Sulfasalazine-induced Pulmonary Disease

Sulfasalazine-induced

Pulmonary

Disease*

M. Abdulgany Hamadeh, M.D.; Janis Atkinson, M.D.; and Lewis J Smith, M.D., F.C.C.P. We report the findings in two patients with sulfasalazineinduced pulmonary disease. The first patient developed pulmonary interstitial 6brosis after more than 4 yr of treatment for Crohn's disease. Pulmonary symptoms and chest roentgenographic and pulmonary function abnormalities gradually reversed after stopping the drug. No speci&c treatment was given. The second patient, who had rheumatoid arthritis without pulmonary disease, received the drug for 1 yr without experiencing any problems. Readmin-

sulfasalazine has been widely used in the treatment of inflammatory bowel disease for over 40 yr and more recently for the treatment of other inflammatory conditions. The most common side effects are gastrointestinal disturbances, anorexia, headache, arthralgias, skin rashes, hemolytic anemia, leukopenia, and hepatitis.' Pulmonary toxicity is rare. There have been only 19 cases reported in the English literature through 1988. 1• 17 We report two additional cases of sulfasalazineinduced pulmonary disease with different manifestations. The first is a patient with pulmonary interstitial fibrosis which developed after more than 4 yr of continuous treatment, was not associated with eosinophilia, and reversed with cessation of the drug and without further therapy. The second patient developed acute interstitial pneumonitis shortly after reintroduction of the drug, which reversed rapidly following discontinuing the drug and treatment with corticosteroids. CASE REPORTS CASE

1

A 69-yMJid businessman without any known occupational expo*From the Departments of Medicine and Pathology, Northwestern University and VA Lakeside Medical Center, Chicago. Manuscript received June 12; revision accepted August 13.

istration seven months later resulted in the development of an acute interstitial pulmonary disease. Discontinuing the drug and treatment with corticosteroids produced rapid improvement. We discuss these patients in relation to other reports of sulfasalazine-induced pulmonary toxicity, highlighting their atypical features. (Cheat 1992; 101:1033-37)

I

5-ASA=5-aminosalicylic acid

I

sures was transferred to Northwestern Memorial Hospital on Aug 15, 1989 for evaluation of worsening dyspnea, hypoxemia, and diffuse pulmonary infiltrates. Crohn"s disease was diagnosed in October 1984. Treatment with sulfasalazine (Azulfidine) at 500 mg three times daily was started at that time. In January 1989 the patient began experiencing shortness of breath with exertion. He was admitted to another hospital in February 1989 for aortobifemoral bypass surgery. A preoperative chest x-ray film revealed bibasilar interstitial infiltrates (Fig 1A). Pulmonary function tests revealed a moderate reduction in flow rates, normal lung volumes, and redm:ed diffusing capacity ('Iable). The patient was not infOrmed of these abnormalities, and no evaluation was performed. He had smoked one package of cigarettes per day for nearly 50 yrs, but stopped at the time of the surgery. After discharge, the dyspnea slowly worsened. On July 27, 1989, he had the acute onset of severe dyspnea and right-sided pleuritic chest pain. A chest x-ray film revealed a hydropneumothorax and extensive bilateral interstitial infiltrates. A chest tube was inserted. The pleural fluid was an exudate with a large number of eosinophils but no malignant cells. Stains and cultures were negative for aerobic bacteria, mycobacteria, and fungi. Because the patient's referring physician considered the possibility of drug-induced pulmonary disease, tbe sulfasalazine was discontinued on Aug 8, 1989, one week before transfer to our hospital. On admission to Northwestern Memorial Hospital, the patient was cyanotic and in moderate respiratory distress at rest. Vital signs included a pulse rate of 88 beats per minute and regular, blood pressure of 14MO mm Hg, respiratory rate of 30/min, and temperature of37.0"C. Inspiratory crackles were heard over the lower half of both lungs. Findings from the remainder of the examination were normal. Laboratory tests included normal red and white blood cell

Table !-Pulmonary Function Dtltafor lbtient 1* Data

115189

FEV., Us FVC,L FEV,IFVC% TLC,L RY,L D, mVmin/mm Hg Flo1 pH PaC01 , mmHg Pao•. mmHg Oxygen saturation, percent

1.79 (58) 2.03 (77) 59 6.56 (106) 3.30 (151) 10 (36) 0.21 7.38 37 86 95

8121189 1.44 1.67 86 4.08 2.24

9112189

(48) (45)

1016189

12/15189

3129190

2.08 (70) 2.23 (60)

2.19 (73) 2.49 (67) 88 4.96 (82) 2.54 (106) 9.6 (39)

