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group versus 53.04 in the R group; p = 0.009). Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively. PGA indicating mild disease was reported in 9 patients in the R group and 23 patients in the 3M group (p = 0.008). |
|
Reference: Rashid et al (2022) Study details: A single-centre, observational study of 47 patients, 18 (38.3%) with pemphigus foliaceus, who were treated with rituximab and had previously failed conventional immunosuppressive therapies. Patients received rituximab 1,000 mg two weeks apart, followed by 500 mg at Months 6 and 12. Main results: During treatment, DQLI and TABQOL score decreased by 100% and 36.4% respectively in the first 6 months; and scores decreased by 100% and 45.4% respectively from Month 0 to 12. HADS depression showed no significant decrease during the rituximab treatment (p = 0.378). Visual analog scale pain decreased among Months 0, Months 0.5, Months 6, and Months 12 (p = 0.018), in particular between Months 6 and Months 12 (-58.1%, n = 34, p = 0.028) and between Months 0 and Months 12 (-60.6%, n = 31, p = 0.043). |
|
Reference: Bohelay et al (2022) Study details: A retrospective single centre study including 109 patients with MMP were treated at a referral hospital in France with two rituximab injections (1000 mg, 2 weeks apart), repeated every 6 months until CR or failure, with a unique consolidation injection (1000 mg) after CR. There was a median follow-up period of 51.4 months. Main results: Patients with MMP received a median of four cycles of rituximab corresponding to six rituximab infusions. Time to DC or complete response CR were determined with Kaplan-Meier survival curves and reported as survival times. Ninety-seven patients (89%) achieved DC with a median survival time of 7.1 months after a median of one rituximab cycle. Ninety-three patients (85.3%) achieved CR with a median survival time of 12.2 months after a median of two rituximab cycles. During the follow-up, 64 of the 109 patients (58.7%) achieved CR off rituximab, which lasted for a median time of 24.9 months. CR off rituximab with only minimum doses of immunomodulatory drugs was achieved in 22.0% of patients. Relapse occurred in 38.7% of cases, of whom 91.7% had achieved CR again at the last follow-up. Twenty-nine patients (26.6%) did not achieve CR off rituximab at the last follow-up and were still in CR on rituximab. At the last follow-up 97.2% of patients were receiving immunomodulatory concomitant therapies, notably dapsone or sulfasalazine (90.8%). During follow-up, 51 of the 109 patients (46.8%) had biological or clinical adverse events, of whom 23 patients (21.1%) had severe adverse events. One patient developed severe neutropenia that led to rituximab cessation after the first cycle. Seven patients (6.4%) with a median age of 79.9 years died during the follow-up. Deaths occurred at a median time of 13.2 months after the last rituximab infusion. Three deaths were not considered as related to rituximab. Four deaths (3.7%) were possibly related to rituximab (one from stage IV breast adenocarcinoma, one with severe bacterial pneumonia complicating an MMP-related tracheal stenosis, and two from unknown causes). |
| CR: clinical response; DC: disease control; DLQI: dermatology life quality index; HADS: hospital anxiety and depression scale; HRQoL: health-related quality of life; MMP: mucous membrane pemphigoid; PGA: patient general assessment; QoL: quality of life; SF-36: 36-Item Short Form Survey; TABQOL: treatment of autoimmune bullous disease quality of life |
Disclaimer: This document includes evidence published since the last review or full assessment of this medicine for the indication under consideration. It does not replace the original full evidence status report. Any previous reviews and the original full evidence status report are available from this webpage in the section '
Care has been taken to ensure the information is accurate and complete at the time of publication. However, the All Wales Therapeutics and Toxicology Centre (AWTTC) do not make any guarantees to that effect. The information in this document is subject to review and may be updated or withdrawn at any time. AWTTC accept no liability in association with the use of its content. An Equality and Health Impact Assessment (EHIA) has been completed in relation to the One Wales policy and this found there to be a positive impact. Key actions have been identified and these can be found in the One Wales Policy EHIA document.
Information presented in this document can be reproduced using the following citation: All Wales Therapeutics & Toxicology Centre. Rituximab for the treatment of pemphigus (excluding pemphigus vulgaris) and pemphigoid disease in adults and children (OW10). 2023
Copyright AWTTC 2023. All rights reserved.
Medicine details |
|
| Medicine name | rituximab |
| One Wales decision status | Supported for use via the One Wales Medicines process |
| Reference number | OW10 |
| Decision issue date | July 2017 |
| Date of last review | July 2023 |
| Review schedule | Every 3 years |