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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 5-12

Rituximab in dermatology: Revisited


Department of Dermatology, IQ City Medical College, Sovapur, Jemua, Durgapur, West Bengal, India

Date of Submission18-Feb-2019
Date of Decision27-Sep-2019
Date of Acceptance30-Sep-2019
Date of Web Publication23-Jun-2020

Correspondence Address:
Dr. Aditya Kumar Bubna
Department of Dermatology, IQ City Medical College, Sovapur, Bijra Road, Jemua, Durgapur - 713 206, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_9_19

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  Abstract 


Rituximab (RTX) is a specific mouse and human chimeric monoclonal antibody that has found to have numerous applications in dermatology. Though initially approved by the US FDA for treating rheumatoid arthritis and non-Hodgkin's lymphoma; currently its approval has extended to involve the pemphigus group of disorders; both as a first line drug as well as a therapeutic strategy for recalcitrant cases of pemphigus, unresponsive to conventional therapy. Apart from pemphigus, there have been a number of cutaneous disorders where rituximab has been found to be useful. This review will give a bird's eye view of the applications of rituximab in dermatology.

Keywords: Cutaneous lupus erythematosus, dermatomyositis, mucous membrane pemphigoid, pemphigus, rituximab


How to cite this article:
Bubna AK. Rituximab in dermatology: Revisited. Indian J Drugs Dermatol 2020;6:5-12

How to cite this URL:
Bubna AK. Rituximab in dermatology: Revisited. Indian J Drugs Dermatol [serial online] 2020 [cited 2020 Aug 5];6:5-12. Available from: http://www.ijdd.in/text.asp?2020/6/1/5/287443




  Introduction Top


Rituximab (RTX) is a specific mouse and human chimeric monoclonal antibody. It is an immunoglobulin G1 (IgG1) kappa monoclonal antibody composed of a murine variable region (Fab portion) that is fused onto a human constant region (Fc portion), which targets the CD20 antigen that is present on pre-B, immature, and mature B cells.


  Mechanism of Action Top


The Fab portion of RTX binds specifically to CD20 antigens on pre-B, immature, and mature B cells.



Once the binding occurs, the Fc portion of RTX recruits immune effector cells.



This leads to:

  • Complement-dependent CD20+ B cell lysis
  • Antibody-dependent cell-mediated cytotoxicity of CD20+ B cells
  • Apoptosis of CD20+ B cells.


CD20 is not expressed on pro-B cells, plasmablasts, and plasma cells; thus, the depletion of B cell subpopulation is transient and does not affect immunoglobulin synthesis. It has also been observed that regeneration of B cells occurs within 6–12 months following therapy and serum immunoglobulins do not have a significant reduction.[1],[2] This can account for relapse as B cells regenerate.


  Pharmacokinetics Top


RTX is administered as an intravenous (IV) infusion. Following the lymphoma protocol, RTX is detectable in the serum of patients even after 3–6 months of completion of therapy. The median terminal elimination half-life of RTX is 22 days (range, 6.1–52 days). No formal studies have been conducted to examine the effects of either hepatic or renal impairment on the pharmacokinetics of RTX.


  Indications Top
[3],[4]



Food and Drug Administration approved

  • Relapsing and refractory follicular lymphoma (non-Hodgkin's type)
  • Rheumatoid arthritis
  • Pemphigus group of disorders (U.S. Food and Drug Administration approval was obtained on June 2018).


Off-label

Autoimmune vesiculobullous disorders

  • Mucous membrane pemphigoid (MMP).


Connective tissue disorders

  • Dermatomyositis
  • Cutaneous lupus erythematosus (CLE)
  • Systemic sclerosis.


Vasculitis

  • Wegener's granulomatosis
  • Churg–Strauss syndrome
  • Microscopic polyangiitis.


Graft-versus-host disease

Atopic dermatitis


  Primary Cutaneous B Cell Lymphoma Top


Others:

  • Melanoma
  • Kimura's disease
  • Schnitzler's syndrome
  • Intravascular large B cell lymphoma.