2.27 (76) 2.62 (71) 87 5.41 (90) 2.87 (120) 7.6 (31)

93 (68) (94)

0.35 7.48 37 54 87

0.21

7.43 38

63 92

4.69 (78) 2.54 (106) 7.7 (31) 0.21 7.42 35 77 95

*Numbers within parentheses represent percentage of predicted value. CHEST I 101 I 4 I APRIL, 1992

1033

t11nnts, normal differe ntial connt . an erythrocyte sedimentation rattof 40 mm/h, normal findings em nrinalysis, and normal resnlts of antomated hlcHKI analysis (SMA-20). 1\lnltiplt• cultures obtained from sputum. blcHKI. and urine were all negative. Arterial blcHKI gas analysis rt•vealed pll of 7.41l, PaCO, of 37 mm Jig, and l'aO, of 5IS mm Jig while breathing :3.'5 percent oxyg<'n by ti~t · e mask. A chest x-ray film revealed bilateral interstitial infiltrates, much nu>r<' extensive than thost• present fi mo earlier (Fig lB). Fiberoptie bronchoscopy, including transhrond1ial hiopsy, failt•d to rewal any abnormalities. \\'ashings and brnshings wen• negative for micretter and with improved pnlmonary fnnction (1i1hle 1). It was decided not to start the prednisone . Over tlw next several months the patient's condition omtinned to improw symptomatically. Pulmonary function tests and arterial hlcHKI gas levels normalized except fur the reduced diffusing t·apacity (l:ahle l). At tht' time of the patient's last visit in April, 1990, he had returned to his premorhid state and a dwst x-ray film showed rwarly t11mplete clearing (Fig lC). In the absence of sulfasalazine and while the pulmonary disease improved, the patient's inflammatory howe! disease worsened ; however, the sulfasalazine was not restarted. and his <.~mditinn was managed with other agents. CASE

2

A 74-yr-nld japanese woman had a lung history of rheumatoid arthritis. She was treated with sulfasalazine .500 rng twice daily fur 1 yr. It was dist,mtinued on May 19, l91l9 hecause of worsening arthritis. Methotrexate (.5 to 7 ..'5 mg orally per week) was given instead. After initial improvement tht• arthritis worsened , and sulfasalazine at .500 mg twice daily was restarted on Dec 1.5, 19H9. The patient presented to Northwestern Memorial Hospital on Dec Ill, 1989 with a two-day history of fever and a nonproductive 111ugh, hut no shortness of hrt'ath. She appeared rneats J>er minnie , hlcHKI pressure of9.515.5 mm Jig, respiration rate of 30/min, and ternJ>erature of 38.0°C. New inspiratory crat·kles were present over the lowt'r half of hoth lungs. Findings from the remainder of the physical examination were normal except li>r joint abrwmmlities mnsistent with rheumatoid arthritis. Results of laboratory tests included normal red and white hlcHKI cell <.1111Uts and normal differential mnnt (no eosinophilia). Arterial hlcHKI gas analysis revealed pll of 7 ..53, PaCO, of 26 rnm Jig, and PaO, of 46 mm Hg while breathing room air; and pll of 7 ..53, PaCO, of 26 mm Jig, and P..aO, of .51 mm Hg while hreathing .50 percent oxygen by face mask . A chest x-ray film revealed hilateral interstitial infiltrates, which were greater at the bases. Multiple cultures of sputum , blond , and urine were negative. The methotrexate and sulfasalazine were dis<.1mtinued , and the patient received brnad-spedrnm antihiotics; however. he r 11mdition worsened, and she required intubation and mechanical ventilation. Fiheroptie hronchoscopy failed to reveal a diagnosis. An open lung FrGl'IU: l. Chest x-ray films taken before (A), during (B), and after resolution (C) of patient's illness. A (lop): February 1989, during admission for aortobifernoral bypass surgery. There are fine bibasilar infiltrates. B (middle): August 1989, during admission to Northwestern Memorial Hospital for interstitial pulmonary disease . Extensive bilateral interstitial infiltrates are present. C (bottom) : April 1990, eight months after stopping sulfasalazine. Chest x-ray film is normal .

