Glinical Investigator
Clin Investig (1992) 70:698-704
Case Repert
© Springer-Verlag 1992
Mesna side effects which imitate vasculitis E. Reinhold-Keller 1, J. Mohr 1, E. Christophers 2, K. Nordmann 3, and W.L. Gross ~ l Abteilung klinische Rheumatologie der Medizinischen Universit/it zu Lfibeck und Medizinische Krankenhausabteilung der Rheumaklinik Bad Bramstedt 2 Hautklinik der Christian-Albrechts-Universit/it Kiel 3 Miihlenberg-Klinik, Malente
Summary. Mesna (sodium-2-mercaptoethansulfonate) is used in the prophylaxis of cyclophosphamide (CYC)-induced hemorrhagic cystitis. Four patients being treated with "low dose" CYC and prednisone for vasculitis developed severe side effects to Mesna. Fever, arthralgia, myalgia, tachycardia, electrocardiogram changes consistent with perimyocarditis, erythroderma, bullous skin and mucous membrane lesions, and abdominal complaints with profuse diarrhea were noted approximately 3 weeks after the initiation of therapy for CYC-induced leukopenia and a conservatively reduced prednisone dosage. Positive reexposure tests confirmed the association to Mesna use, and hypersensitivity skin tests demonstrated a delayed hypersensitivity reaction.
Key words: Mesna - Hemorrhagic cystitis - Vasculids
Cyclophosphamide (CYC)-induced hemorrhagic cystitis has been reported in up to one-third of a patient population treated for severe necrotizing vasculitis using the Fauci therapy scheme [6], CYC 2-4 mg/kg daily and prednisone 1 mg/kg daily (Table 1). Carcinoma of the bladder is known to follow hemorrhagic cystitis in some cases. Stillwell et al. [17] reports 3 cases of bladder cancer in 111 Wegener's granulomatosis patients treated with CYC over a period of 13-144 months at a total CYC dosage of 56-534 g. All 3 bladder cancers followed hemorrhagic cystitis. Of the 78 patients treated with low dose CYC for Wegener's granuloAbbreviations: C Y C = c y c l o p h o s p h a m i d e ; W B C = w h i t e blood count; A N A = antinuclear antibodies; AP = alkaline phosphatase; SGPT = serum glutamic pyruvic transaminase; SGOT = serum glutamic oxaloacetic transaminase; S G G T = s e r u m 7glutamyl transaminase; E C G = e l e c t r o c a r d i o g r a p h y ; A N C A = antineutrophil cytoplasmic antibodies; c A N C A = c y t o p l a s m i c fluorescence pattern; p A N C A = p e r i n u c l e a r fluorescence pattern; PR3 = proteinase-3-antibodies ; W G = Wegener's granulomatosis
matosis (WG) in our clinic, 6 (8%) developed hemorrhagic cystitis, and the therapy was discontinued. In order to reduce normal and low dose CYC urotoxicity, Mesna (sodium-2-mercaptoethansulfonate) is used in an oral and parenteral form to bind CYC metabolites toxic to the bladder mucosa [16]. At present, side effects of Mesna have only been described in oncological cases and were always mild. They are normally gastrointestinal in nature and, due to the distinctive taste, often lead to problems of noncompliance when the drug is given orally. We earlier reported in a short letter [i0] 3 occasions of severe, in some cases life-threatening, hypersensitivity reactions to Mesna in the treatment of systemic vasculitis using the Fauci therapy scheme. In addition to the 3 cases mentioned above, we now present detailed clinical and allergological information on a total of 4 cases (1 Wegener's granulomatosis, 2 microscopic polyarteritis, 1 classic polyarteritis nodosa).
Case reports Case 1
A 38-year-old man was admitted in December 1990 because of a generalized vasculitis and granulomatous process with involvement of the upper and lower airways, kidneys, heart, arthralgias, myalgias, and constitutional symptoms. Serologically, a high inflammatory activity and a positive cytoplasmic fluorescence pattern (cANCA) (PR 3-antibody) were found. Histology study of the nasal mucosa was compatible with Wegener's granulomatosis. The patient was treated with the Fauci therapy scheme (CYC 2-4 mg/kg daily and methylprednisolone 40 mg/day) and 1000 mg Mesna per os three times daily (qid) starting December18, 1990 (day 1). The patient's condition continued to deteriorate, however, and parenteral therapy was started
699 Table 1. Hemorrhagic cystitis in cyclophosphamide (CYC) treatment of nononcological patients Reference
Disease/mean daily CYC dose
1968
Fosdick et al. [7]
1973
Dale et al. [4]
1973
Fries et al. [8]
1973
Aptekar et al. [1]
1975
Reza et al. [15]
1976
Townes et al. [18]
1978
Donadio et al. [5]
1979
Plotz et al. [13]
1980
Williams et al. [19]
1983
Carette et al. [3]
1983
Fauci et al. [6]
1986
Austin et al. [2]
1988
Stillwell et al. [17]
1991
Haubitz et al. [11]
Rheumatoid arthritis 50-150 mg Wegener's granulomatosis 50-150 mg Connective tissue diseases 125 mg Systemic lupus erythematosus, rheumatoid arthritis Wegener's granulomatosis 1.5 mg/kg Wegener's granulomatosis 117 mg Rheumatoid arthritis 1.8 mg/kg Systemic lupus erythematosus 107 mg Systemic lupus erythematosus, rhenmatoid arthritis 1-4 mg/kg Rheumatoid arthritis 75-150 mg Systemic lupus erythematosus up to 4 mg/kg Wegener's granulomatosis 2 mg/kg Systemic lupus erythematosus up to 4 mg/kg Wegener's granulomatosis 100 mg Wegener's granulomatosis 2 mg/kg
on day 4, the steroids being increased to 40 mg qid and Mesna 400 mg i.v. three times daily. CYC and Mesna were discontinued on day 17 when a leukopenia of 3000/mm and increased hepatic enzymes activities - serum glutamic pyruvic transaminase (SGPT) 704 U/l, serum glutamic oxaloalacetic transaminase (SGOT) 150 U/l, serum ~-glutamyl transaminase (SGGT) 128 U/l, and alkaline phosphatase (AP) 193 U/1 - were noted. The white blood cell (WBC) continued to fall despite the stop of CYC and reached a minimum of 230/mm 3 on day 22. Broad antibiotic and antimycotic coverage was achieved with fluconazole, piperacillin, cefotaxime, and colistin sulfate during the leukopenic phase from days 20 to 26. A macular exanthema appeared on day 25 on the arms and legs which prompted the termination of the antibiotic and antimycotic therapy. The exanthema resolved quickly and without further consequence. CYC therapy was restarted after the leukocyte count normalized on day 28. Mesna was given per os, and the daily steroid dosage was reduced to 16 rag. Signs and symptoms of the original disease were no longer observed.