  Contraindications Top


  • Hypersensitivity to the drug
  • Hypersensitivity to murine proteins
  • Severe heart failure
  • HIV infection with CD4 count <250/μl


Pregnancy prescribing status: Category “C.”


  Dermatologic Considerations Top


Dosage and administration of rituximab for the Food and Drug Administration-approved indications

  • Non-Hodgkin's lymphoma: RTX 375 mg/m2 is administered as an IV infusion once a week with four infusions over a month. It can be used either as monotherapy or combined with other chemotherapy regimens such as cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisone (CHOP regimen)
  • Rheumatoid arthritis: RTX 1 g is administered as an IV infusion. Two infusions, one on day 1 and the other on day 15, are given.[5],[6]


Rituximab in pemphigus

RTX was first used by Heizmann et al.[7] for paraneoplastic pemphigus with a successful outcome. Subsequently, RTX has been utilized by many dermatologists for the same.

Indications of RTX in pemphigus

  • Patients who have failed to respond adequately to conventional therapy
  • Patients in whom corticosteroids or other immune suppressives are contraindicated or are causing severe adverse reactions necessitating discontinuation of the drug
  • Patients who relapse after conventional therapy for pemphigus
  • Approved as first-line therapy in pemphigus.[8],[9],[10],[11],[12]


Treatment protocols followed in pemphigus

  • Lymphoma protocol: This is the most commonly followed protocol in pemphigus. Here, 375/m2 of RTX is administered per week for 4 weeks[13],[14]
  • Rheumatoid arthritis protocol: This protocol is being increasingly followed by most dermatologists. Two doses, 1 g each of RTX is administered at an interval of 15 days apart. This regimen is economical to the patient due to less number of infusions involved[10]
  • Combination therapy: RTX is combined with IVIG, dexamethasone pulse, or immunoadsorption.[15],[16] Rheumatoid arthritis protocol is followed here
  • Long-term therapy with regular infusions of RTX every 4 or 12 weeks following the induction phase of RTX infusion[9]
  • Low-dose RTX: Two doses of 500 mg each of RTX are administered at an interval of 15 days. This can be followed up with one injection of 500 mg once in 6 months or if there is a relapse.


Premedication

The patient is premedicated with:

  • Injection hydrocortisone 100 mg IV stat
  • Injection pheniramine maleate 22.75 mg IV stat
  • Tablet paracetamol 500 mg PO; 30 min prior to RTX infusion.


Rituximab infusion

First infusion is infused at 50 mg/h IV.



After 30 min, escalate the infusion speed by 50 mg/h.



Every 30 min, the infusion speed is increased to reach a maximum infusion rate of 400 mg/h.

The total infusion time is usually 5–6 h.

Subsequent infusions are administered at 100 mg/h, and increase the rate by 50 mg/h every 30 min till the maximum infusion rate of 400 mg/h is obtained.

It would be easier to administer as follows with an infusion pump:

  • 30 ml/h for half hour (15 ml)
  • 60 ml/h for half hour (30 ml)
  • 90 ml/h till infusion is over (455 ml) (5 h)
  • Total infusion period – 6 h.


Eming et al.[17] have demonstrated that RTX in pemphigus vulgaris works by depleting autoreactive T cells and downregulating desmoglein-3 specific CD4+ Th cells.

In India, however, the cost of the drug may pose an important drawback in patient management. As pemphigus is not a neoplastic disease, it has been suggested that lower doses of RTX (500 mg given at 2 weeks interval) could also suffice without compromising on the efficacy, and at the same time maintaining a better safety profile.[18] Gupta et al.[19] in a study conducted on fifty patients with refractory pemphigus utilized RTX in the lower dosing schedule as described above. In those cases where satisfactory results were not obtained, two additional doses of RTX were administered after 6 months in the similar dosing regimen. Complete remission was seen in 82% of their patients. In the remaining 18%, maintenance therapy using low dose steroids, either 5 mg once daily or on alternate days or cyclophosphamide 50 mg, or azathioprine 50 mg daily, was continued with no relapses. Kanwar et al.[20] have compared two doses of 1 g given 2 weeks apart and 2 doses of 500 mg given 2 weeks apart. They concluded that there was no statistically significant difference in clinical outcomes or relapse rates in the two regimens.

