Kasuistiken Z Rheumatol 2015 DOI 10.1007/s00393-015-1632-z © Springer-Verlag Berlin Heidelberg 2015
A.C. Chowdhury · D.P. Misra · P.S. Patro · V. Agarwal Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow
Toxic epidermal necrolysis due to therapy with cyclophosphamide and mesna A case report of a patient with seronegative rheumatoid arthritis and rheumatoid vasculitis
Introduction Rheumatoid vasculitis (RV) is a rare but serious complication usually occurring on the background of long-standing seropositive rheumatoid arthritis (RA) [1, 2]. Toxic epidermal necrolysis (TEN) is a serious cutaneous adverse reaction associated with drug therapy, defined as erythema and desquamation involving more than 30% of body surface area [3]. We describe a patient with seronegative RA with RV who developed TEN on treatment with pulsed intravenous cyclophosphamide and mesna.
History A 39-year-old woman presented with symmetric inflammatory polyarthritis (early morning stiffness lasting 1 h) involving both wrists, metacarpophalangeal joints, proximal interphalangeal joints of hands, elbows, knees, and ankles for 6 years. She was on alternative medications for her symptoms prior to presentation. Over the past 3 months, she had developed tingling sensation in both feet followed by both hands, and during the past month she had difficulty in making a fist in both hands. In the hospital, she developed new onset weakness of dorsiflexion of the right ankle. She had no upper or lower respiratory tract symptoms, ear discharge or hearing loss, pedal edema, skin
rash, oral ulcers, malar rash, or photosensitivity. She had no history of contact with leprosy.
Findings Examination revealed bilateral median and ulnar claw hand with loss of fine touch and pain over palms and dorsa of feet. Right foot and right toe dorsiflexion were weak along with loss of pain and fine touch below ankles in both feet. Both knee and ankle reflexes were absent. There were no thickened or tender nerves. Musculoskeletal exam revealed tenderness, swelling, and restricted flexion and extension of both wrists, swelling and tenderness of right second and third metacarpophalangeal and left third metacarpophalangeal joints. Otherwise, systemic examination was normal.
Diagnostic work-up Investigations revealed normocytic anemia (hemoglobin 9.6 g%), neutrophilic leucocytosis (total leucocyte count 14,600/mm3 with 82% neutrophils), normal platelet count (348,000/mm3), elevated C-reactive protein (11.6 mg/dl, normal below 0.6 mg/dl), normal serum C3 (103 mg/dl, range 60–120 mg/dl), elevated C4 (33.7 mg/dl, range 15–25 mg/dl), negative rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibod-
ies, antinuclear antibodies (ANA, by immunofluoroscence), antibodies to doublestranded DNA (ELISA), antibodies to extractable nuclear antigens (ENA, by immunoblot), anti-neutrophil cytoplasmic antibody (ANCA, both by ELISA and immunofluorescence). Computerized tomography of the thorax, performed to look for evidence of infective foci, cavitating nodules or interstitial lung disease to suggest plausible alternate diagnoses, was normal. Nerve conduction study showed axonal neuropathy; sural nerve biopsy revealed focal axonal loss with small vessels showing fibrinoid necrosis of vessel wall with infiltration of neutrophils in the vessel wall, consistent with necrotising vasculitis. Hepatitis B surface antigen and antihepatitis C virus antibody were negative.
Treatment and course Our patient had mononeuritis multiplex with biopsy evidence of acute necrotizing arteritis on a background of rheumatoid arthritis (symmetric deforming inflammatory polyarthritis). Negative ANA and ENA as well as absence of urinary abnormalities, lymphopenia, or thrombocytopenia were against a diagnosis of systemic lupus erythematosus or Sjogren’s syndrome, which should be considered in a woman of this age group. Negative ANCA as well as absence of any otorhinolaryngologic or chest imaging abnormalities Zeitschrift für Rheumatologie 2015
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Kasuistiken
Fig. 1 8 a Maculopapular skin rash with bulla formation and desquamation involving left forearm. b Desquamating bullous lesions over the back characteristic of toxic epidermal necrolysis
were against a diagnosis of ANCA-associated small vessel vasculitis. Hence, she was classified as having RV as per Scott and Bacon criteria [4]. She was given pulsed intravenous methylprednisolone 1000 mg for 3 days followed by 1 mg/kg oral prednisolone. After 2 weeks she was started on pulses of intravenous cyclophosphamide (with mesna to decrease bladder toxicity) as per the European Vasculitis Study Group (EUVAS) protocol [5]. Seven days following the third 2-week pulse of cyclophosphamide (15 mg/kg) with mesna, she presented with maculopapular rash, starting in the legs but which soon involved most of her body surface area (. Fig. 1a, b) including palms and soles, with mucosal involvement in the form of oral ulcerations. Her skin lesions gradually became bullous and started desquamating. Investigations showed a low total leukocyte count (1600/mm3, 74% neutrophils, 25% lymphocytes; expected due to cyclophosphamide; recovered spontaneously over a week) and a persisting anemia (hemoglobin 10.2 g%) and were otherwise unremarkable. The clinical diagnosis was a severe cutaneous adverse reaction, and since erythema and desquamation involved more than 30% of the body surface area, she was diagnosed as toxic epidermal necrolysis (TEN) [depending on area of body surface involved: 30%=TEN] [3]. The SCORTEN score is useful to assess prognosis in patients with TEN, scoring presence of the following factors at presentation: age greater than 40 years, tachycardia (pulse rate more than 120/min), presence of concomitant malignancy, involvement of greater than 10% body surface area, serum urea greater than 10 mmol/l, serum