No. affected/ total no. of patients 3/38
(8%)
1/8
(12%)
2/12
(17%)
13/46
(28%)
1/10
(10%)
4/24
(17%)
0/24
(0%)
7/54
(13%)
13/74
(18%)
3/18
(17%)
27/80
(34%)
3/18
(17%)
17/111 (15%) 0/15
(0%)
On the evening of day 28, the oral temperature was measured at 39.2 ° C, and the heart rate was 120/min. Facial edema, conjunctivitis, massive mucosa ulceration, general erythema and pruritus, arthralgia, and myalgia were noted. Massive skin bullae formation occurred, followed by flaky, lamellar exfoliation and severe malaise (Fig. 1). The various medications, were discontinued, apart from the CYC and the steroid therapy, which was temporarily increased, and the signs and symptoms resolved without consequence over the next 3 weeks. The patient was reexposed to Mesna on day 59, and similar - but less severe - symptoms were noted. A positive delayed type reaction was demonstrated with Mesna (Uromitexan oral and i.v. ampules) in hypersensitivity skin testing. Immunoglobulin E radioallergosorbent tests for various antibiotics and antimycotics were negative. Case 2
In a 38-year-old man, a microscopic polyarteritis was diagnosed in 1991 with involvement of the
700
Fig. 1. Massive skin bullae followed by lamellar exfoliation (case 1)
kidneys, lungs, heart, skin, and gut. Further symptoms included arthralgias, myalgias, mucosal ulcerations, and constitutional symptoms. Serum analysis yielded an inflammatory activity and a positive perinuclear fluorescence pattern (pANCA) test (myeloperoxidase-specific antibodies). Fine needle renal biopsy demonstrated severe focal/segmental sclerosing glomerulonephritis, while the immunohistology result was negative. The patient was started on an intravenous Fauci therapy scheme: CYC 2.5 mg/kg daily, methylprednisolone 40 mg/day, and Mesna 400 mg i.v. each morning, 1000 mg per os at noon and in the evening on 20 February 1991 (day 1). Starting on day 13, all medications were given orally. CYC and Mesna were discontinued on day 19 when a leukopenia of 3360/mm 3 and increased hepatic enzymes activities were noted - SGPT 285 U/ 1, SGOT 100 U/l, and SGGT 36 U/1. AP activity was normal. Upon normalization of the WBC on day 22, CYC and Mesna therapy was restarted, the methylprednisolone dosage being 16 mg/day. A heart rate of 100/min was noted on the evening of day 22, as well as a maculopapular rash on the trunk, arms, and legs. CYC and Mesna were discontinued on day 24 because of a decrease in the WBC to 2860/mm 3, and the skin lesions resolved shortly thereafter. A similar clinical picture developed upon restarting therapy on day 29, and the temperature was measured at 39 ° C. A skin biopsy specimen was taken, and the histology was consistent with erythema exsudativum multiforme.
Case 3
A 64-year-old woman was admitted with the diagnosis of a microscopic polyarteritis. Clinically, she showed signs of a perimyocarditis, kidney involvement, polyneuropathy, arthralgias, myalgias, and constitutional symptoms and serologically proved to have a high inflammatory activity. Repeated testing for c/pANCA and antinuclear antibodies (ANA) was negative. The patient was treated according to the Fauci therapy scheme (CYC 2-4 mg/kg daily and 40 mg methylprednisolone/day) and 1000 mg Mesna per os tid starting 31 October 1990 (day 1). CYC and Mesna were discontinued on day 20 when a leukopenia of 3300/mm 3 was noted. Upon normalization of the WBC on day 31, CYC and Mesna therapy was restarted, the daily methylprednisolone dosage being 8 mg. A flaming red facial erythema developed on the evening of day 31. A rash over the entire body was noted, which progressed to bullae formation over all skin areas, as well as the oral, anal, and vulval mucosa. Her temperature was measured at 40 ° C, and the heart rate at 120/ rain. The patient coughed up bloody sputum and suffered from tachypnea and massive, watery diarrhea mixed with mucosa residue. ST segment elevation appeared in leads II, III, and aVF, and T negativity in all precordial leads on day 32 (Figs. 2, 3). CYC and Mesna therapy was discontinued, and intensive medical attention and high-dose steroids were given. The symptoms resolved within 2 weeks. A similar, but less severe, medical picture
701
Figs. 2 and 3. Electrocardiography (ECG) changes following Mesna side-effects (case 3) in ST segment elevation in leads II, III, aVF and T negativity in all precordial leads (left side: before Mesna side-effects)
occurred when the CYC and Mesna therapy was restarted. The daily steroid dosage at this time was 14mg. A positive delayed reaction to Mesna per os and i.v. (Uromitexan) was demonstrated with hypersensitivity skin testing (at a methyl-prednisolone dosage of 12 mg/day !). A considerable general reaction occurred during testing, with tachycardia, hypotension, malaise, conjunctivitis, and stomatitis. Case 4