Londhe et al.[21] have used a modified dosing of the lymphoma protocol wherein the fourth dose of RTX was administered 3 months after the third dose, with an efficacious result. Apart from improvement of cutaneous lesions, they also demonstrated an 82.8% fall in the mean antibody levels of desmoglein 3 in these patients.

Therefore, it would be worthwhile to point out that the optimal dose of RTX in pemphigus has not been clearly determined, with modifications in its dosing schedule being continuously contemplated by various authors, in order to reduce the cost and the interval of dosing without compromising on the therapeutic efficacy of RTX.

In most cases, the duration of remission after RTX therapy is 2 years. However, when RTX is readministered during relapses, its safety and therapeutic benefits are still maintained.[22] A long-term follow up is therefore mandatory, to determine the appropriate dosing of RTX for pemphigus paients.[18] Dosing can also be individualized based on patient requirement.

Rituximab in mucous membrane pemphigoid

MMP is a rare and orphan disease. The estimated incidence is 1 case per million individuals in the general population.[23] Owing to its rarity, literature on the use of RTX in MMP is limited. Le Roux-Villet et al.[24] in their study on 25 patients with severe refractory MMP have demonstrated RTX to be a valuable therapeutic agent for MMP, administered according to the lymphoma protocol. In the study, within 3 months of the first RTX cycle, complete response was seen for both ocular and extraocular manifestations in 68% of patients. In 20% of patients, a second cycle of RTX was required to obtain complete clinical remission. However, in the remaining three patients, owing to complications related to RTX, therapy had to be discontinued. In 88% of patients who developed complete clinical remission, 40% of patients relapsed within 4 months after completion of treatment, thereby suggesting that the effects of RTX in MMP are short lived. In the above study, concomitant immunotherapy with dapsone and sulfasalazine was also utilized.

There have been six more case reports highlighting the use of RTX, using the lymphoma protocol for MMP. In all these patients, RTX was used because of unresponsiveness of the disease to conventional treatment. Concomitant immunosuppressive treatment was also continued in them.[25],[26],[27],[28],[29] In one patient, four additional infusions of RTX (375/m2) had to be given every 3 months as maintenance therapy.[29] Of these six cases, three demonstrated reasonable stabilization of conjunctival scarring,[25],[26],[29] one had partial response,[28] and one became totally blind.[27] Optimum response was seen in the cutaneous component of the disease. It has been, therefore, postulated that the principal response of RTX is obtained during the phase of active inflammation owing to its ability to destroy pathogenic B cells and eliminating pathogenic antibodies while simultaneously influencing the inflammatory processes by its effects on T cells.[17],[30] Consequently, if scarring has occurred, the response demonstrated by RTX is poor. The onus whether or not to initiate therapy with RTX lies on the treating clinician and it becomes his/her obligation to carefully assess the extent and severity of the disease, evaluate lesions, blister formation, and compare active inflammation versus irreversible scarring.[31] Once the clinician arrives at a concrete conclusion, he/she can begin therapy with RTX for MMP, based on his/her discretion. It needs to be emphasized that mortality caused by septicemia in patients treated with RTX for many autoimmune diseases has been reported.[2],[32] This becomes an alarming concern in patients with MMP where mortality from the disease is limited even though morbidity and sequel of scarring are considerably disabling and serious.[33]

Rituximab in dermatomyositis

Dermatomyositis (DM) is a systemic autoimmune disease that primarily affects the muscles, skin, and lungs and is associated with considerable morbidity.