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glucose above 14 mmol/l, and serum bicarbonate less than 20 mmol/l. The higher the number of points on the SCORTEN score, the greater the risk of mortality [6]. Our patient had a SCORTEN score of 1 (area of involvement greater than 10%). As the most recent drugs introduced were cyclophosphamide and mesna, and the reaction occurred 7 days following administration of the third dose of these drugs, these were thought to be the culprits for TEN. Cyclophosphamide and mesna were withheld. Considering severity of involvement, intravenous immunoglobulin (IVIG) was administered 400 mg/kg for 5 days, and supportive care with intravenous fluids and daily dressing of affected areas was provided. Over the next month, she gradually improved with slow healing of her lesions. She was discharged after 3 weeks of hospitalization; follow-up 3 months later showed skin lesions had almost completely healed. Further cyclophosphamide was withheld, and immunosuppression with mycophenolate mofetil was started. Four months after the admission for TEN, her sensory symptoms had improved and there was no additional motor involvement.
Discussion RV is a rare but potentially life-threatening complication of long-standing untreated rheumatoid arthritis, usually of 10 years duration, classically in patients who are seropositive, i.e., positive for RF or anti-CCP antibodies [1, 2]. The pathogenesis involves secondary immune-complexmediated vasculitis complicating rheumatoid arthritis. Only isolated cases have been described in seronegative patients [7]. Since extensive evaluation revealed no other plausible alternative diagnosis, and
she satisfied criteria [4], she was classified as having seronegative RA with RV. However, on therapy with cyclophosphamide and mesna, she developed TEN. Such an association is extremely rare, with only 5 reported cases in the literature [8, 9, 10, 11], considering that cyclophosphamide has been used for more than six decades for varying indications [12]. TEN is associated with mortality in excess of 20% [3]. Ideally, rechallenge would confirm or refute the causative agent, but was considered inappropriate in view of such a severe and potentially life-threatening adverse effect. Although difficult to pinpoint which of these two drugs was the causative agent, review of prior literature suggests that mesna is not associated with a disproportionate increase in relative reporting frequency for severe cutaneous adverse reactions [13]. Hence, the most likely etiology was cyclophosphamide therapy. Fortunately, our patient had a favorable outcome on IVIG and appropriate supportive care. Steven Johnson’s syndrome (SJS)/TEN has a genetic predisposition, with recently identified associations with HLA-B*1502 (for SJS/TEN induced by carbamazepine) and HLA-B*5801 (for severe cutaneous adverse drug reactions, including SJS/ TEN, induced by allopurinol) [14]. Unfortunately, the extreme rarity of cyclophosphamide as a causative agent of TEN/SJS makes any genetic associations untenable. Hence, it becomes almost impossible to predict risk of developing this devastating severe cutaneous adverse reaction. Thus, clinicians to be all the more aware of such unusual drug reactions, when a decision to withdraw the potential drug culprit may be life saving. In patients with TEN, retrospective analyses have shown earlier healing and potential mortality benefit with IVIG therapy. Mechanistically, blocking Fas-mediated interactions by IVIG inhibits keratinocyte apoptosis [3], and this may account for its therapeutic efficacy in TEN. The decision to administer IVIG in our patient was made in view of the severity of skin involvement, and along with adjuvant supportive care, she made an excellent recovery. Cyclophosphamide for vasculitis in the context of seronegative rheumatoid arthritis causing TEN has not been de-
Abstract · Zusammenfassung scribed before. TEN with cyclophosphamide therapy is particularly challenging, because cyclophosphamide is a therapeutic option well described in TEN [3]. This case serves to highlight this rare association and educate clinicians about a rare but serious adverse effect of a commonly prescribed immunosuppressive agent.
Practical conclusion F Rheumatoid vasculitis can occur in the context of seronegative rheumatoid arthritis. F Therapy with cyclophosphamide/ mesna can cause Steven Johnson’s syndrome/toxic epidermal necrolysis. F Severe TEN is associated with high risk of mortality. F Supportive care is key in the management of SJS/TEN. F Early administration of intravenous immunoglobulin may hasten healing and confer a reduction in mortality in patients with extensive involvement.
