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Stevens–Johnson syndrome after treatment with rituximab
Annals of Oncology 13: 1948–1950, 2002 DOI: 10.1093/annonc/mdf350
Clinical case
Stevens–Johnson syndrome after treatment with rituximab S. Lowndes1*, A. Darby1, G. Mead1 & A. Lister2 1
Cancer Research UK Department of Medical Oncology, Royal South Hants Hospital, Southampton; 2Cancer Research UK Department of Medical Oncology, St Bartholomew’s Hospital, London, UK Received 26 August 2002; accepted 16 September 2002
Introduction
Case report
The CD20 antigen is an attractive target in lymphoma treatment as it is present on the surface of mature B-cells and the majority of B-cell lymphomas, but not on B-cell precursors [1]. Rituximab is a highly specific chimeric mouse/human anti-CD20 antibody produced by grafting the variable regions from murine antibody genes that target CD20 onto the constant regions of the human immunoglobulin G (IgG) gene. Rituximab acts by killing CD20+ cells in vitro by a mixture of complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity and induction of apoptosis [2]. Several trials of single agent rituximab in adult patients with follicular nonHodgkin’s lymphoma have been reported, including a pivotal 166 patient study, in which half the patients responded to a four dose treatment programme, with a median duration of response of 13 months [3]. A recent randomised trial comparing CHOP plus rituximab with CHOP chemotherapy alone in elderly patients with diffuse large B-cell lymphoma also showed a significantly higher response rate in the rituximab arm [4]. These and other trials have reported only mild toxicity with rituximab; adverse events associated with treatment were mainly mild infusion-related reactions such as fever, nausea and headache. Occasional skin eruptions and erythema have been reported, but none as severe as in this case.
A 33-year-old Causasian male presented in April 1994 with right groin and left axillary lymphadenopathy. He had no past medical history of note and had not had any fevers, night sweats or weight loss. A biopsy of one of these lymph nodes showed grade 1 follicular non-Hodgkin’s lymphoma and a computed tomography (CT) scan revealed extensive intraabdominal and pelvic lymphadenopathy with splenomegaly. A bone marrow biopsy confirmed marrow involvement and the patient was therefore diagnosed as pathological stage IV A. The patient was treated with six cycles of chlorambucil, which initially lead to a good clinical response, but progressive abdominal disease was confirmed on an abdominal CT scan in 1995 and no response was seen with further chlorambucil therapy. In June 1996, a biopsy of a mesenteric mass again showed follicular lymphoma. The disease proved resistant to i.v. fludarabine and, therefore, i.v. combination chemotherapy with doxorubicin, vincristine and prednisolone was commenced. This lead to marked leucopenia but minimal disease response, and was discontinued in November 1996. In February 1997, the patient entered a phase II trial of rituximab [5]. Prior to entering the trial a repeat biopsy confirmed CD20+ follicular lymphoma. A baseline CT scan was complicated by a mild nonpruritic rash that settled quickly with antihistamines. The rituximab was administered i.v. 2 days later at a dose of 375 mg/m2 with i.v. chlorpheniramine premedication. It was planned that he should receive weekly rituximab injections for 4 weeks. The first two cycles were given on schedule with no infusion related toxicity. During the second cycle, grade 1
*Correspondence to: Dr S. Lowndes, Department of Medical Oncology, Royal South Hants Hospital, Brinton’s Terrace, Southampton SO14 0YG, UK. Tel: +44-2380-825973; Fax: +44-2380-825441; E-mail: [email protected] © 2002 European Society for Medical Oncology
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on July 1, 2015
Rituximab is a chimeric mouse/human anti-CD20 antibody licensed for the treatment of low-grade nonHodgkin’s lymphoma and has recently also been shown to have a role in the treatment of diffuse large B-cell lymphoma. We report a case of Stevens–Johnson syndrome after treatment with rituximab, which occurred in a 36-year-old man with relapsed follicular lymphoma. The patient developed mucositis and fevers after the first two injections, followed by a florid maculopapular rash with severe orogenital ulceration after the third infusion. Over several weeks his symptoms progressed with severe cutaneous, orogenital and conjunctival ulceration, leading to visual problems and malnutrition. No improvement occurred with steroids and immunosuppressant therapy. A review of the literature reveals this to be the first reported case of Stevens–Johnson syndrome associated with rituximab therapy. Key words: Stevens–Johnson syndrome, rituximab, side effects, follicular lymphoma
1949
Figure 1. (A) Diffuse maculopapular rash. (B) Oral mucositis and ulceration.