There is substantial evidence suggesting the role of B lymphocytes in its pathogenesis. Moreover, muscle biopsy specimens exhibit a predominance of perivascular B cells and up to 40% of DM patients have detectable myositis-specific autoantibodies.[34],[35]

RTX has been utilized in treating both adult and juvenile DM.

In the study by Cooper et al.,[36] with RTX on four children for recalcitrant juvenile DM, utilizing the standard lymphoma protocol, three reported clinical improvement with the fourth patient demonstrating progression of the disease. Of these, one patient who was positive for anti-Mi-2 demonstrated a dramatic response to two cycles of RTX given at an interval of 1 year. Along with RTX, this patient also received weekly methotrexate. This excellent response could be explained by the presence of a strong B cell-driven component in the disease of this patient, depicted by the presence of the myositis-specific autoantibody anti-Mi-2.

In adult DM also, RTX has demonstrated good results. Levine[37] has expressed that both muscle symptoms and cutaneous signs improve following RTX administration according to the lymphoma protocol. However, in the pilot study conducted by Chung et al.,[38] it was only myositis that revealed improvement, with cutaneous manifestations exhibiting meager changes. In this study, rheumatoid arthritis protocol was followed. This differential efficacy for skin and muscle disease could be explained by the fact that skin inflammation is predominantly characterized by CD4+ T cells rather than B cells.[39],[40] However, there are reports also of the beneficial effects of RTX on cutaneous manifestations of DM.[37],[41]

Rituximab in cutaneous lupus erythematosus

According to the SLICC (Systemic Lupus International Collaborating Clinics) classification criteria for systemic lupus erythematosus (SLE), mucocutaneous manifestations include acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), oral ulcers, and nonscarring alopecia.[42]

First-line therapy in CLE is generally initiated with antimalarials and oral or topical glucocorticoids. In cases that are unresponsive to the above agents, other immunosuppressives such as azathioprine, mycophenolate mofetil, cyclophosphamide, and methotrexate have also been employed for patient management. However, till date, there exists no reliable evidence to conclude an optimal therapeutic regimen for CLE.[43],[44] RTX has been introduced in those patients who are unresponsive or intolerant to standard conventional treatment. It has been proven that CD20+ B cells play an important role in the pathogenesis of SLE and SCLE. Apart from being an antigen presenter, B cells produce autoantibodies and are responsible for secreting a number of inflammatory cytokines that enhance inflammation.[45],[46] As RTX plays an antagonistic role against these B cells, it may be of value in these patients.

It has also been observed that RTX has been more valuable in patients with ACLE and SCLE and in patients with nonspecific cutaneous lesions in SLE. In contrast, the role of RTX in CCLE has been limited. This can be attributed to the CD8+ cytotoxic T cells rather than B cells being involved in the pathogenesis of CCLE, particularly in the scarring and disseminated variant of discoid lupus erythematosus.[47],[48]

There have been various reports describing the successful use of RTX in CLE. Both lymphoma and rheumatoid arthritis protocols have been utilized with equal efficacy.[49],[50],[51],[52] Marks et al.[53] have utilized a modified protocol wherein 2 weekly infusions of 750 mg/m2 of RTX was administered with good results. In most patients in the above-mentioned studies, oral prednisolone at a dose <15 mg and oral antimalarials were continued as maintenance therapy. The duration of remission in majority of patients after the first cycle of RTX was around 10 months. After administration of the second cycle, the period of remission extended up to 18 months.

Rituximab in vasculitis

RTX has been utilized in treating ANCA-associated vasculitis (AAV).[54] The rationale behind using RTX in AAV is secondary to findings that B cell-targeted therapy reduced ANCA levels and in this way blocked disease pathogenesis.[55],[56] Further, it was also seen that levels of B cells in the circulation had a positive correlation to disease activity wherein when levels of B cells came down, activity of the disease halted.[57] RTX is usually used in cases that are refractory to conventional therapy or when cyclophosphamide is contraindicated. Both lymphoma and rheumatoid arthritis protocols have been followed in patients with AAV, and both have been equally effective. Further, maintenance dosing of 1 g RTX once in 4–6 months has also been used for relapses.[58]