1034

Sulfasalazine-induced

Pl.llmonary Disease (Hamadeh, Atkinson, Smith)

Fua 'IIE 2. Lnn~ tissue ohtained durin~ open Inn~ hiopsy pt•rl
hiopsy was performed on the fifth day of lmspitali1~1tion. Tissue ohtaint-d from the ri~ht lower lollt' revealed acnlt' interstitial minimal interpnt•tunonitis with abundant alveolar macmpha~es, stitial thiekt•nin~. and no evidence of ~rannlomas , eosinophils, mierr~nisms , or bronchiolitis. The patient was starlt'd on me thylprt•dnisolone (20 m~ t•very 6 h), and her mndition improved rapidly. \Vithin two days of mrtieostt•ruid treatment, sht• was weaned from tlw ventilator and required only low-dose oxy~en by nasal cannula. Slw was dischar~t · d ei~ht days after the ope n Inn~ hiopsy, feelin~ mueh improved ; the ehest x-ray film showed resolvin~ infiltrates; and artt'rial hlcHtd ~as analysis on rm air rt•vt•aled pll of 7 .52, PaCO, of 35 mm H~ . and PaO, of 67 mm II~ . Tlw <.11rtk11steroids we re slowly tapert'd ove r the next several weeks, and the patit•nt remained free of respiratory symptoms. DISCUSSION

Sulfasalazine is a poorly absorbed sulfonamide used to treat inflammatory bowel disease and other inflammatory processes. The incidence of pulmonary reactions due to sulfasalazine appears to he low. Jones and Malone 2 in 1972 were the first to report a case of pulmonary eosinophila which they attributed to sulfasalazine . Since then, 18 other cases have been reported. 1·17 The pulmonary response to sulfasalazine appears to he limited . A few distinct clinical syndromes have been described, including hypersensitivity pneumonitis, diffuse interstitial fibrosis,"·H· 111 ·11 bronchiolitis obliterans,H·15 and tracheolaryngitis with bronchospasm . 1 Hypersensitivity pneumonitis, which is thought to represent an immunologic response to a number of agents including drugs, is the most common.1H Sulfasalazine is metabolized in the bowel to 5aminosalicylic acid (5-ASA), which is the active therapeutic agent, and sulfapyridine, which transports 5ASA to the colon. 17 The sulfapyridine moiety is thought to be responsible for the toxicity. In one report a patient developed eosinophilic pneumonia while being treated with sulfasalazine and improved when the drug was stopped; however, when rechallenged with sulfapyridine, symptoms recurred. Subsequently, the

patient was treated with olsalazine, a 5-ASA compound, without recurrence of pulmonary symptoms. 17 Clinical features of hypersensitivity pneumonitis due to sulfasalazine include cough , dyspnea, fever, pulmonary infiltrates which are usually patchy and bilateral, and peripheral blood eosinophilia, which is present in most but not all patients.·1·13·14 In one patient who was rechallenged with the drug, symptoms recurred, but the eosinophil count remained normal.• Symptoms usually develop between 1 and 6 mo after starting sulfasalazine and quickly resolve when the drug is stopped; however, there have been two deaths despite stopping therapy. 3·11 The dose of sulfasalazine associated with the development of pulmonary disease is usually between 4 and 6 g daily. The most common pulmonary function test abnormality is a reduced Dco. Furthermore, a reduction in the Dco has been reported after rechallenge with sulfasalazine. 4 An obstructive pattern has also been described in some patients. 4·5·1" A tissue diagnosis was obtained in three patients; two had a transhronchial biopsy, 12 ·14 and one had an open hmg biopsy. 15 The histopathologic findings included interstitial pneumonitis and slight fibrosis hut no tissue eosinophilia. 12 ·14 There was associated bronchiolitis obliterans in one patient. 15 The other pulmonary syndromes associated with sulfasalazine are less frequent. They are considered by some authors to be a subset of hypersensitivity pneumonitis because they have similar signs and symptoms and they are commonly associated with fever and peripheral eosinophilia. m The prognosis of patients who develop sulfasalazineinduced pulmonary disease is generally good. Most patients rapidly improve symptomatically with stopping the drug. Their pulmonary function also rapidly becomes normal, although the Dco may take longer to recover; however, two patients died in spite of stopping the sulfasalazine. One had fibrosing alveolitis on postmortem examination;3 the other had fibrosis without a significant inflammatory response . 11 Although there is some suggestion that corticosteroids may speed recovery, and they may have done that in our second patient, most patients appear to recover at about the same rate whether or not corticosteroids are used . Risk factors for any of the syndromes associated with sulfasalazine therapy are unclear. No studies, either clinical or using animal models, have identified a specific mechanism by which sulfasalazine induces pulmonary disease. Two patients with known salicylate hypersensitivity 2·5 and one with a previous alleq.,ry to sulfonamides 12 developed pulmonary disease while taking sulfasalazine. Seven patients were rechallenged with sulfasalazine, and symptoms and pulmonary infiltrates recurred in all of them.z..t·5·7·111•15·17 One CHEST I 101 I 4 I APRIL. 1992

