Sulphasalazine and lung toxicity

Study subjects

The retrospective case study involved all patients in published reports between 1972–1999 who were taking sulphasalazine and who had developed a possible adverse reaction to the drug.

Methods

All published case reports/letters referring to sulphasalazine and lung toxicity were identified from the databases Medline and PubMed. The search terms “sulphasalazine” and “sulfasalazine” were combined with the terms “lung”, “pulmonary disease”, “pneumonitis” and “pleuritis”. Information on 50 patients (48 reports), 17 female and 33 male, was found in the literature between 1972–1999 8–54.

One case 55 not found on the databases was uncovered during the course of this study and included. Another possible case described in a letter 56 is not included because no details were given. The demographics of the case population, the diagnosis of the underlying disease, the dose of sulphasalazine prescribed, the duration of exposure to the drug, the presenting features, laboratory investigations, radiological and histocytopathology findings and the management and eventual outcome of the likely adverse event were noted.

Demographics

The mean age of the patients was 48.3 yrs (range 12–88) and ulcerative colitis was the commonest underlying condition for which sulphasalazine had been prescribed (in 36 patients, 72%). Three patients had Crohn's disease, one patient had unspecified IBD, six patients had rheumatoid arthritis, two seronegative arthritis, one Sjörgrens syndrome and one patient had been prescribed sulphasalazine for nonspecific bowel symptoms (table 1⇓). Two of the patients had previously documented aspirin sensitivity 19, 35 and one of the cases had previous sulphonamide sensitivity 20.

Sulphasalazine dose

The daily dose of sulphasalazine ranged from 1–8 g (mean 3 g) (table 1⇑). Nine patients were receiving concurrent corticosteroids, most of them towards the end of a reducing course when their pulmonary symptoms of toxicity began. The average duration of exposure to sulphasalazine was 17.8 months with a range of 0.5–120 months (a case where re-exposure, after an initial treatment of 12 months and a break of 7 months, caused pulmonary symptoms within a few days 17 has not been included). In a report detailing two cases 17, one was taking concurrent methotrexate. In another report the patient was on concurrent ibuprofen 48. Both methotrexate 57, 58 and ibuprofen 59–61 have been implicated in pulmonary disease.

Symptoms and signs

The main clinical symptoms were breathlessness, present in 40 cases (80%), fever in 35 cases (70%) and cough in 32 cases (64%). Less common symptoms were weight loss, present in 11 cases, and chest pain in 10 cases. The triad of breathlessness, cough and fever was present in 21 of the 50 cases (42%). Rash was commented on in 4 cases 16, 27, 36, 37. One of these patients developed an initial rash and underwent desensitization with the drug only to subsequently develop a pneumonitis on re-exposure 36. Skin pigmentation was also noted in one case 49. Clinical signs included crackles/crepitations/rales on chest auscultation in 26 of the cases (52%) (table 2⇓).

Laboratory investigations

Documented peripheral eosinophilia occurred in 26 of cases (52%) with a range varying between 432·mm³–7500·mm³ (mean 1995·mm³) (table 1⇑).

Hypoxia on blood gas analysis was mentioned in 27 out of 30 of the reports (90%), including three reports where blood gas analysis was performed only after drug rechallenge 19, 26, 35. Three cases reported normal gases 29, 41, 51 and in the remaining cases hypoxia was not mentioned. Some element of pulmonary function testing was performed in 29 cases, and in the remaining 21 cases lung function was either not assessed or mentioned. Nineteen cases out of 29 (66%) documented a restrictive deficit and 7 (24%), an obstructive deficit on pulmonary function tests, with two cases showing a combined restrictive and obstructive picture 15, 18 (tables 1 and 2⇑⇑). In one case lung function carried out on rechallenge was obstructive 35, in another case lung function revealed diminished diffusing capacity with normal vital capacity and forced expiratory volume 49. In three cases lung function was reported as normal 21, 29, 38.

Radiology

Chest radiographs were abnormal in all cases with the majority showing pulmonary infiltrates (46 cases or 92%). One of these also revealed a hydropneumothorax 17. There were reports of fine reticular shadowing in one case 14, collapse/consolidation in another case 31, an increase in interstitial markings and bronchiectasis in one case 45 and nodular interstitial markings in another case 46.