In a 52-year-old man, a classical polyarteritis was diagnosed in 1990 with involvement of the heart (4 myocardial infarctions between July 1990 and February 1991), eyes, gut, central nervous system, Raynaud and constitutional symptoms. Serum analysis showed a high inflammatory activity, but tests for c/pANCA and A N A remained negative. Severe disseminated angiopathy, especially in the
peripheral areas, was noted in coronary angiography studies. Inflammatory vessel disease was suspected. A generalized pathological picture with rarefaction of the hepatic and superior mesenteric arteries and many microaneurysms in numerous branches were seen on celiac angiography. The patient was treated according to the Fauci therapy scheme (CYC 3 mg/kg daily and 40 rag/ day methylprednisolone) and Mesna orally 1000 mg tid starting 28 March 1991 (day 1). Cardiac therapy included isosorbide dinitrate, nifedipine, metoprolol, and low-dose heparin. The CYC dosage was halved on day 24 when a leukopenia of 3500/mm 3 and increased hepatic enzymes activities - SGPT 92 U/l, SGGT 63 U/1 - were noted. SGOT and AP activities were normal. The steroid dosage was 12 mg/day. Keeping in mind that the preceding 3 hypersensitivity reactions to Mesna had occurred using per os application, Mesna was given i.v., 200 mg tid, starting on day 24. A maculopapular rash appeared on day 29 accompanied
702
Fig. 4. A positive delayed type reaction after 48 h: 1= Mesna oral (Uromitexan); 2 = ethylene diamine tetra-acetic acid; 3/4 = two different product batches of Mesna; 5 = Mesna i.v. (Uromitexan); 6 = Mistabronco (Mesna for expectoration); case 4
by malaise. The skin lesion resolved quickly after the Mesna was discontinued. Reexposure to Mesna on day 33 brought about an identical reaction. A positive delayed type reaction was demonstrated to oral and i.v. Mesna (Uromitexan), 2 different product batches, and to Mistabronco (Mesna for expectoration) with hypersensitivity skin testing (Fig. 4). Discussion
Hypersensitivity reactions to Mesna are uncommon in the literature and have only been reported in oncological patients. Frosch et al. [9] described a 25-year-old, male patient with Hodgkin's disease taking Mesna who developed a maculopapular rash and temperatures of up to 39 ° C. The connection to Mesna was confirmed by hypersensitivity
skin test (delayed hypersensitivity reaction type IV, Coombs and Gell). Pratt et al. [14] also reported minor urticarial reactions to Mesna in 3 osteosarcoma patients in 1986. A maculopapular rash was observed in 1 case. Lang and Goos [12] report a reaction to Mesna in a patient suffering from Hodgkin's disease in 1985. They observed fever, vertigo, nausea, myalgia, conjunctivitis, periorbital edema, and a maculo-papular rash in 1 case. All three authors classify the reactions as mild. In a review of the literature, no case of hypersensitivity reactions to Mesna can be found in nononcological cases. The four patients presented here were being treated with the Fauci therapy scheme for severe, systemic vasculitis. Mesna was given in oral and i.v. form to reduce the urotoxicity of CYC. Severe, in some cases lifethreatening, hypersensitivity reactions to Mesna occurred in all 4 patients. The hypersensitivity symptoms in all cases occurred after approximately 3 weeks of therapy with CYC, prednisolone, and Mesna. All patients developed a leukopenia of ca. 3000/mm 3 at that time, probably as a result of the therapy with CYC, which forced the termination of the CYC - and thus also Mesna - therapy in 3 of 4 cases. The CYC dosage was halved in the 4th case. The steroid therapy dosage, which was not interrupted, was relatively low, between 8 and 16 mg/day. The side effects occurred in the 3 patients who discontinued the CYC plus Mesna therapy on the evening of restarting therapy after W B C normalization. The clinical picture observed in the different cases is quite variable. The possibility that the reaction was due to the medication was vaguely indicated by the common skin and mucosa lesions. The skin and mucosa signs progressed in 2 cases to a generalized butlae formation, with severe mucosa ulcerations and pronounced malaise. The symptoms are reminiscent of toxic epidermal necrolysis (Lyell's syndrome). The rapid and complete resolution of symptoms makes a pathology in the lower dermal strata doubtful. A generalized maculopapular rash was observed in the other 2 patients. In three cases, temperature rises of up to 40 ° C accompanied the clinical symptoms, and tachycardia persisted after the fever returned to baseline. E C G changes consistent with perimyocarditis accompanied the hypersensitivity reaction in 1 patient (case 3). It is also notable that 3 patients had, in some cases, highly pathological hepatic enzyme levels when the leukopenia arose, ca. 3 weeks after the initiation of therapy, and that these values normalized after only Mesna was discontinued.