ening of the skin. During this time the lymphoma remained relatively clinically stable and the steroid dose was gradually reduced. In the autumn of 1997, the patient developed a persistent cough, wheeze and progressive dyspnoea. A chest radiograph was unremarkable but spirometry showed marked airflow obstruction (forced expiratory volume in 1 s, 1.04; forced vital capacity, 2.76) with some restriction of lung volumes. Oxygen saturations were normal. Sputum culture grew Haemophilus influenzae and treatment with appropriate antibiotics led to some improvement. Bronchoscopy was performed and transbronchial biopsy showed nonspecific inflammation. In spring 1998, a CT scan confirmed progressive disease in the abdomen with some mediastinal nodes. Bronchiectasis was seen but no evidence of bronchiolitis obliterans. Over the ensuing months his respiratory function rapidly deteriorated and his cutaneous problems persisted. He eventually developed peripheral oedema, clinically felt to be due to inferior vena cava obstruction, and died in August 1998.
Discussion Rituximab was the first antibody licenced for the treatment of malignancy. It has been shown to be effective as a single agent in relapsed or refractory follicular non-Hodgkin’s lymphoma,
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on July 1, 2015
mucositis was noticed and mouthwashes were prescribed. Prior to receiving the third cycle the patient presented with fevers associated with a pruritic trunk rash, grade 2 mucositis and weight loss. He was treated with oral fluconazole, acyclovir and antihistamines, which led to some clinical improvement, and the cycle was given 5 days after schedule. However, 1 week after the third infusion he experienced overt grade 3 orogenital mucositis and the maculopapular trunk rash had spread with areas of ulceration. Treatment with rituximab was discontinued and an urgent dermatological review requested. A clinical diagnosis of Stevens–Johnson syndrome was made, with a differential diagnosis of pemphigus or toxic epidermal necrolysis. Skin biopsies were taken and showed a chronic inflammatory infiltrate rich in eosinophils attacking the basal keratinocytes, with basal cell liquefaction and degeneration. The epidermis showed some spongiosis, and in areas there was loss of the epidermis, presumably secondary to the basal cell damage. There was no evidence of acantholysis and therefore no evidence of pemphigus. This was supported by the patient lacking any pemphigus or pemphigoid antibodies. There was no evidence of lymphomatous infiltration of the skin and immunohistochemistry using antibody L26 did not demonstrate any CD20+ cells in the infiltrate. The histological features were considered consistent with erythema multiforme, and in the presence of so many eosinophils it was highly suggestive of a drug-related aetiology. No other new drugs had been given and it therefore appeared to be related to the introduction of rituximab. Comprehensive microbiological investigation revealed no other cause for the erythema multiforme. Cytomegalovirus (CMV) IgG was positive, indicating past infection, but CMV IgM was negative, along with a CMV DEAFF (detection of early antigen fluorescent foci) test and virus isolation. No virus was isolated from skin swabs and serological tests including those for Epstein–Barr virus, hepatitis A, B and C, mycoplasma and legionella were negative. Biochemistry results, including lactate dehydrogenase and full blood count, were normal and autoimmune profiles were negative. Compliment levels were normal, but IgG and IgM were low at 4.4 g/l (normal range 5.4–16.1) and 0.4 g/l (normal range 0.5–1.9), respectively. Circulating IgG and IgA immune complexes were present. A chest X-ray was consistent with nodal disease, but the lungs were clear. Intensive treatment was started with mouthwashes, acyclovir, fluconazole, antibiotics, antiseptic cream and potassium permanganate bath solution. No improvement was noted, so high dose prednisolone was introduced. Over several weeks his symptoms progressed with severe cutaneous, orogenital, anal and conjunctival ulceration (Figure 1) leading to visual problems and malnutrition. Cyclosporin A was commenced, but there was no additional benefit and it was discontinued. After 4 months, some mild improvement was noted, though the skin lesions remained active and there was gradual thick-
1950 Roche pharmaceuticals report the incidence of severe skin reactions to rituximab as 0.01% in a series of 167 000 patients who received the drug, but were unable to define the individual cases further. No similar cases have been reported in the literature, but as rapidly increasing numbers of patients are receiving rituximab an awareness of the possible side effects of such treatment is crucial.