High resolution computed tomography chest scans (HRCT) were performed in only 5 cases 8, 23, 49, 51, 52 showing typical infiltrates and ground glass opacities. Taking these cases sequentially the descriptions are as follows. In the first case the HRCT pattern was one of predominantly alveolar and ground glass opacities with air bronchograms but no pulmonary nodules were seen. In the second case the HRCT revealed multiple bilateral peripheral wedge shaped infiltrates with one of the nodules showing central cavitation. In the third case the HRCT showed patchy ground glass shadowing mainly in the middle and upper lobes. In the fourth case, the HRCT showed interstitial opacities with pleural thickening in the upper lung. Finally in the last case the HRCT showed extensive bilateral upper-lobe infiltration with areas of ground glass appearance.

Histocytopathology

Lung biopsy was performed in 40% of patients (n=20). Ten patients underwent open lung biopsy, nine patients underwent transbronchial biopsy and one patient had a videothoracoscopic lung biopsy.

Bronchoalveolar lavage (BAL) was performed in 11 patients (22%) with five demonstrating an increase in eosinophils ranging from 23%–69% 16, 24, 27, 30, 43. In one of these cases there was also an increase in lymphocytes 27. In the remaining cases, the BAL was reported as abnormal in three with elevated lymphocytes ranging from 31%–43% but with no increase in eosinophils 22, 23, 54. In one case there was an increase in neutrophils only 48. In another case no mention of the cellular differential was made 41. In only one case where it was performed was the BAL reported as normal 51.

Final histological diagnoses varied in the literature. The common histological theme was one of interstitial pneumonitis/inflammation. Fibrosing alveolitis was diagnosed in four cases, and in another four biopsies comments were made regarding fibrosis on the histology. In 11 cases the diagnosis was of eosinophilic pneumonia/pneumonitis or pulmonary eosinophilia and in 10 of these cases lung biopsy was not performed. In addition, there were clinical diagnoses of hypersensitivity pneumonitis or sulphasalazine pneumonitis/alveolitis in seven cases. Less specific terms such as pneumopathy, sulphasalazine lung disease and pulmonary hypersensitivity reaction were also used in terms of a clinical diagnosis in a further six cases (table 3⇓). Granulomas were seen in four cases, but it should be noted that in one of these the patient had coexistent tuberculosis 43.

Other, less common, histological diagnoses included bronchiolitis obliterans, bronchiolitis organising obliterative pneumonia and desquamative interstitial pneumonia (DIP). DIP has histological features of interstitial inflammation and macrophages in airspaces, is a reaction of lung tissue to a variety of agents and is not felt to be a specific disease. Both fibrosing alveolitis and eosinophilic pneumonia are related to DIP and the histopathological differentiation between them may be difficult 62. Further discussion regarding the various histological terms and features of interstitial lung disease are out of the scope of this article.

Rechallenge/desensitization or provocation tests were carried out in 13 cases 11, 13, 18, 19, 21, 26, 28–30, 35, 37, 51, 55 and are discussed later.

Management and outcome

Clinical improvement occurred in the majority of cases (90%) with resolution occurring within an average of six and a half weeks from initiation of management (range 1–32 weeks). Management included withdrawal of sulphasalazine in 47 cases. In the three cases where the drug was not withdrawn, two of the patients died 10, 33. In 20 cases (40%) management included the addition of corticosteroids and is discussed later.

Five patients on sulphasalazine with lung symptoms died and the cause of death was due to pulmonary pathology 10, 11, 33, 45, 46. All patients who died had ulcerative colitis as their underlying condition. The mean dose of sulphasalazine was 3.6 g. In three cases the patients had been on sulphasalazine for a number of years before the onset of their pulmonary symptoms and in two of these cases, a number of years had elapsed from onset of lung symptoms to death. The drug was not withdrawn in two cases (table 4⇓).

What is it about sulphasalazine that can cause potential adverse effects?

Sulphasalazine is a compound of 5‐aminosalicylic acid (5‐ASA) and sulphapyridine joined by an azo bond. The sulphapyridine component is the carrier of the 5‐ASA to the colon. The azo bond is broken down by gut organisms and the 5‐ASA exerts its anti-inflammatory action whilst the sulphur moiety is slowly absorbed and excreted in the urine. Sulphapyridine is believed to be responsible for most of the hypersensitivity reactions that occur, although the salicylate component may also be implicated since aspirin has been reported in association with eosinophilic pneumonia 63, and more recently, with pulmonary oedema 64. Therefore, it is possible that there is cross-reactivity in the two aspirin sensitive susceptible patients in this study to the aminosalicylate component of sulphasalazine 19–35. However, the component of the drug implicated is still not known and nor is the mechanism causing pulmonary toxicity. The suggestion that both components may be responsible is supported by the different adverse reactions in the same patient to sulphasalazine and then, on later rechallenge, to sulphpyridine 26. Further evidence that sulphapyridine is the culprit is supported in the case report describing alveolitis in a female prescribed sulphamethoxypyridazine for cicatrical pemphigoid. The patient developed dyspnoea and cough, but no peripheral eosinophilia, after 6 months. Chest radiography revealed reticulonodular shadowing. The patient's symptoms resolved in 6 months after steroid therapy and cessation of the drug 65. In addition, there were other case reports where the patients were later managed on newer 5‐aminosalicylates without further pulmonary symptoms, mesalazine in one case 28 and olsalazine in another 30. Conversely, one case published reported mesalazine as being implicated in pneumonitis 66.