703 All patients demonstrated normal levels of hepatic enzyme at the height of the course of the original disease prior to therapy. These values became pathological at a time when the signs of disease had declined. Thus, a relationship between the original disease and the reported symptoms is improbable. An association with Mesna therapy must be assumed. C o m m o n among all cases was the clinical picture of arthralgia, myalgia, and general malaise. Numerous symptoms indicated a relapse of the original disease. This is especially true in case 3, where the Mesna hypersensitivity was associated with ECG changes consistent with perimyocarditis. Cardiac pathology was also a major element in the clinical picture of the original disease. Increases in temperature, and in some cases fever-independent tachycardia, arthralgia, and myalgia are all consistent with a relapse of vasculitis. Leukopenia and stable A N C A serology are examples of laboratory data inconsistent with this diagnosis. The cause of the reaction to Mesna appears allergic in nature. To omit uroprotection in patients on long-term CYC therapy could result in serious problems due to bladder toxicity. Furthermore, allergic reactions to Mesna as seen in our patients had not been described before. This was the rationale for performing reexposure tests using small doses of Mesna, which led to the predicted symptoms in all patients. The hypersensitivity skin test result is also consistent with a delayed hypersensitivity reaction after 24-72 h (type IV, Coombs and Gell) to both the oral and parenteral application forms. Corresponding controls (for example with penicillin, other antibiotics, and other allergens) did not demonstrate skin reactions. This is consistent with the findings of Frosch et al. [9], who also observed a delayed reaction in hypersensitivity skin testing with an oncological patient sensitive to Mesna. Further supporting evidence is the observation that 8 additional vasculitis patients being treated with CYC and a similar Mesna dosage over at least a 6-month period also had negative hypersensitivity skin test results to Mesna (both the oral and parenteral application forms). The association between the hypersensitivity symptoms and the exposure to Mesna is strengthened by the uncomplicated clinical course after the termination of Mesna therapy, while all other medication was continued at the same dose. It is unclear why such severe hypersensitivity symptoms do not seem to occur in oncological cases, but rather, in patients suffering from autoimmune diseases (connective tissue disease, vasculitis, etc.). These types of diseases
may predispose patients to the severe reactions described, although the pathomechanism is uncertain. Perhaps Mesna is not used for uroprotection in nononcological cases, resulting in the lack of hypersensitivity reports in this group of diseases. In the various CYC studies listed in Table 1, Mesna was included in the therapy regimen in only one instance, by Haubitz et al. [11]. Notably, there are no cases of hemorrhagic cystitis in this study. At least 3 of the 6 vasculitis patients who suffered from hemorrhagic cystitis in our treatment group had documented, irregular Mesna uroprotection. This report certainly does not contraindicate a general uroprotection with Mesna in low-dose CYC therapy. While nononcological patients are treated with lower CYC doses than oncological patients, they are often younger and frequently require long-term therapy with high cumulative doses. Up to one-third of the nononcological patients treated with CYC developed hemorrhagic cystitis (Table 1), and Stillwell et al. report an incidence of bladder carcinoma of 18% following hemorrhagic cystitis. Thus, this complication is a serious problem in the treatment of autoimmune disease and forces an interruption in therapy. Due to the severity of the reactions to Mesna described here, we informed the German Drug Council and the manufacturer of Mesna. The manufacturer withdrew the oral application form from the market, which we regret. Uroprotection is not contraindicated in autoimmune diseases, especially as serious side effects seem rare. The reason for the increased incidence of Mesna hypersensitivity reactions within a 6-month period is unclear. It is also interesting that similar observations in nononcological patients during the same time were reported from other centers as well. In a retrospective review of our vasculitis patient population, we found at least 2 additional cases of probable Mesna hypersensitivity. They presented as a mild rash and did not indicate further work-up. It is possible that severe hypersensitivity reactions in the past were not recognized as such. The purpose of' this report is to call attentiof~ to the possibility of severe side effects to Mesna and to suggest considering a Mesna hypersensitivity reaction during vasculitis therapy before taking other, possibly fatal therapeutic steps when this clinical picture occurs. The identification of patients at risk using skin tests should be considered among oncological and nononcological patients; this would help clarify the scope of the problem.
704
Acknowledgement. We wish to thank to Mr. David Maslen for his assistance. References
1. Aptekar RG, Atkinson JP, Decker JL, Wolff SM, Chu EW (1973) Bladder toxicity with chronic oral cyclophosphamide therapy in non-malignant disease. Arthritis Rheum 16:461467 2. Austin HA, Klippel JH, Balow JE, LeRiche NGH, Steinberg AD, Plotz PH, Decker JL (1986) Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314 : 614-619 3. Carette S, Klippel JH, Decker JL, Austin HA, Plotz PH, Steinberg AD, Balow JE (1983) Controlled studies of oral immunosuppressive drugs in lupus nephritis. Ann Intern Med 99 : 1-8 4. Dale DC, Fauci AS, Wolff SM (1973) The effect of cyclophosphamide on leukocyte kinetics and susceptibility to infection in patients with Wegener's granulomatosis. Arthritis Rheum 16:657-664 5. Donadio JV, Holley KE, Ferguson RH, Ilstrup DM (1978) Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. N Engl J Med 299:1151-1155 6. Fauci AS, Haynes BF, Katz P, Wolff SM (1983) Wegener's granulomatosis : prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98:7685 7. Fosdick WM, Parsons JL, Hill DF (1968) Long-term cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 11 : 151 160 8. Fries JF, Sharp GC, McDevitt HO, Holman HR (1973) Cyclophosphamide therapy in systemic lupus erythematosus and polymyositis. Arthritis Rheum 16 : 154-162 9. Frosch PJ, Weickel R, Deboben A, Hunstein W (1986) A1lergie vom Spfittyp nach Mesna. Dtsch Med Wochenschr 111 : 1901-1902 10. Gross WL, Mohr J, Christophers E (1991) Allergic reactions to Mesna. Lancet 338:381
11. Haubitz M, Frei U, Rother U, Brunkhorst R, Koch KM (1991) Cyclophosphamide pulse therapy in Wegener's granulomatosis. Nephrol Dial Transplant 6:531-535 12. Lang E, Goos M (1985) Hypersensitivity to Mesna. Lancet: 329 13. Plotz PH, Klippel JH, Decker JL, Grauman D, Wolff B, Brown BC, Rutt G (1979) Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann Intern Med 91:221-223 14. Pratt CB, Sandlund JT, Meyer WH, Cain AM (1988) Mesha-induced urticaria. Drug Intelligence Clin Pharm 22:913914 15. Reza MJ, Dornfeld L, Goldberg LS, Bluestone R, Pearson CM (1975) Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide. Arthritis Rheum 18 : 501-506 16. Shaw IC, Graham MI (1987) Mesna - a short review. Cancer Treat Rev 14:6%86 17. Stillwell T J, Benson RC, DeRemee RA, McDonald TJ, Weiland LH (1988) Cyclophosphamide-induced bladder toxicity in Wegener's granulomatosis. Arthritis Rheum 31:465 470 18. Townes AS, Sowa JM, Shulman LE (1976) Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 19:563-573 19. Williams HJ, Reading JC, Ward JR, O'Brien WM (1980) Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 23 : 521-527
Received: February 11, 1992 Returned for revision: April 15, 1992 Accepted: May 21, 1992
Dr. Eva Reinhold-Keller Rheumaklinik Bad Bramstedt Oskar-Alexander-Strasse 26 W-2357 Bad Bramstedt, FRG
Clin Investig (1992) 70:698-704
Case Repert
© Springer-Verlag 1992
Mesna side effects which imitate vasculitis E. Reinhold-Keller 1, J. Mohr 1, E. Christophers 2, K. Nordmann 3, and W.L. Gross ~ l Abteilung klinische Rheumatologie der Medizinischen Universit/it zu Lfibeck und Medizinische Krankenhausabteilung der Rheumaklinik Bad Bramstedt 2 Hautklinik der Christian-Albrechts-Universit/it Kiel 3 Miihlenberg-Klinik, Malente
Summary. Mesna (sodium-2-mercaptoethansulfonate) is used in the prophylaxis of cyclophosphamide (CYC)-induced hemorrhagic cystitis. Four patients being treated with "low dose" CYC and prednisone for vasculitis developed severe side effects to Mesna. Fever, arthralgia, myalgia, tachycardia, electrocardiogram changes consistent with perimyocarditis, erythroderma, bullous skin and mucous membrane lesions, and abdominal complaints with profuse diarrhea were noted approximately 3 weeks after the initiation of therapy for CYC-induced leukopenia and a conservatively reduced prednisone dosage. Positive reexposure tests confirmed the association to Mesna use, and hypersensitivity skin tests demonstrated a delayed hypersensitivity reaction.