1035

patient 13 exhibited a skin reaction to sulfasalazine, for which he received desensitization treatment with the drug. After restarting the drug, the skin reaction did not recur, but an acute pneumonitis developed 2 mo later. There is only one report of an unsuccessful attempt to desensitize a patient with sulfasalazineinduced pulmonary disease.l 4 The wisdom of such an approach is unclear. Our first patient had chronic interstitial pneumonitis with fibrosis (fibrosing alveolitis) which differed from those previously reported in several major aspects. First, he had received the drug continuously for nearly 5 yr before developing significant pulmonary symptoms. This is only the second report of pulmonary toxicity after such a long exposure to the drug. The first had a duration of exposure of 6 yr. 16 Prior to that report, the longest duration of exposure was 36 mo. 6 In all other reports the duration was between 1 and 6 mo. Secondly, he presented with diffuse interstitial pneumonitis confirmed by open lung biopsy and no evidence of a hypersensitivity reaction, although he did have pleural ftuid eosinophilia. Thirdly, the patient's condition improved following withdrawal of the drug, in the absence of treatment with corticosteroids. Pulmonary complications due to inftammatory bowel disease have been reported. They include pulmonary vasculitis, 20 chronic bronchial suppuration and bronchiectasis, 2 1.22 an isolated reduction in the Dco, 23 and interstitial pulmonary fibrosis; 24 however, our first patient's pulmonary disease is unlikely to be due to inftammatory bowel disease because his bowel disease was stable when the pulmonary disease developed, the bowel disease worsened after the sulfasalazine was stopped, and there was a strong relationship between withdrawal of the drug and subsequent symptomatic and objective improvement of his pulmonary disease. The second patient had a different presentation, one consistent with an acute pulmonary interstitial reaction. In contrast to the first patient, it is more difficult to be absolutely certain that her pulmonary disease was due to sulfasalazine, since rheumatoid arthritis and methotrexate both produce pulmonary disease. Pulmonary manifestations of rheumatoid arthritis include necrobiotic nodules, pleural effusions, obliterative bronchiolitis, and fibrosing alveolitis. 25 Fibrosing alveolitis usually presents in an indolent fashion, and clubbing is a common feature. The mean duration of joint symptoms before the development of pulmonary disease is approximately 5 yr. The response to <-"Orticosteroids is fair at best, and mortality exceeds 50 percent at 5 yr. 25 It is unlikely that our patients pulmonary disease was due to rheumatoid arthritis because of the acute onset, the prolonged duration of joint disease before development of the pulmonary disease, differences in pathology, and the excellent 1036

response to corticosteroid treatment. The incidence of pulmonary toxicity due to lowdose methotrexate in patients with rheumatoid arthritis appears to be low (approximately 5 percent).•·17 The clinical presentation is usually subacute, with shortness of breath, nonproductive cough, and fever. Pathologic changes include a hypersensitivity reaction with interstitial pneumonitis, granuloma fonnation, bronchiolitis, and diffuse alveolar damage. 17 There does not appear to be any correlation between toxicity and the dose or duration of treatment. It is unlikely that the pulmonary disease in our patient was due to methotrexate, since it occurred in proximity to restarting treatment with sulfasalazine, while the dose of methotrexate remained constant, the onset was very rapid, and there was no clinical evidence of pulmonary disease before the sulfasalazine was begun. The absence of peripheral blood and lung eosinophilia in both patients cannot be explained; however, this is not an unusual finding in drug-induced pulmonary disease, where only 40 percent or so of the patients have peripheral eosinophilia. 18 Furthennore, 25 percent of the patients with sulfasalazine-induced pulmonary disease have been reported not to have eosinophilia. Although rechallenge with the drug and redevelopment of disease would have strengthened the diagnosis in both patients, especially the second patient, we were reluctant to do this because the pulmonary disease was severe at the time of presentation. In summary, we have presented the findings in two new patients with sulfasalazine-induced pulmonary disease who had several atypical features, and we have reviewed the earlier literature. Sulfasalazine-induced pulmonary disease, although rare, has varying presentations, as illustrated by our patients, and is an important complication to recognize in view of the potential for pennanent lung damage and even death. Prompt recognition of the disease, even when the drug has been ingested for years and symptoms have been present for months, followed by immediate cessation of the drug, should result in an excellent prognosis. REFERENCES