What is the evidence for drug withdrawal as soon as the diagnosis is suspected?

The evidence for drug withdrawal as soon as diagnosis is suspected can be shown by the rapid resolution of symptoms in most cases, and by the fact that in the three cases where the drug was not withdrawn, two patients died 10, 33. The patient that recovered was given a clinical diagnosis of reversible pulmonary disease and eosinophilia associated with sulphasalazine 44. It should be noted that in this case where the drug was not withdrawn and there was clinical resolution of symptoms, the patient had been intermittently exposed to sulphasalazine for 3 yrs with a further period of 2 yrs of continuous treatment before the development of symptoms. The authors considered sulphasalazine as a possible cause but felt it unlikely in view of the long time interval before exposure. It is possible that this case represents an example of pulmonary eosinophilia associated with IBD.

What is the evidence for rechallenge with sulphasalazine?

The rapid resolution of symptoms in most of the published cases after drug withdrawal points to a delayed allergic mechanism. It can be argued that rechallenge with sulphasalazine is the only way to establish causality, but rechallenge has practical and ethical implications, and in only one of the 13 cases where rechallenge or provocation tests were carried out was desensitization deemed successful 21. In one case, rechallenge with sulphasalazine followed by a later rechallenge with the sulphapyridine component 26 was positive in both challenges. There was documentation of reduced lung volumes and transfer factor after the second dose of sulphasalazine. However, a more obvious clinical response to the sulphapyridine challenge occurred, with the patient spiking a fever 30 min after the dose and demonstrating a marked fall in ventilatory capacity with arterial hypoxia. Another case describes a challenge using only the sulphapyridine component of sulphasalazine 30. After 3 days the patient complained of progressive dyspnoea, cough and rash. This patient was later successfully treated with olsalazine for Crohn's disease.

Provocation tests can produce a number of serious adverse effects in patients challenged and many doctors would now be reluctant to perform them in view of this. Likewise, desensitization to sulphasalazine would not be appropriate unless there were extenuating circumstances, since there are a number of alternative 5‐aminosalicylates on the market for the management of IBD as well as alternative DMARDs available for the management of rheumatoid arthritis.

What is the evidence for prescribing corticosteroids?

Although the majority of patients were managed with drug withdrawal, less than half (40%) were prescribed corticosteroids/additional corticosteroids. One patient was prescribed Transilast only (a mast cell stabilizer) 21, one patient was prescribed azathioprine 46 and another penicillamine 14 in addition to corticosteroids. Two patients were kept on maintenance corticosteroids of whom one died within 1 month 10 and the other improved over a number of days 49. Of the patients prescribed corticosteroids for management of their pulmonary disease, 16 (80%) improved, and in 13 (65%) pulmonary symptoms had resolved by 2 months. In three other patients, resolution of symptoms occurred, two within 6 months and one over an unknown time period. One patient given corticosteroids did not improve and three eventually died from their pulmonary disease despite corticosteroids.

Contrasting this with the remaining patients not prescribed corticosteroids, 26 (96%) improved, 18 or 67% had symptom improvement by 2 months, 6 (22%) had improved by 6 months, two had improved over an unknown time period, and one died. In the fatal case, corticosteroids had actually been stopped because of a possible diagnosis of congestive cardiac failure 33.

It can be seen that the evidence for corticosteroids influencing the outcome of patients with suspected sulphasalazine lung toxicity is not strong.

What other conditions may mimic sulphasalazine lung disease?