References 1. Anderson K, Bates M, Slaughenhoupt B et al. Expression of human B-cell associated antigens in leukaemias and lymphomas: a model of human B-cell differentiation. Blood 1984; 63: 1424–1433. 2. Johnson PWM, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001; 85: 1619–1623. 3. McLaughlin P, Grillo-Lopez AJ et al. Rituximab chimeric anti-CD 20 monoclonal antibody therapy for relapsed indolent lymphoma. J Clin Oncol 1998; 16: 2825–2833. 4. Coiffier B, Lepage E et al. CHOP chemotherapy plus rituximab compared with CHOP chemotherapy alone in elderly patients with diffuse large B cell lymphoma. N Engl J Med 2002; 346: 235–242. 5. Foran JM, Gupta RK, Cunningham D et al. A UK multicentre phase II study of rituximab in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 2000; 109: 81–88. 6. Davis TA, White CA, Grillo-Lopez AJ et al. Single agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma. J Clin Oncol 1999; 17: 1851–1857. 7. Maloney DG, Grillo-Lopez AJ, White CA et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188–2195. 8. Piro LD, White CA, Grillo-Lopez AJ et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1999; 10: 655–661. 9. Byrd JC, Murphy T, Howard RS et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lyphocytic leukaemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001; 19: 2153–2164. 10. Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 2001; 345: 1000. 11. Walewski J, Kraszewska E, Mioduszewska O et al. Rituximab (Mabthera, Rituxan) in patients with recurrent indolent lymphoma: evaluation of safety and efficacy in a multicentre study. Med Oncol 2001; 18: 141–148. 12. Weatherall DJ, Leddingham JGG, Warrell DA (eds). Oxford Textbook of Medicine, 3rd edition. Oxford, UK: Oxford University Press 1996.
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on July 1, 2015
producing a response in half of patients [2, 5–9] with a median duration of response of 13 months. A recent randomised trial comparing CHOP plus rituximab with CHOP chemotherapy alone in elderly patients with diffuse large B-cell lymphoma showed a significantly higher response rate in the rituximab arm (76% versus 63%) and this is likely to pave the way for more widescale use of rituximab in lymphoma treatment [4]. These trials have reported only mild toxicity with rituximab, most adverse events being mild to moderate infusion reactions [5–9]. More serious toxicity is rare and is limited in the literature to case reports. Of interest to this case, there is one report of bronchiolitis obliterans related to rituximab [6], one of dyspnoea, haemoptysis and death 3 days after infusion [9], and one of fatal CMV reactivation [10]. Reports of cutaneous toxicity are usually limited to urticaria or pruritis, although in one study of single agent rituximab in 38 patients, one patient had to discontinue treatment due to fever and painful erythema, and several had infusion-related skin eruptions [11]. This, however, is the first reported case of Stevens–Johnson syndrome following treatment with rituximab. Stevens–Johnson syndrome is a severe variant of erythema multiforme, a mucocutaneous abnormality usually following a drug reaction or infection [12]. Common causes include Herpes simplex virus, hepatitis A or B, mycoplasma, pregnancy and malignancy. Nonscaling annular plaques are seen, often involving the limbs and plantar palmar surfaces. The lesions can become paler centrally appearing like targets. Mucous membranes can be involved with blistering and ulceration. The nose, mouth, eyes, anogenital areas and tracheobronchial tree can also be involved, and bronchiolitis obliterans is a well recognised complication. The differential diagnosis of Stevens–Johnson syndrome includes other bullous disorders, toxic epidermal necrolysis and lymphoma itself. In this case, histology did not show any features of pemphigus and on serological testing the patient had no pemphigus or pemphigoid antibodies. Histology did not show any infiltration by lymphoma and immunohistochemistry did not show any CD20+ cells; this makes lymphoma itself an unlikely cause of the skin reaction. Likewise, no viruses were isolated and viral serology was negative. The eosinophilic infiltrates suggested a drug as the cause. The patient had developed a mild rash after i.v. injection of contrast for his CT scan 1 month earlier, and as a cause this cannot be excluded, but the temporal relationship of the rituximab to the florid skin changes makes it the most likely candidate.