Key words: Mesna - Hemorrhagic cystitis - Vasculids
Cyclophosphamide (CYC)-induced hemorrhagic cystitis has been reported in up to one-third of a patient population treated for severe necrotizing vasculitis using the Fauci therapy scheme [6], CYC 2-4 mg/kg daily and prednisone 1 mg/kg daily (Table 1). Carcinoma of the bladder is known to follow hemorrhagic cystitis in some cases. Stillwell et al. [17] reports 3 cases of bladder cancer in 111 Wegener's granulomatosis patients treated with CYC over a period of 13-144 months at a total CYC dosage of 56-534 g. All 3 bladder cancers followed hemorrhagic cystitis. Of the 78 patients treated with low dose CYC for Wegener's granuloAbbreviations: C Y C = c y c l o p h o s p h a m i d e ; W B C = w h i t e blood count; A N A = antinuclear antibodies; AP = alkaline phosphatase; SGPT = serum glutamic pyruvic transaminase; SGOT = serum glutamic oxaloacetic transaminase; S G G T = s e r u m 7glutamyl transaminase; E C G = e l e c t r o c a r d i o g r a p h y ; A N C A = antineutrophil cytoplasmic antibodies; c A N C A = c y t o p l a s m i c fluorescence pattern; p A N C A = p e r i n u c l e a r fluorescence pattern; PR3 = proteinase-3-antibodies ; W G = Wegener's granulomatosis
matosis (WG) in our clinic, 6 (8%) developed hemorrhagic cystitis, and the therapy was discontinued. In order to reduce normal and low dose CYC urotoxicity, Mesna (sodium-2-mercaptoethansulfonate) is used in an oral and parenteral form to bind CYC metabolites toxic to the bladder mucosa [16]. At present, side effects of Mesna have only been described in oncological cases and were always mild. They are normally gastrointestinal in nature and, due to the distinctive taste, often lead to problems of noncompliance when the drug is given orally. We earlier reported in a short letter [i0] 3 occasions of severe, in some cases life-threatening, hypersensitivity reactions to Mesna in the treatment of systemic vasculitis using the Fauci therapy scheme. In addition to the 3 cases mentioned above, we now present detailed clinical and allergological information on a total of 4 cases (1 Wegener's granulomatosis, 2 microscopic polyarteritis, 1 classic polyarteritis nodosa).
Case reports Case 1
A 38-year-old man was admitted in December 1990 because of a generalized vasculitis and granulomatous process with involvement of the upper and lower airways, kidneys, heart, arthralgias, myalgias, and constitutional symptoms. Serologically, a high inflammatory activity and a positive cytoplasmic fluorescence pattern (cANCA) (PR 3-antibody) were found. Histology study of the nasal mucosa was compatible with Wegener's granulomatosis. The patient was treated with the Fauci therapy scheme (CYC 2-4 mg/kg daily and methylprednisolone 40 mg/day) and 1000 mg Mesna per os three times daily (qid) starting December18, 1990 (day 1). The patient's condition continued to deteriorate, however, and parenteral therapy was started
699 Table 1. Hemorrhagic cystitis in cyclophosphamide (CYC) treatment of nononcological patients Reference
Disease/mean daily CYC dose
1968
Fosdick et al. [7]
1973
Dale et al. [4]
1973
Fries et al. [8]
1973
Aptekar et al. [1]
1975
Reza et al. [15]
1976
Townes et al. [18]
1978
Donadio et al. [5]
1979
Plotz et al. [13]
1980
Williams et al. [19]
1983
Carette et al. [3]
1983
Fauci et al. [6]
1986
Austin et al. [2]
1988
Stillwell et al. [17]
1991
Haubitz et al. [11]
Rheumatoid arthritis 50-150 mg Wegener's granulomatosis 50-150 mg Connective tissue diseases 125 mg Systemic lupus erythematosus, rheumatoid arthritis Wegener's granulomatosis 1.5 mg/kg Wegener's granulomatosis 117 mg Rheumatoid arthritis 1.8 mg/kg Systemic lupus erythematosus 107 mg Systemic lupus erythematosus, rhenmatoid arthritis 1-4 mg/kg Rheumatoid arthritis 75-150 mg Systemic lupus erythematosus up to 4 mg/kg Wegener's granulomatosis 2 mg/kg Systemic lupus erythematosus up to 4 mg/kg Wegener's granulomatosis 100 mg Wegener's granulomatosis 2 mg/kg
on day 4, the steroids being increased to 40 mg qid and Mesna 400 mg i.v. three times daily. CYC and Mesna were discontinued on day 17 when a leukopenia of 3000/mm and increased hepatic enzymes activities - serum glutamic pyruvic transaminase (SGPT) 704 U/l, serum glutamic oxaloalacetic transaminase (SGOT) 150 U/l, serum ~-glutamyl transaminase (SGGT) 128 U/l, and alkaline phosphatase (AP) 193 U/1 - were noted. The white blood cell (WBC) continued to fall despite the stop of CYC and reached a minimum of 230/mm 3 on day 22. Broad antibiotic and antimycotic coverage was achieved with fluconazole, piperacillin, cefotaxime, and colistin sulfate during the leukopenic phase from days 20 to 26. A macular exanthema appeared on day 25 on the arms and legs which prompted the termination of the antibiotic and antimycotic therapy. The exanthema resolved quickly and without further consequence. CYC therapy was restarted after the leukocyte count normalized on day 28. Mesna was given per os, and the daily steroid dosage was reduced to 16 rag. Signs and symptoms of the original disease were no longer observed.
