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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 657-660
Rituximab-induced urticarial dermatitis during the treatment of membranous nephropathy

1 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India

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Date of Web Publication18-May-2017


Rituximab is a monoclonal antibody directed against B cells and is being increasingly used for various renal indications. Acute dermatologic manifestations such as urticaria are well known to occur during rituximab infusion. Here, we report the case of a 53- year-old female who was treated with rituximab for membranous nephropathy and developed an exanthematous rash, which progressed with a further dose of rituximab and was diagnosed as urticarial dermatitis. A review of literature showed that urticarial dermatitis following rituximab therapy has been seldom reported and identification of this complication is very important to avoid giving further doses and thus, increasing the severity of lesions.

How to cite this article:
Radhakrishnan RC, Basu G, George RE, Parmar H, Tamilarasi V. Rituximab-induced urticarial dermatitis during the treatment of membranous nephropathy. Saudi J Kidney Dis Transpl 2017;28:657-60

How to cite this URL:
Radhakrishnan RC, Basu G, George RE, Parmar H, Tamilarasi V. Rituximab-induced urticarial dermatitis during the treatment of membranous nephropathy. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Jul 9];28:657-60. Available from: http://www.sjkdt.org/text.asp?2017/28/3/657/206462

   Introduction Top

Rituximab, a chimeric monoclonal antibody against anti-CD20 in B cells, is being increasingly used in nephrology practice for various indications such as membranous nephropathy (MN), resistant lupus nephritis, and prevention and treatment of antibody mediated rejection.[1] Although considered as relatively safe among the monoclonal antibodies, it can be associated with several dermatologic reactions. Cytokine release during intravenous infusion of rituximab can be associated with urticaria and angio- edema. Postinfusion syndromes include Stevens- Johnson syndrome, serum sickness, and vasculitis.[2],[3] Urticaria has usually been reported as an acute dermatologic manifestation occurring during rituximab infusion.[4] We report the case of a female with MN who developed delayed-onset urticarial dermatitis during rituximab therapy and discuss the importance of early identification of this adverse effect.

   Case Report Top

A 53-year-old female presented with relapse of the nephrotic syndrome for the last eight months. About 12 years earlier, she was diagnosed to have biopsy-proven MN associated with acute hepatitis B virus (HBV) infection. She was treated with prednisolone and cyclophosphamide followed by prednisolone and cyclosporine along with telmisartan. In view of the nephrotic syndrome recurring a long period after the occurrence of the first episode, she underwent renal biopsy which confirmed that it was a relapse of MN. No secondary cause for MN could be identified. Hepatitis B surface antigen and HBV DNA polymerase chain reaction were negative. Serum complements were normal, and anti-dsNA antibody was negative. However, in spite of adequate trough levels of cyclosporine (C0 level maintained >100), there was no response to the treatment after three months, with increasing proteinuria and development of edema.

In view of worsening of proteinuria despite being on adequate immunosuppression and maximal angiotensin receptor blocker therapy, and poor prognostic factors such as older age, hypertension, focal sclerosis on biopsy, further treatment options were discussed and an informed decision to use rituximab was taken after counseling regarding efficacy and adverse effects. Four weekly doses of rituximab, each of 500 mg were planned. During rituximab therapy, the patient was continued on 30 mg of oral prednisolone on alternate days since she was already on steroids. Intravenous chlorpheniramine, intravenous hydrocortisone, and oral paracetamol were used as pre- medication before infusion as per treating unit protocol. The infusion was initially started at 50 mg/h for one hour followed by 100 mg/hour till the end of infusion. She received first and second rituximab infusion without any infusion-related toxicity. Two days after the second dose, the patient noticed pruritic rashes on both arms and right thigh but did not consider it significant and hence did not bring it to the notice of treating doctors. She received her third dose as per schedule. The next day, the lesions increased in severity and extent. On examination, there were erythe- matous urticated maculopapular lesions predominantly involving flexor and extensor aspects of bilateral upper limbs, nape of the neck, and anterior aspect of thighs [Figure 1]. There were no mucosal lesions. Eosinophil counts and serum IgE levels were 0.1 x 10[9]/L and 0.1 mg/L (0.01–0.24),respectively. A clinical diagnosis of urticarial dermatitis was made, and a skin biopsy from left forearm was taken. The epidermis showed basket-weave orthokeratosis with focal basal cell vacuolization with lym- phocytic exocytosis and flattening of rete pegs with occasional necrotic keratinocytes. The superficial dermis showed edema, telangiectasia, and mild perivascular infiltrate of lymphocytes, histiocytes, and occasional eosinophils [Figure 2]. These findings were consistent with a diagnosis of drug-induced urticarial dermatitis.[5] She was treated with topical betamethasone and oral antihistaminics, and the lesions regressed. She was continued on oral predni- solone and telmisartan for MN.
Figure 1: Erythematous raised maculopapular lesions involving flexor and extensor aspects of bilateral upper limbs.