Clinical case
Stevens–Johnson syndrome after treatment with rituximab S. Lowndes1*, A. Darby1, G. Mead1 & A. Lister2 1
Cancer Research UK Department of Medical Oncology, Royal South Hants Hospital, Southampton; 2Cancer Research UK Department of Medical Oncology, St Bartholomew’s Hospital, London, UK Received 26 August 2002; accepted 16 September 2002
Introduction
Case report
The CD20 antigen is an attractive target in lymphoma treatment as it is present on the surface of mature B-cells and the majority of B-cell lymphomas, but not on B-cell precursors [1]. Rituximab is a highly specific chimeric mouse/human anti-CD20 antibody produced by grafting the variable regions from murine antibody genes that target CD20 onto the constant regions of the human immunoglobulin G (IgG) gene. Rituximab acts by killing CD20+ cells in vitro by a mixture of complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity and induction of apoptosis [2]. Several trials of single agent rituximab in adult patients with follicular nonHodgkin’s lymphoma have been reported, including a pivotal 166 patient study, in which half the patients responded to a four dose treatment programme, with a median duration of response of 13 months [3]. A recent randomised trial comparing CHOP plus rituximab with CHOP chemotherapy alone in elderly patients with diffuse large B-cell lymphoma also showed a significantly higher response rate in the rituximab arm [4]. These and other trials have reported only mild toxicity with rituximab; adverse events associated with treatment were mainly mild infusion-related reactions such as fever, nausea and headache. Occasional skin eruptions and erythema have been reported, but none as severe as in this case.
A 33-year-old Causasian male presented in April 1994 with right groin and left axillary lymphadenopathy. He had no past medical history of note and had not had any fevers, night sweats or weight loss. A biopsy of one of these lymph nodes showed grade 1 follicular non-Hodgkin’s lymphoma and a computed tomography (CT) scan revealed extensive intraabdominal and pelvic lymphadenopathy with splenomegaly. A bone marrow biopsy confirmed marrow involvement and the patient was therefore diagnosed as pathological stage IV A. The patient was treated with six cycles of chlorambucil, which initially lead to a good clinical response, but progressive abdominal disease was confirmed on an abdominal CT scan in 1995 and no response was seen with further chlorambucil therapy. In June 1996, a biopsy of a mesenteric mass again showed follicular lymphoma. The disease proved resistant to i.v. fludarabine and, therefore, i.v. combination chemotherapy with doxorubicin, vincristine and prednisolone was commenced. This lead to marked leucopenia but minimal disease response, and was discontinued in November 1996. In February 1997, the patient entered a phase II trial of rituximab [5]. Prior to entering the trial a repeat biopsy confirmed CD20+ follicular lymphoma. A baseline CT scan was complicated by a mild nonpruritic rash that settled quickly with antihistamines. The rituximab was administered i.v. 2 days later at a dose of 375 mg/m2 with i.v. chlorpheniramine premedication. It was planned that he should receive weekly rituximab injections for 4 weeks. The first two cycles were given on schedule with no infusion related toxicity. During the second cycle, grade 1
*Correspondence to: Dr S. Lowndes, Department of Medical Oncology, Royal South Hants Hospital, Brinton’s Terrace, Southampton SO14 0YG, UK. Tel: +44-2380-825973; Fax: +44-2380-825441; E-mail: [email protected] © 2002 European Society for Medical Oncology
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on July 1, 2015
Rituximab is a chimeric mouse/human anti-CD20 antibody licensed for the treatment of low-grade nonHodgkin’s lymphoma and has recently also been shown to have a role in the treatment of diffuse large B-cell lymphoma. We report a case of Stevens–Johnson syndrome after treatment with rituximab, which occurred in a 36-year-old man with relapsed follicular lymphoma. The patient developed mucositis and fevers after the first two injections, followed by a florid maculopapular rash with severe orogenital ulceration after the third infusion. Over several weeks his symptoms progressed with severe cutaneous, orogenital and conjunctival ulceration, leading to visual problems and malnutrition. No improvement occurred with steroids and immunosuppressant therapy. A review of the literature reveals this to be the first reported case of Stevens–Johnson syndrome associated with rituximab therapy. Key words: Stevens–Johnson syndrome, rituximab, side effects, follicular lymphoma
1949
Figure 1. (A) Diffuse maculopapular rash. (B) Oral mucositis and ulceration.