Corresponding address Dr. D.P. Misra Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences Rae Bareily Road, 226 014 Lucknow Uttar Pradesh India
[email protected]
Compliance with ethical guidelines Conflict of inzterest. A.C. Chowdhury, D.P Misra, P.S. Patro, and V. Agarwal state that there are no conflicts of interest. Written informed consent was sought from the patient prior to submitting the article.
References 1. Turesson C, Matteson EL (2009) Vasculitis in rheumatoid arthritis. Curr Opin Rheumatol 21:35–40 2. Bartels CM, Bridges AJ (2010) RV: vanishing menace or target for new treatments? Curr Rheumatol Rep 12:414–419 3. Worswick S, Cotliar J (2011) Stevens-Johnson syndrome and TEN: a review of treatment options. Dermatol Ther 24:207–218
Z Rheumatol 2015 · [jvn]:[afp]–[alp] DOI 10.1007/s00393-015-1632-z © Springer-Verlag Berlin Heidelberg 2015 A.C. Chowdhury · D.P. Misra · P.S. Patro · V. Agarwal
Toxic epidermal necrolysis due to therapy with cyclophosphamide and mesna. A case report of a patient with seronegative rheumatoid arthritis and rheumatoid vasculitis Abstract Rheumatoid vasculitis usually occurs on the background of seropositive rheumatoid arthritis, although in rare cases the patients can be seronegative. We report a woman with seronegative rheumatoid arthritis with rheumatoid vasculitis who developed toxic epidermal necrolysis involving most of her body surface area, while on therapy with intravenous cyclophosphamide and mesna. After withdrawal of suspected offending agents, administration of intravenous immunoglob-
ulin, and supportive therapy, she had a favorable outcome. Such an occurrence is rare and serves to educate about a potentially lifethreatening adverse event associated with a commonly used immunosuppressive agent. Keywords Rheumatoid vasculitis · Seronegative rheumatoid vasculitis · Immunoglobulin · Adverse drug reaction · Immunosuppressive agents
Toxische epidermale Nekrolyse unter Therapie mit Cyclophosphamid und Mesna. Eine Kasuistik eines Patienten mit seronegativer rheumatoider Arthritis und rheumatoider Vaskulitis Zusammenfassung Eine rheumatoide Vaskulitis tritt meist vor dem Hintergrund einer seropositiven rheumatoiden Arthritis auf, selten auch bei Seronegativität. Berichtet wird über eine Patientin mit seronegativer rheumatoider Arthritis, die unter Therapie mit i.v. Cyclophosphamid und Mesna eine toxische epidermale Nekrolyse im Bereich von nahezu der gesamten Körperoberfläche entwickelte. Nach Sistieren der im Verdacht stehenden Substanzen, i.v. Gabe von Immunglobulinen und Implementierung einer supportiven Therapie kam es zu einem
4. Scott DG, Bacon PA (1984) Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic RV. Am J Med 76:377–384 5. Mukhtyar C, Guillevin L, Cid MC et al (2009) EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 68:310–317 6. Bastuji-Garin S, Fouchard N, Bertocchi M et al (2000) SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 115:149–153 7. Ikeda E, Uchigasaki S, Endo M et al (1998) RV in a patient with seronegative rheumatoid arthritis. Eur J Dermatol 8:268–270 8. Assier-Bonnet H, Aaractingi S, Cardranel J et al (1996) Stevens-Johnson syndrome induced by cyclophosphamide: report of two cases. Br J Dermatol 135:864–866 9. Patel MP, Kute VB, Vanikar AV, Trivedi HL (2014) Cyclophosphamide-induced toxic epidermal necrolysis: vigilance needed. Clin Kidney J 7:323–324 10. Leititis JU, Burghard R, Rietschel E et al (1985) Stevens-Johnson syndrome during an immunosuppressive therapy with cyclophosphamide and prednisone. Klin Padiatr 197:441–442
günstigen Verlauf und Outcome. Die Schilderung dieses selten vorkommenden Ereignisses soll für eine potenziell lebensbedrohliche Nebenwirkung in Verbindung mit einem häufig eingesetzten Immunsuppressivum sensibilisieren. Schlüsselwörter Rheumatoide Vaskulitis · Seronegative rheumatoide Vaskulitis · Immunglobulin · Unerwünschte Arzneimittelreaktion · Immunsuppressiva
11. Fernandes NC, Menezes M (2013) Pulse therapy in pemphigus: report of 11 cases. An Bras Dermatol 88:672–675 12. Friedman OM, Seligman AM (1954) Preparation of N-phosphorylated derivatives of bis-βchloroethylamine1a. J Am Chem Soc 76:655–658 13. Papay J, Yuen N, Powell G et al (2012) Spontaneous adverse event reports of Stevens-Johnson syndrome/toxic epidermal necrolysis: detecting associations with medications. Pharmacoepidemiol Drug Saf 21:289–296 14. Chung WH, Hung SI, Chen YT (2007) Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 7:317–323
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