No. affected/ total no. of patients 3/38
(8%)
1/8
(12%)
2/12
(17%)
13/46
(28%)
1/10
(10%)
4/24
(17%)
0/24
(0%)
7/54
(13%)
13/74
(18%)
3/18
(17%)
27/80
(34%)
3/18
(17%)
17/111 (15%) 0/15
(0%)
On the evening of day 28, the oral temperature was measured at 39.2 ° C, and the heart rate was 120/min. Facial edema, conjunctivitis, massive mucosa ulceration, general erythema and pruritus, arthralgia, and myalgia were noted. Massive skin bullae formation occurred, followed by flaky, lamellar exfoliation and severe malaise (Fig. 1). The various medications, were discontinued, apart from the CYC and the steroid therapy, which was temporarily increased, and the signs and symptoms resolved without consequence over the next 3 weeks. The patient was reexposed to Mesna on day 59, and similar - but less severe - symptoms were noted. A positive delayed type reaction was demonstrated with Mesna (Uromitexan oral and i.v. ampules) in hypersensitivity skin testing. Immunoglobulin E radioallergosorbent tests for various antibiotics and antimycotics were negative. Case 2
In a 38-year-old man, a microscopic polyarteritis was diagnosed in 1991 with involvement of the
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Fig. 1. Massive skin bullae followed by lamellar exfoliation (case 1)
kidneys, lungs, heart, skin, and gut. Further symptoms included arthralgias, myalgias, mucosal ulcerations, and constitutional symptoms. Serum analysis yielded an inflammatory activity and a positive perinuclear fluorescence pattern (pANCA) test (myeloperoxidase-specific antibodies). Fine needle renal biopsy demonstrated severe focal/segmental sclerosing glomerulonephritis, while the immunohistology result was negative. The patient was started on an intravenous Fauci therapy scheme: CYC 2.5 mg/kg daily, methylprednisolone 40 mg/day, and Mesna 400 mg i.v. each morning, 1000 mg per os at noon and in the evening on 20 February 1991 (day 1). Starting on day 13, all medications were given orally. CYC and Mesna were discontinued on day 19 when a leukopenia of 3360/mm 3 and increased hepatic enzymes activities were noted - SGPT 285 U/ 1, SGOT 100 U/l, and SGGT 36 U/1. AP activity was normal. Upon normalization of the WBC on day 22, CYC and Mesna therapy was restarted, the methylprednisolone dosage being 16 mg/day. A heart rate of 100/min was noted on the evening of day 22, as well as a maculopapular rash on the trunk, arms, and legs. CYC and Mesna were discontinued on day 24 because of a decrease in the WBC to 2860/mm 3, and the skin lesions resolved shortly thereafter. A similar clinical picture developed upon restarting therapy on day 29, and the temperature was measured at 39 ° C. A skin biopsy specimen was taken, and the histology was consistent with erythema exsudativum multiforme.
Case 3
A 64-year-old woman was admitted with the diagnosis of a microscopic polyarteritis. Clinically, she showed signs of a perimyocarditis, kidney involvement, polyneuropathy, arthralgias, myalgias, and constitutional symptoms and serologically proved to have a high inflammatory activity. Repeated testing for c/pANCA and antinuclear antibodies (ANA) was negative. The patient was treated according to the Fauci therapy scheme (CYC 2-4 mg/kg daily and 40 mg methylprednisolone/day) and 1000 mg Mesna per os tid starting 31 October 1990 (day 1). CYC and Mesna were discontinued on day 20 when a leukopenia of 3300/mm 3 was noted. Upon normalization of the WBC on day 31, CYC and Mesna therapy was restarted, the daily methylprednisolone dosage being 8 mg. A flaming red facial erythema developed on the evening of day 31. A rash over the entire body was noted, which progressed to bullae formation over all skin areas, as well as the oral, anal, and vulval mucosa. Her temperature was measured at 40 ° C, and the heart rate at 120/ rain. The patient coughed up bloody sputum and suffered from tachypnea and massive, watery diarrhea mixed with mucosa residue. ST segment elevation appeared in leads II, III, and aVF, and T negativity in all precordial leads on day 32 (Figs. 2, 3). CYC and Mesna therapy was discontinued, and intensive medical attention and high-dose steroids were given. The symptoms resolved within 2 weeks. A similar, but less severe, medical picture
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Figs. 2 and 3. Electrocardiography (ECG) changes following Mesna side-effects (case 3) in ST segment elevation in leads II, III, aVF and T negativity in all precordial leads (left side: before Mesna side-effects)
occurred when the CYC and Mesna therapy was restarted. The daily steroid dosage at this time was 14mg. A positive delayed reaction to Mesna per os and i.v. (Uromitexan) was demonstrated with hypersensitivity skin testing (at a methyl-prednisolone dosage of 12 mg/day !). A considerable general reaction occurred during testing, with tachycardia, hypotension, malaise, conjunctivitis, and stomatitis. Case 4