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Figure 2: Epidermis showing occasional necrotic keratinocytes (big arrow) and patchy basal cell vacuolization (small arrow). Papillary dermis shows edema, telangiectasia, and mild perivascular infiltrates of lymphocytes and a few eosinophils (H and E, ×40).

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Six weeks later, she had a recurrence of similar lesions albeit in milder form. This episode subsided in 4–5 days with topical steroid application. Three months later, she was doing well with reduction in proteinuria to 363 mg/day and no further relapse of urticarial dermatitis.

   Discussion Top

Rituximab is one of the leading second-line drugs for the treatment of resistant MN, but the side effects remain a concern. Adverse events can occur during rituximab infusion and are thought to be due to the release of cytokines. Walewski et al reported that 60% of the first, and 20% of subsequent rituximab infusions were associated with infusion-related reactions including mild fever, chills, and occasional skin eruptions.[2] In a study on multiple sclerosis patients, infusion-associated events occurred in 25.7% of the patients. Reactions were mild-to-moderate, most commonly occurred during the first infusion and most patients went on to receive subsequent doses without any further reactions.[6] Errante et al reported urticarial reactions occurring one hour after the start of rituximab infusion which spontaneously disappeared after temporary stoppage of infusion. They hypothesized that the urticarial reaction in that patient with primary cutaneous B-cell lymphoma was an epiphenomenon of the killing of the B-cells bearing the CD20 antigen in the sites of the disease, with a local cytokine release, rather than the occurrence of a hypersensitivity reac- tion.[4] In addition to infusion reactions, delayed reactions such as serum sickness have been seen in up to 20% cases.[3] Diffuse, pruritic, maculopapular rash with generalized edema, associated with aphthous ulcers, diarrhea, arthralgias, and myalgia occurring 48-h after rituximab injection was described by Hellerstedt and Ahmed in a patient with systemic lupus erythematosis.[7] Severe reactions including Stevens-Johnson syndrome and vasculitis have been observed.[8],[9],[10] Lowndes et al reported the occurrence of Stevens-Johnson syndrome in a patient with non-Hodgkin’s lymphoma, which started as mild mucosal lesions and trunk rashes after the second dose of rituximab and worsened following the third dose to develop severe ulcerative rash and mucositis unresponsive to steroids and immunosuppressive therapy.[8]

Urticarial dermatitis was clinically defined by Hannon et al as pruritic, erythematous papules and plaques resembling urticaria but that last longer than 24-h and are sometimes accompanied by eczematous lesions.[5] In our patient, the lesions resembled urticaria but lasted one week and hence, a clinical diagnosis of urti- carial dermatitis was considered. Histopatho- logic findings were consistent with the diag- nosis.[5] The lesions developed after the second dose of rituximab and worsened following the third dose both in extent and severity. The patient was on bisoprolol, cilnidipine, telmi- sartan, pantoprazole, and atorvastatin for several months, and these drugs were ruled out to be the cause of urticarial dermatitis in consult with the dermatologist. No other new drugs were given, and hence, rituximab was considered as the likely etiological agent. She responded to topical steroids and oral anti- histamines. She had recurrence of similar lesions six weeks after the initial episode. This is also consistent with rituximab as this drug has been found to be present in serum even after six months of treatment with prolongation of half-life with each dose.[11]

The pathophysiology of urticarial dermatitis is not yet clear, but it is thought to represent a delayed type of hypersensitivity reaction. Clinically and histologically, similar lesions have been described in melanoma patients treated with anticytotoxic T-lymphocyte antigen- 4 antibodies and are suggested to be due to TH2-type T cell activation.[12] Hitherto unrepor- ted, rituximab, an anti-B cell agent, has caused similar cutaneous lesions in our patient, but the exact mechanism of rituximab action on regulation of TH2-type immune response needs to be further clarified.