Recognition of sulphasalazine pulmonary damage is important but it should be noted that whilst not common, IBD as well as rheumatoid arthritis can be complicated by pulmonary pathology which typically presents in the form of a progressive diffuse interstitial pneumonitis. Lung disease in patients with Crohn's disease has included acute alveolitis, granulomatous interstitial pneumonitis and interstitial fibrosis 67, 68 and in patients with ulcerative colitis, bronchitis or bronchiectasis 69–71. The association between IBD and inflammatory lung disease is not well understood and pulmonary manifestations of IBD are still thought to be rare. In 1968, Isenberg et al. 72 suggested that pulmonary vasculitis was an uncommon complication of ulcerative colitis. In 1971 Rogers et al. 73 studied 1,400 patients with IBD and found 94 patients with pulmonary diagnoses. However, only six of these cases were unexplained and possibly attributable to lung disease related to IBD. Further case reports followed 74, 75 together with the publication of case series of IBD associated pulmonary disease. Kraft et al. 76 reported six cases where the patients developed severe, unexplained, chronic bronchopulmonary disease in the form of chronic bronchitis with or without bronchiectasis, up to 13 yrs from the onset of nonspecific colonic inflammatory disease. They found an initial correlation between the pulmonary symptoms and intestinal disease severity, except in two patients who developed overt pulmonary disease following total proctocolectomy. Butland et al. 77 reported seven cases with three cases developing rapidly progressive bronchiectasis within one year of proctocolectomy. Two of these cases developed in association with an exacerbation of colitis and in a further two cases a milder, limited colitis postdated the start of the lung disease. In a review article, Camus et al. 78 noted that of the 33 cases of respiratory involvement and IBD reviewed, 23 were not on drug therapy. In 28 of the cases, the respiratory disease followed the onset of the bowel disease with eight of the cases being postcolectomy. The pattern of involvement of lung disease included airway inflammation and varied interstitial lung disease mainly bronchiolitis obliterans with organizing pneumonia and pulmonary infiltrates with eosinophilia. In the majority of the reported cases of IBD associated lung disease (76%) corticosteroids were of benefit 78.

A further, more recent case series reported seven IBD patients with large airways disease where their respiratory symptoms followed the onset of their bowel symptoms by an average of 12 yrs 79. Interestingly, three of the patients developed their lung symptoms after colectomy. The appearance or persistence of lung symptoms despite colectomy is unusual since extra-colonic manifestations of IBD normally improve after surgery. The pathogenesis of IBD associated lung disease is not known, but one theory is that the circulating inflammatory mediators released by the inflamed bowel affect the lung 80. However, this theory does not hold in those cases where the lung symptoms occur after colectomy.

With regard to the fatal reports of sulphalsalazine-induced pulmonary pathology, the duration between onset of symptoms and time of death in two of the cases 45, 46 prompted the authors to correctly consider the possibility that the underlying disease was the cause of death rather than the drug. In addition, neither patients' lung conditions improved despite cessation of sulphasalazine and treatment with corticosteroids and, in one case, despite colectomy 45.

Correspondingly, Baillie 33 stated that a patient was atypical since the patient had been on sulphasalazine for many years. Again, in this case other diagnoses were considered.

Finally, although the clinical manifestations of IBD associated pulmonary disease are believed to be rare, perhaps the association is more common. In 1980, Eade et al. 81 compared 36 patients with IBD to a control group and found that there was a significant decrease in the diffusing capacity of the lung for carbon monoxide in the patient group. However, there was no significant decrease in the patients taking sulphasalazine compared with patients not on this drug. This suggested that it was the underlying disease, and not the drug, which accounted for the decrease in diffusion capacity. A later study reported abnormalities in pulmonary function in one-third of IBD patients, although only some of the variables appeared to be related to disease activity and smokers were included in the cohort 82.

To conclude, it appears that despite the increasing number of prescriptions for sulphasalazine per year, pulmonary toxicity remains rare and the main fatal toxicity of sulphasalazine is haematological (table 5⇓). Fatal case reports are infrequent and of the five fatal cases described in this study, all suffered from ulcerative colitis and two died from possible underlying pulmonary disease rather than drug reaction. It is known that patients with inflammatory bowel disease or rheumatoid arthritis can develop various inflammatory lung complications. Sulphasalazine lung disease should be distinguished from interstitial lung disease due to the underlying primary disease, although this may not be easy. In the majority of patients with suspected sulphasalazine-induced lung disease, pulmonary symptoms will resolve completely in a few weeks upon withdrawal of the drug. The need for steroid treatment of patients with suspected sulphasalazine induced lung disease is still debatable. Ultimately the decision regarding the need for steroid therapy should be based on the severity of each individual case, the underlying pulmonary diagnosis and clinical progress.