Rituximab in pemphigus vulgaris - Standard operating procedure

Advantages

1. Rituximab at spaced intervals can sufficiently control the disease activity in pemphigus and can substitute the prolonged and daily treatment with other immunosuppressants^[1,6]

2. Following an initial period of combination treatment with systemic steroids, rituximab permits a faster tapering and withdrawal of the former. This in turn helps to avoid the side effects of long-term treatment with corticosteroids^[1]

3. Rituximab may help to avoid other steroid-sparing agents that may be required daily on a long-term basis^[2]

4. As per the existing evidence, there is an 80% chance of achieving drug-free remission in 2 years.^[1]

Disadvantages

1. Possibility of severe immunosuppression and infections^[7-10]

2. High cost compared to corticosteroids and most of the other steroid-sparing drugs

3. The need for immunization against various infectious agents^[10]

4. Pre-treatment evaluation requiring expensive investigations

5. A comparatively limited period of experience with the drug.

Rituximab can be the therapeutic option in the following scenarios:

1. Those who failed to respond adequately to conventional treatment modalities^[2]

2. Any significant contraindication for the use of systemic corticosteroids or other immunosuppressants^[2,11]

3. Severe adverse effects requiring discontinuation of corticosteroids or other immunosuppressants^[12]

4. Relapsing pemphigus, even at high doses of steroid^[13]

5. As first line, in severe disease (along with systemic corticosteroids with or without other immunosuppressants).^[1,2,14]

Contraindications

1. Known hypersensitivity to rituximab or other murine proteins^[11]

2. Active severe infection^[15]

3. HIV with CD4 <250 cells/mm^3[15]

4. Severe heart failure^[7,11]

5. History of bronchospasm, hypotension, and angioedema^[16]

6. Pregnancy (FDA category C)^[3,5,10,17]

7. Lactation.^[3,5,10,17]

Pregnant woman should be warned regarding the risks to the fetus. Women with childbearing potential should use effective contraception during treatment and continue the same for at least 12 months after the last dose.^[10]

The unknown risks to the infant from oral ingestion of rituximab should be weighed against the known benefits of breastfeeding. The existing evidence shows that the transmission of rituximab through breast milk to infant is very small, and guidelines do suggest normal immunization schedule for infants exposed to rituximab early in life.^[17,18] However, it is advised to regularly update with evolving evidence and guidelines in this area.

Dosing and interval

One gram on day 1 and 14 and then 500 mg at month 12 and every 6 months thereafter or based on clinical evaluation.^[18]

Preparation of the infusion

• 2 vials would provide 1 g/100 ml

• It is to be mixed with 400 ml of normal saline (after letting out 100 ml from the 500 ml bottle).

Infusion rate

Total quantity to be infused = 500 ml first infusion is started at a rate of 50 mg/h. If there is no evidence of infusion toxicity, infusion rate is incremented by 50 mg/h every 30 min to a maximum of 400 mg/h.^[18]

Infusion pump can improve the ease and accuracy of administration.

• 30 ml/h for 30 min (15 ml)

• 60 ml/h for next 30 min (30 ml)

• 90 ml/h till infusion is over (455 ml in 5 h)

• Total infusion period for the first infusion - 6 h.^[20]

Recommended total infusion time is 5–6 h for the first infusion

Subsequent infusions are administered at a rate of 100 mg/h, and in the absence of infusion reaction, the rate can be increased at 30 min interval by 100 mg/h to a maximum of 400 mg/h.^[18] These infusions will take 2–3 h.

Patient monitoring during infusion

• Check pulse, BP, and respiratory rate and do pulse oximetry every 30 min^[3]

• Watch for infusion reactions (fever, rigors, nausea, vomiting, headache, hypotension, and abdominal pain)^[23]

• On most occasions, infusion reactions can be managed by reducing the speed of infusion (half the flow rate and re-administer the premedication)^[11,23]

• Serious adverse effects such as angioedema and anaphylaxis require complete cessation of infusion^[19]

• Adequate hydration should be ensured immediately after infusion.

Follow-up

• Biweekly during the 1^st month, once a month till 6 months after the 4^th dose or complete withdrawal of steroids, whichever is later, once in 3 months for the next 1 year followed by once in 6 months for 1 year and once a year thereafter^[3]

• Complete hemogram every 3 months^[13]

• Repeat serology for antidesmoglein 1 and 3 antibodies at month 6, 12, and 24 and when there is clinical evidence of relapse^[3]

Treatment of relapse

European academy of dermatology and venereology (EADV) guideline suggests that a relapse that occurs during the tapering of systemic corticosteroid between month 0 and month 4 may be managed with increasing the dose of the latter. It is recommended to administer an additional cycle of 2 g of rituximab (1 g, 2 weeks apart), if the relapse occurs during the tapering of the systemic corticosteroid between month 4 and 6. In that case, the maintenance infusion of rituximab scheduled for 6^th month will be avoided. No standard guidelines are available for the management of relapse that occurs after the withdrawal of the steroids and after the maintenance infusion of rituximab at month 6; hence, we recommend that a case-by-case approach may be adopted and systemic steroids may be resumed.^[3]