In a 52-year-old man, a classical polyarteritis was diagnosed in 1990 with involvement of the heart (4 myocardial infarctions between July 1990 and February 1991), eyes, gut, central nervous system, Raynaud and constitutional symptoms. Serum analysis showed a high inflammatory activity, but tests for c/pANCA and A N A remained negative. Severe disseminated angiopathy, especially in the
peripheral areas, was noted in coronary angiography studies. Inflammatory vessel disease was suspected. A generalized pathological picture with rarefaction of the hepatic and superior mesenteric arteries and many microaneurysms in numerous branches were seen on celiac angiography. The patient was treated according to the Fauci therapy scheme (CYC 3 mg/kg daily and 40 rag/ day methylprednisolone) and Mesna orally 1000 mg tid starting 28 March 1991 (day 1). Cardiac therapy included isosorbide dinitrate, nifedipine, metoprolol, and low-dose heparin. The CYC dosage was halved on day 24 when a leukopenia of 3500/mm 3 and increased hepatic enzymes activities - SGPT 92 U/l, SGGT 63 U/1 - were noted. SGOT and AP activities were normal. The steroid dosage was 12 mg/day. Keeping in mind that the preceding 3 hypersensitivity reactions to Mesna had occurred using per os application, Mesna was given i.v., 200 mg tid, starting on day 24. A maculopapular rash appeared on day 29 accompanied
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Fig. 4. A positive delayed type reaction after 48 h: 1= Mesna oral (Uromitexan); 2 = ethylene diamine tetra-acetic acid; 3/4 = two different product batches of Mesna; 5 = Mesna i.v. (Uromitexan); 6 = Mistabronco (Mesna for expectoration); case 4
by malaise. The skin lesion resolved quickly after the Mesna was discontinued. Reexposure to Mesna on day 33 brought about an identical reaction. A positive delayed type reaction was demonstrated to oral and i.v. Mesna (Uromitexan), 2 different product batches, and to Mistabronco (Mesna for expectoration) with hypersensitivity skin testing (Fig. 4). Discussion
Hypersensitivity reactions to Mesna are uncommon in the literature and have only been reported in oncological patients. Frosch et al. [9] described a 25-year-old, male patient with Hodgkin's disease taking Mesna who developed a maculopapular rash and temperatures of up to 39 ° C. The connection to Mesna was confirmed by hypersensitivity
skin test (delayed hypersensitivity reaction type IV, Coombs and Gell). Pratt et al. [14] also reported minor urticarial reactions to Mesna in 3 osteosarcoma patients in 1986. A maculopapular rash was observed in 1 case. Lang and Goos [12] report a reaction to Mesna in a patient suffering from Hodgkin's disease in 1985. They observed fever, vertigo, nausea, myalgia, conjunctivitis, periorbital edema, and a maculo-papular rash in 1 case. All three authors classify the reactions as mild. In a review of the literature, no case of hypersensitivity reactions to Mesna can be found in nononcological cases. The four patients presented here were being treated with the Fauci therapy scheme for severe, systemic vasculitis. Mesna was given in oral and i.v. form to reduce the urotoxicity of CYC. Severe, in some cases lifethreatening, hypersensitivity reactions to Mesna occurred in all 4 patients. The hypersensitivity symptoms in all cases occurred after approximately 3 weeks of therapy with CYC, prednisolone, and Mesna. All patients developed a leukopenia of ca. 3000/mm 3 at that time, probably as a result of the therapy with CYC, which forced the termination of the CYC - and thus also Mesna - therapy in 3 of 4 cases. The CYC dosage was halved in the 4th case. The steroid therapy dosage, which was not interrupted, was relatively low, between 8 and 16 mg/day. The side effects occurred in the 3 patients who discontinued the CYC plus Mesna therapy on the evening of restarting therapy after W B C normalization. The clinical picture observed in the different cases is quite variable. The possibility that the reaction was due to the medication was vaguely indicated by the common skin and mucosa lesions. The skin and mucosa signs progressed in 2 cases to a generalized butlae formation, with severe mucosa ulcerations and pronounced malaise. The symptoms are reminiscent of toxic epidermal necrolysis (Lyell's syndrome). The rapid and complete resolution of symptoms makes a pathology in the lower dermal strata doubtful. A generalized maculopapular rash was observed in the other 2 patients. In three cases, temperature rises of up to 40 ° C accompanied the clinical symptoms, and tachycardia persisted after the fever returned to baseline. E C G changes consistent with perimyocarditis accompanied the hypersensitivity reaction in 1 patient (case 3). It is also notable that 3 patients had, in some cases, highly pathological hepatic enzyme levels when the leukopenia arose, ca. 3 weeks after the initiation of therapy, and that these values normalized after only Mesna was discontinued.