ening of the skin. During this time the lymphoma remained relatively clinically stable and the steroid dose was gradually reduced. In the autumn of 1997, the patient developed a persistent cough, wheeze and progressive dyspnoea. A chest radiograph was unremarkable but spirometry showed marked airflow obstruction (forced expiratory volume in 1 s, 1.04; forced vital capacity, 2.76) with some restriction of lung volumes. Oxygen saturations were normal. Sputum culture grew Haemophilus influenzae and treatment with appropriate antibiotics led to some improvement. Bronchoscopy was performed and transbronchial biopsy showed nonspecific inflammation. In spring 1998, a CT scan confirmed progressive disease in the abdomen with some mediastinal nodes. Bronchiectasis was seen but no evidence of bronchiolitis obliterans. Over the ensuing months his respiratory function rapidly deteriorated and his cutaneous problems persisted. He eventually developed peripheral oedema, clinically felt to be due to inferior vena cava obstruction, and died in August 1998.
Discussion Rituximab was the first antibody licenced for the treatment of malignancy. It has been shown to be effective as a single agent in relapsed or refractory follicular non-Hodgkin’s lymphoma,
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on July 1, 2015
mucositis was noticed and mouthwashes were prescribed. Prior to receiving the third cycle the patient presented with fevers associated with a pruritic trunk rash, grade 2 mucositis and weight loss. He was treated with oral fluconazole, acyclovir and antihistamines, which led to some clinical improvement, and the cycle was given 5 days after schedule. However, 1 week after the third infusion he experienced overt grade 3 orogenital mucositis and the maculopapular trunk rash had spread with areas of ulceration. Treatment with rituximab was discontinued and an urgent dermatological review requested. A clinical diagnosis of Stevens–Johnson syndrome was made, with a differential diagnosis of pemphigus or toxic epidermal necrolysis. Skin biopsies were taken and showed a chronic inflammatory infiltrate rich in eosinophils attacking the basal keratinocytes, with basal cell liquefaction and degeneration. The epidermis showed some spongiosis, and in areas there was loss of the epidermis, presumably secondary to the basal cell damage. There was no evidence of acantholysis and therefore no evidence of pemphigus. This was supported by the patient lacking any pemphigus or pemphigoid antibodies. There was no evidence of lymphomatous infiltration of the skin and immunohistochemistry using antibody L26 did not demonstrate any CD20+ cells in the infiltrate. The histological features were considered consistent with erythema multiforme, and in the presence of so many eosinophils it was highly suggestive of a drug-related aetiology. No other new drugs had been given and it therefore appeared to be related to the introduction of rituximab. Comprehensive microbiological investigation revealed no other cause for the erythema multiforme. Cytomegalovirus (CMV) IgG was positive, indicating past infection, but CMV IgM was negative, along with a CMV DEAFF (detection of early antigen fluorescent foci) test and virus isolation. No virus was isolated from skin swabs and serological tests including those for Epstein–Barr virus, hepatitis A, B and C, mycoplasma and legionella were negative. Biochemistry results, including lactate dehydrogenase and full blood count, were normal and autoimmune profiles were negative. Compliment levels were normal, but IgG and IgM were low at 4.4 g/l (normal range 5.4–16.1) and 0.4 g/l (normal range 0.5–1.9), respectively. Circulating IgG and IgA immune complexes were present. A chest X-ray was consistent with nodal disease, but the lungs were clear. Intensive treatment was started with mouthwashes, acyclovir, fluconazole, antibiotics, antiseptic cream and potassium permanganate bath solution. No improvement was noted, so high dose prednisolone was introduced. Over several weeks his symptoms progressed with severe cutaneous, orogenital, anal and conjunctival ulceration (Figure 1) leading to visual problems and malnutrition. Cyclosporin A was commenced, but there was no additional benefit and it was discontinued. After 4 months, some mild improvement was noted, though the skin lesions remained active and there was gradual thick-
1950 Roche pharmaceuticals report the incidence of severe skin reactions to rituximab as 0.01% in a series of 167 000 patients who received the drug, but were unable to define the individual cases further. No similar cases have been reported in the literature, but as rapidly increasing numbers of patients are receiving rituximab an awareness of the possible side effects of such treatment is crucial.