It has been postulated by Hellerstedt and Ahmed that the underlying disease may contribute to the occurrence of delayed or cutaneous reactions during rituximab therapy, as serum sickness was seen in patients with autoimmune polyneuropathy and autoimmune thrombocytopenia while vasculitis and Stevens- Johnson syndrome were reported in patients with chronic lymphocytic leukemia and follicular non-Hodgkins lymphoma, respectively.[7] Whether the cutaneous reactions of rituximab are milder in patients with MN requires further elucidation. In addition, our patient was on oral corticosteroids while she received ritu- ximab which could have reduced the severity of skin reaction.

   Conclusion Top

With increasing indications for the use of rituximab in nephrology practice, it is imperative for clinicians to identify and manage complications of therapy with this monoclonal antibody. This case highlights the importance of watching out for urticarial dermatitis as a late manifestation of rituximab toxicity and educating patients to report any minor rash that occurs during rituximab therapy as it has the potential to evolve into more severe lesions if further doses are given.

Conflict of interest: None declared.

   References Top

Evans R, Salama AD. Update on rituximab: An established treatment for all immune- mediated kidney diseases? Nephron Clin Pract 2014;126:97-109.  Back to cited text no. 1
Walewski J, Kraszewska E, Mioduszewska O, et al. Rituximab (Mabthera, Rituxan) in patients with recurrent indolent lymphoma: Evaluation of safety and efficacy in a multi- center study. Med Oncol 2001;18:141-8.  Back to cited text no. 2
Le Guenno G, Ruivard M, Charra L, Philippe P. Rituximab-induced serum sickness in refractory immune thrombocytopenic purpura: Brief communications. Intern Med J 2011;41: 202-5.  Back to cited text no. 3
Errante D, Bernardi D, Bianco A, De Nardi S, Salvagno L. Rituximab-related urticarial reaction in a patient treated for primary cutaneous B- cell lymphoma. Ann Oncol 2006;17:1720-1.  Back to cited text no. 4
Hannon GR, Wetter DA, Gibson LE. Urti- carial dermatitis: Clinical features, diagnostic evaluation, and etiologic associations in a series of 146 patients at Mayo Clinic (20062012). J Am Acad Dermatol 2014;70:263-8.  Back to cited text no. 5
Brown BA, Torabi M. Incidence of infusion- associated reactions with rituximab for treating multiple sclerosis: A retrospective analysis of patients treated at a US centre. Drug Saf 2011;34:117-23.  Back to cited text no. 6
Hellerstedt B, Ahmed A. Delayed-type hyper- sensitivity reaction or serum sickness after rituximab treatment. Ann Oncol 2003;14:1792.  Back to cited text no. 7
Lowndes S, Darby A, Mead G, Lister A. Stevens-Johnson syndrome after treatment with rituximab. Ann Oncol 2002;13:1948-50.  Back to cited text no. 8
Allen KP, Funk AJ, Mandrell TD. Toxic epidermal necrolysis in two rhesus macaques (Macaca mulatta) after administration of rituximab. Comp Med 2005;55:377-81.  Back to cited text no. 9
Kim MJ, Kim HO, Kim HY, Park YM. Rituximab-induced vasculitis: A case report and review of the medical published work. J Dermatol 2009;36:284-7.  Back to cited text no. 10
Berinstein NL, Grillo-Lopez AJ, White CA, et al. Association of serum Rituximab (IDEC- C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1998;9:995-1001.  Back to cited text no. 11
Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T- lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol 2006 ;142:166- 72.  Back to cited text no. 12

Correspondence Address:
Radhika Chemmangattu Radhakrishnan
Department of Nephrology, Christian Medical College, Vellore - 632 004, Tamil Nadu
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DOI: 10.4103/1319-2442.206462

PMID: 28540910

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