Retro-orbital disease in Wegener's granulomatosis is usually refractory to treatment, which has shown response to RTX. However, more than one treatment course is generally needed before a therapeutic response is evident.[59]

Rituximab in graft-versus-hostdisease

Teshima et al.[60] have utilized RTX according to the lymphoma protocol in seven patients following hematopoietic stem cell transplantation. Following 1 year of treatment, partial response was seen in three patients, three patients had stable disease, and in the remaining one patient, the disease was progressive. It was, therefore, concluded that RTX is mainly effective in those cases of steroid refractory graft-versus-host disease that is not advanced, and if the manifestations involving the skin, eye, and fascia are severe, the role of RTX in this scenario is minimal.

Rituximab in atopic dermatitis

Although T cells are the prime players in the pathogenesis of atopic dermatitis (AD), B cells too have a role here. RTX administered according to the rheumatoid arthritis protocol has demonstrated a significant improvement both clinically and histologically along with a slight reduction in the level of IgE. These effects were evident within 1–2 months of initiating treatment with RTX. It must be remembered, however, that RTX should only be reserved for refractory severe cases of AD.[61],[62]

Rituximab in melanoma

Schlaak et al.[63] have used intralesional injections of RTX along with low-dose systemic dacarbazine therapy for melanoma. Long-lasting remission of tumor lesions was demonstrated by RTX. Furthermore, RTX also helped in reducing the melanoma serum marker S-100 to physiological levels and potentiated a switch of serum cytokines from a T helper-2 to a pro-inflammatory T helper-1 cell profile. Therefore, targeting the minor subsets of CD20+ melanoma-sustaining cells does have a role in inducing regression of chemotherapy refractory melanoma.

Rituximab in primary cutaneous B cell lymphoma

In general, treatment of CBCL consists of a combination of antibiotics, topical, or intralesional corticosteroids and/or localized radiotherapy. In case lesions are diffuse, systemic or intralesional interferons can be considered as an alternative in primary cutaneous B cell lymphoma (PCBCL). Only in aggressive forms of PCBCL does RTX have a role, which too at present is in the evolving phase. RTX has been administered both intralesionally (10 mg/lesion)[64] and systemically for PCBCL. In the systemic therapy, apart from the usual four doses at weekly intervals, in a selected subset of patients, six doses of RTX had been administered in the study by Valencak et al.[65] In their study, it was found that 87.5% of patients achieved complete clinical resolution, making them postulate that a single-agent treatment with IV RTX does result in a high rate of durable remissions and can be comparable to radiotherapy. Similarly, the response seen with intralesional RTX has been satisfactory. Further, combining RTX with anthracycline-containing chemotherapies could be more effective.[66]

Rituximab in the pediatric population

It has been stated that the use of RTX in children is not recommended owing to limited clinical experience in this age group.[8] However, there have been a few reports of recalcitrant pemphigus wherein RTX had to be used to obtain clinical remission. In majority of patients, the lymphoma protocol has been followed,[67],[68],[69],[70] except for the case of Kanwar et al.[71] who used RTX at a dose of 375 mg/m2 BSA, two doses 15 days apart. In all cases, good clinical remission was obtained. No serious infections were encountered in the patients, except for one patient wherein bacteremia secondary to the central venous port was the cause. With all data available, it would be prudent to conclude that RTX could be a good alternative therapy in recalcitrant cases of childhood pemphigus. However, long-term prospective studies with an adequate sample size for RTX in childhood pemphigus are required to determine its safety and efficacy.