References 1. Anderson K, Bates M, Slaughenhoupt B et al. Expression of human B-cell associated antigens in leukaemias and lymphomas: a model of human B-cell differentiation. Blood 1984; 63: 1424–1433. 2. Johnson PWM, Glennie MJ. Rituximab: mechanisms and applications. Br J Cancer 2001; 85: 1619–1623. 3. McLaughlin P, Grillo-Lopez AJ et al. Rituximab chimeric anti-CD 20 monoclonal antibody therapy for relapsed indolent lymphoma. J Clin Oncol 1998; 16: 2825–2833. 4. Coiffier B, Lepage E et al. CHOP chemotherapy plus rituximab compared with CHOP chemotherapy alone in elderly patients with diffuse large B cell lymphoma. N Engl J Med 2002; 346: 235–242. 5. Foran JM, Gupta RK, Cunningham D et al. A UK multicentre phase II study of rituximab in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 2000; 109: 81–88. 6. Davis TA, White CA, Grillo-Lopez AJ et al. Single agent monoclonal antibody efficacy in bulky non-Hodgkin’s lymphoma. J Clin Oncol 1999; 17: 1851–1857. 7. Maloney DG, Grillo-Lopez AJ, White CA et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188–2195. 8. Piro LD, White CA, Grillo-Lopez AJ et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1999; 10: 655–661. 9. Byrd JC, Murphy T, Howard RS et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lyphocytic leukaemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001; 19: 2153–2164. 10. Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 2001; 345: 1000. 11. Walewski J, Kraszewska E, Mioduszewska O et al. Rituximab (Mabthera, Rituxan) in patients with recurrent indolent lymphoma: evaluation of safety and efficacy in a multicentre study. Med Oncol 2001; 18: 141–148. 12. Weatherall DJ, Leddingham JGG, Warrell DA (eds). Oxford Textbook of Medicine, 3rd edition. Oxford, UK: Oxford University Press 1996.
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on July 1, 2015
producing a response in half of patients [2, 5–9] with a median duration of response of 13 months. A recent randomised trial comparing CHOP plus rituximab with CHOP chemotherapy alone in elderly patients with diffuse large B-cell lymphoma showed a significantly higher response rate in the rituximab arm (76% versus 63%) and this is likely to pave the way for more widescale use of rituximab in lymphoma treatment [4]. These trials have reported only mild toxicity with rituximab, most adverse events being mild to moderate infusion reactions [5–9]. More serious toxicity is rare and is limited in the literature to case reports. Of interest to this case, there is one report of bronchiolitis obliterans related to rituximab [6], one of dyspnoea, haemoptysis and death 3 days after infusion [9], and one of fatal CMV reactivation [10]. Reports of cutaneous toxicity are usually limited to urticaria or pruritis, although in one study of single agent rituximab in 38 patients, one patient had to discontinue treatment due to fever and painful erythema, and several had infusion-related skin eruptions [11]. This, however, is the first reported case of Stevens–Johnson syndrome following treatment with rituximab. Stevens–Johnson syndrome is a severe variant of erythema multiforme, a mucocutaneous abnormality usually following a drug reaction or infection [12]. Common causes include Herpes simplex virus, hepatitis A or B, mycoplasma, pregnancy and malignancy. Nonscaling annular plaques are seen, often involving the limbs and plantar palmar surfaces. The lesions can become paler centrally appearing like targets. Mucous membranes can be involved with blistering and ulceration. The nose, mouth, eyes, anogenital areas and tracheobronchial tree can also be involved, and bronchiolitis obliterans is a well recognised complication. The differential diagnosis of Stevens–Johnson syndrome includes other bullous disorders, toxic epidermal necrolysis and lymphoma itself. In this case, histology did not show any features of pemphigus and on serological testing the patient had no pemphigus or pemphigoid antibodies. Histology did not show any infiltration by lymphoma and immunohistochemistry did not show any CD20+ cells; this makes lymphoma itself an unlikely cause of the skin reaction. Likewise, no viruses were isolated and viral serology was negative. The eosinophilic infiltrates suggested a drug as the cause. The patient had developed a mild rash after i.v. injection of contrast for his CT scan 1 month earlier, and as a cause this cannot be excluded, but the temporal relationship of the rituximab to the florid skin changes makes it the most likely candidate.