703 All patients demonstrated normal levels of hepatic enzyme at the height of the course of the original disease prior to therapy. These values became pathological at a time when the signs of disease had declined. Thus, a relationship between the original disease and the reported symptoms is improbable. An association with Mesna therapy must be assumed. C o m m o n among all cases was the clinical picture of arthralgia, myalgia, and general malaise. Numerous symptoms indicated a relapse of the original disease. This is especially true in case 3, where the Mesna hypersensitivity was associated with ECG changes consistent with perimyocarditis. Cardiac pathology was also a major element in the clinical picture of the original disease. Increases in temperature, and in some cases fever-independent tachycardia, arthralgia, and myalgia are all consistent with a relapse of vasculitis. Leukopenia and stable A N C A serology are examples of laboratory data inconsistent with this diagnosis. The cause of the reaction to Mesna appears allergic in nature. To omit uroprotection in patients on long-term CYC therapy could result in serious problems due to bladder toxicity. Furthermore, allergic reactions to Mesna as seen in our patients had not been described before. This was the rationale for performing reexposure tests using small doses of Mesna, which led to the predicted symptoms in all patients. The hypersensitivity skin test result is also consistent with a delayed hypersensitivity reaction after 24-72 h (type IV, Coombs and Gell) to both the oral and parenteral application forms. Corresponding controls (for example with penicillin, other antibiotics, and other allergens) did not demonstrate skin reactions. This is consistent with the findings of Frosch et al. [9], who also observed a delayed reaction in hypersensitivity skin testing with an oncological patient sensitive to Mesna. Further supporting evidence is the observation that 8 additional vasculitis patients being treated with CYC and a similar Mesna dosage over at least a 6-month period also had negative hypersensitivity skin test results to Mesna (both the oral and parenteral application forms). The association between the hypersensitivity symptoms and the exposure to Mesna is strengthened by the uncomplicated clinical course after the termination of Mesna therapy, while all other medication was continued at the same dose. It is unclear why such severe hypersensitivity symptoms do not seem to occur in oncological cases, but rather, in patients suffering from autoimmune diseases (connective tissue disease, vasculitis, etc.). These types of diseases
may predispose patients to the severe reactions described, although the pathomechanism is uncertain. Perhaps Mesna is not used for uroprotection in nononcological cases, resulting in the lack of hypersensitivity reports in this group of diseases. In the various CYC studies listed in Table 1, Mesna was included in the therapy regimen in only one instance, by Haubitz et al. [11]. Notably, there are no cases of hemorrhagic cystitis in this study. At least 3 of the 6 vasculitis patients who suffered from hemorrhagic cystitis in our treatment group had documented, irregular Mesna uroprotection. This report certainly does not contraindicate a general uroprotection with Mesna in low-dose CYC therapy. While nononcological patients are treated with lower CYC doses than oncological patients, they are often younger and frequently require long-term therapy with high cumulative doses. Up to one-third of the nononcological patients treated with CYC developed hemorrhagic cystitis (Table 1), and Stillwell et al. report an incidence of bladder carcinoma of 18% following hemorrhagic cystitis. Thus, this complication is a serious problem in the treatment of autoimmune disease and forces an interruption in therapy. Due to the severity of the reactions to Mesna described here, we informed the German Drug Council and the manufacturer of Mesna. The manufacturer withdrew the oral application form from the market, which we regret. Uroprotection is not contraindicated in autoimmune diseases, especially as serious side effects seem rare. The reason for the increased incidence of Mesna hypersensitivity reactions within a 6-month period is unclear. It is also interesting that similar observations in nononcological patients during the same time were reported from other centers as well. In a retrospective review of our vasculitis patient population, we found at least 2 additional cases of probable Mesna hypersensitivity. They presented as a mild rash and did not indicate further work-up. It is possible that severe hypersensitivity reactions in the past were not recognized as such. The purpose of' this report is to call attentiof~ to the possibility of severe side effects to Mesna and to suggest considering a Mesna hypersensitivity reaction during vasculitis therapy before taking other, possibly fatal therapeutic steps when this clinical picture occurs. The identification of patients at risk using skin tests should be considered among oncological and nononcological patients; this would help clarify the scope of the problem.
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Acknowledgement. We wish to thank to Mr. David Maslen for his assistance. References
1. Aptekar RG, Atkinson JP, Decker JL, Wolff SM, Chu EW (1973) Bladder toxicity with chronic oral cyclophosphamide therapy in non-malignant disease. Arthritis Rheum 16:461467 2. Austin HA, Klippel JH, Balow JE, LeRiche NGH, Steinberg AD, Plotz PH, Decker JL (1986) Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314 : 614-619 3. Carette S, Klippel JH, Decker JL, Austin HA, Plotz PH, Steinberg AD, Balow JE (1983) Controlled studies of oral immunosuppressive drugs in lupus nephritis. Ann Intern Med 99 : 1-8 4. Dale DC, Fauci AS, Wolff SM (1973) The effect of cyclophosphamide on leukocyte kinetics and susceptibility to infection in patients with Wegener's granulomatosis. Arthritis Rheum 16:657-664 5. Donadio JV, Holley KE, Ferguson RH, Ilstrup DM (1978) Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. N Engl J Med 299:1151-1155 6. Fauci AS, Haynes BF, Katz P, Wolff SM (1983) Wegener's granulomatosis : prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98:7685 7. Fosdick WM, Parsons JL, Hill DF (1968) Long-term cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 11 : 151 160 8. Fries JF, Sharp GC, McDevitt HO, Holman HR (1973) Cyclophosphamide therapy in systemic lupus erythematosus and polymyositis. Arthritis Rheum 16 : 154-162 9. Frosch PJ, Weickel R, Deboben A, Hunstein W (1986) A1lergie vom Spfittyp nach Mesna. Dtsch Med Wochenschr 111 : 1901-1902 10. Gross WL, Mohr J, Christophers E (1991) Allergic reactions to Mesna. Lancet 338:381
11. Haubitz M, Frei U, Rother U, Brunkhorst R, Koch KM (1991) Cyclophosphamide pulse therapy in Wegener's granulomatosis. Nephrol Dial Transplant 6:531-535 12. Lang E, Goos M (1985) Hypersensitivity to Mesna. Lancet: 329 13. Plotz PH, Klippel JH, Decker JL, Grauman D, Wolff B, Brown BC, Rutt G (1979) Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann Intern Med 91:221-223 14. Pratt CB, Sandlund JT, Meyer WH, Cain AM (1988) Mesha-induced urticaria. Drug Intelligence Clin Pharm 22:913914 15. Reza MJ, Dornfeld L, Goldberg LS, Bluestone R, Pearson CM (1975) Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide. Arthritis Rheum 18 : 501-506 16. Shaw IC, Graham MI (1987) Mesna - a short review. Cancer Treat Rev 14:6%86 17. Stillwell T J, Benson RC, DeRemee RA, McDonald TJ, Weiland LH (1988) Cyclophosphamide-induced bladder toxicity in Wegener's granulomatosis. Arthritis Rheum 31:465 470 18. Townes AS, Sowa JM, Shulman LE (1976) Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 19:563-573 19. Williams HJ, Reading JC, Ward JR, O'Brien WM (1980) Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 23 : 521-527
Received: February 11, 1992 Returned for revision: April 15, 1992 Accepted: May 21, 1992
Dr. Eva Reinhold-Keller Rheumaklinik Bad Bramstedt Oskar-Alexander-Strasse 26 W-2357 Bad Bramstedt, FRG