1 Collins JR. Adverse reactions to salicylazosulfapyridine (Azulfidine) in the treatment of ulcerative colitis. South Med J 1968; 61:354-58 2 Jones GR, Malone NS. Sulphasalazine induced lung disease. Thorax 1972; 27:713-17 3 Davies D, MacFarlane A. Fibrosing alveolitis and treatment with sulphasalazine. Gut 1974; 15:185-88 4 Thomas P, Seaton A, Edwards J. Respiratory disease due to sulphasalazine. Clio Allergy 1974; 4:41-7 5 Tydd TF, Dyer NH. Sulphasalazine lung. Med J Aust 1976; 1:570-73 6 Constantinidis KA. Eosinophilic pneumonia: an unusual side effect of therapy with salicylazosulfapyridine. Chest 1976; 70:315-16

7 BerlinerS, Neeman Y, Shoenfeld Y, Eldar M, Rousso I, Kadish U, et al. Salazopyrin-induced eosinophilic pneumonia. Respiration 1980; 39:119-20 8 WilliamsT, Eidus L, Thomas P. Fibrosingalveolitis, bronchiolitis obliterans and sulfasalazine therapy. Chest 1982; 81:766-68 9 Yaffe BH, Korelitz BI. Sulfasalazine pneumonitis. Am J Gastroenterol 1983; 78:493-94 10 Sigvaldason A, Sorenson S. Interstitial pneumonia due to sulfasalazine. Eur J Respir Dis 1983; 64:229-33 11 Baillie J. Sulfasalazine and pulmonary infiltrates. Am J Gastroenterol1984; 79:77 12 Wang KK, Bowyer BA, Fleming CR, Schroeder KW. Pulmonary infiltrates and eosinophilia associated with sulfasalazine. Mayo Clin Proc 1984; 59:343-46 13 Averbuch M, Halpern Z, Hallak A, Topilsky M, Levo Y. Sulfasalazine pneumonitis. Am J Gastroenterol1985; 80:343-45 14 Moseley RH, Barwick KW, Dobuler K, DeLuca VA. Sulfasalazine-induced pulmonary disease. Dig Dis Sci 1985; 30:901-04 15 Sullivan SN. Desensitization to sulfasalazine and treatment with acrylic coated 5-ASA and azodisalicylate. J Clin Gastroenterol 1987; 9:461-63 16 Jordan A, Cowan RE. Reversible pulmonary disease and eosinophilia associated with sulphasalazine. J lloy Soc Med 1988; 81:233-35 17 Scherpenisse J, van der Valk LPM, van den Bosch JMM, van Hees PAM, Nadorp JHSM. Olsalazine as an alternative therapy in a patient with sulfasalazjne-induced eosinophilic pneumonia. J Clin Gastroenterol1988; 10:218-20

18 Cooper JAD Jr, Matthay RA. Drug-induced pulmonary disease. Dis Mon 1987; 33:61-120. 19 Cooper JAD Jr, White DA, Matthay RA. State of the art: druginduced pulmonary disease. Am Rev Respir Dis 191l6; 133:488505 20 Isenberg JI, Goldstein H, Korn AR, Ozeran RS, Rosen V. Pulmonary vasculitis-an uncommon complication of ulcerative colitis. N Engl J Med 1968; 279:1376-77 21 Kraft SC, Earle RH, Roesler M, Esterley JR. Unexplained bronchopulmonary disease with inftammatory bowel disease. Arch Intern Med 1976; 136:454-59 22 Butland RJA, Cole P, Citron KM. Chronic bronchial suppuration and inflammatory bowel disease. Quart J Med 1981; 197:63-5 23 Eade OE, Smith CL, Alexander JR, Whorwell PJ. Pulmonary function in patients with inflammatory bowel disease. Am J Gastroenterol1980; 73:154-56 24 McKee AL, Rajapaksa A, Kalish PE, Pitchumoni CS. Severe interstitial pulmonary fibrosis in a patient with chronic ulcerative colitis. Am J Gastroenterol1983; 78:86-9 25 Turner-Warwick M, Evans RC. Pulmonary manifestations of rheumatoid disease. Clin Rheum Dis 1977; 3:549-64 26 Gispen JG, Alarcon GS, Johnson JJ, Acton RT, Barger BO, Koopman WJ. Toxicity to methotrexate in rheumatoid arthritis. J Rheumatol1987; 14:74-9 27 Carson CW, Cannon GW, Egger MJ, Ward JR, Clegg DO. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 1987; 16:186-95

1992 Spoleto Pulmonary Symposium The American College of Chest Physicians, the Medical University of South Carolina, and Ohio State University will present this program at the Omni Hotel at Charleston Place, Charleston, South Carolina, June 4-5. For information, contact the Division of Education, ACCP, 3300 Dundee Road, Northbrook, IL 60062 (708:498-1400).

CHEST I 101 I 4 I APRIL, 1992

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