Rituximab in pemphigus patients with viral hepatitis

In patients with hepatitis C virus (HCV), it has been largely concluded that there is no evidence that RTX therapy accelerates the course of HCV infection.[72] However, the 2008 American College of Rheumatology Guidelines recommend that RTX is contraindicated in Child–Pugh class B and C chronic HCV infection.[73] Therefore, the decision to treat such patients should be individualized along with active involvement of the hepatologist or gastroenterologist. Although the use of RTX is contraindicated in HCV, RTX paradoxically can be used as a therapeutic modality for the treatment of HCV-associated rheumatic diseases including cryoglobulinemic vasculitis.[74] Kanwar et al.[75] have treated two HCV-positive pemphigus patients with RTX using the rheumatoid arthritis protocol: one had partial remission and the other complete remission of pemphigus. The patient who had partial remission was further administered two more cycles of RTX. In none of the patients, were the hepatic parameters deranged.

For hepatitis B virus (HBV) infections, various studies and case series have clearly established the risk of worsening/reactivation of undetected chronic HBV infection following RTX administration.[76] The current European Association for the Study of the Liver (EASL) guidelines state that patients with active hepatitis B (HBsAg+ and/or HBV-DNA+) must undergo preemptive antiviral treatment before starting RTX.[77] The EASL recommends prophylactic lamivudine for patients with low baseline HBV-DNA levels (<2000 IU/ml) when a finite and short duration of immunosuppression is scheduled. In patients with a high baseline HBV-DNA levels (>2000 IU/ml) and/or those patients likely to receive a prolonged duration of immunosuppression, entecavir and tenofovir are recommended.[77] Antiviral treatment must be continued for at least 1 year after stopping RTX to prevent late reactivation of the virus.

The third patient of Kanwar et al.[75] was an active carrier of HBV with progressive derangement of liver function tests while on steroids and azathioprine. The patient was administered lamivudine by the hepatologist with progressive improvement in her liver function tests and viral load. Following this, RTX was administered adhering to the EASL guidelines, with no worsening of the viral hepatitis.

Therefore, RTX can be given in pemphigus patients with hepatitis, provided that appropriate monitoring and the EASL guidelines are followed along with good collaboration with the hepatologist, when regular treatment modalities have failed.


  Adverse Effects Top


Cutaneous

  • Frequent but not so serious: Night sweats, skin rash, urticaria, and pruritus
  • Serious side effects: Paraneoplastic pemphigus, Stevens–Johnson syndrome, lichenoid dermatitis, toxic epidermal necrolysis, serum sickness, vasculitis, and novel delayed proinflammatory syndrome occurring at or near completion of a 4-week intense course of RTX.[78]


Noncutaneous

  • Fatal infusion reactions usually in the first infusion
  • Tumor lysis syndrome
  • Hepatitis B reactivation with related fulminant hepatitis
  • Severe life-threatening cardiac arrhythmias
  • Cytopenias
  • Rarely, progressive multifocal leukoencephalopathy.



  Monitoring Guidelines Top


Baseline

  • Complete hemogram
  • Liver function tests
  • Renal function tests
  • Chest X-ray
  • Mantoux test
  • HRCT chest (when indicated)
  • Screening test for HBsAg, anti-HBc, anti-HCV, HIV 1 and 2
  • ECG and echocardiography
  • Baseline IgG levels (as there is an increased risk of severe infections with RTX if IgG is low and is therefore recommended by some authors).



  Drug Interactions Top


Cisplatin: Associated with nephrotoxicity.


  Management Of Adverse Reactions Secondary To Rituximab Top


  • If an infusion reaction develops, discontinue treatment
  • Administer hydrocortisone and antihistamines again
  • After 30 min, consider reinfusion with RTX.


In the following conditions, RTX should be discontinued:

  • Severe infections
  • Anaphylaxis in those patients who do not tolerate mouse proteins
  • Pregnancy.



  Conclusion Top


RTX has proven to be a substantial boon for dermatologists in difficult to treat cases of pemphigus. With its horizons expanding in dermatology, and with better information regarding its efficacy and safety profile, RTX has now become an approved first-line therapy for pemphigus.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Mechanism of Action
Pharmacokinetics
Indications...
Primary Cutaneou...
Contraindications
Dermatologic Con...
Adverse Effects
Monitoring Guide...
Drug Interactions
Management Of Ad...
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Indications
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