- Email: [email protected]
Acute polyarthritis associated with azathioprine for interstitial lung disease
Respiratory
Medicine
(1995) 89, 63-64
Acute polyarthritis associated with azathioprine for interstitial lung disease P. I. PILLANS*,
A. F. R. Toomt~,
E. D. BATEMAN$
AND G. M. AINSLIE~
Departments of *Pharmacology, TRheumatology, IMedicine, and GRespiratory Clinic, University of Cape Town Medical School and Groote Schuur Hospital, Cape Town, South Africa
Introduction Hypersensitivity reactions to azathioprine are uncommon, and may be associated with fever, rash, myalgia, arthralgia, hypotension, interstitial nephritis, jaundice and pneumonitis (l-8). To our knowledge only one case of florid azathioprine-associated arthritis has been described in the medical literature (9). We report on a case of acute polyarthritis in a man taking azathioprine for interstitial lung disease, and describe the features of another eight cases reported to the World Health Organisation (WHO) Collaborating Centre for International Drug Monitoring. Case Report A 54-year-old male power-tool mechanic whose work regularly involved grinding of hard metals presented with a 2 yr history of progressive exertional dyspnoea, an unproductive cough, episodes of left pleuritic chest pain, and mild arthralgias of fingers, wrists and shoulders, without features of arthritis. He had a 37 pack-year cigarette-smoking history. Examination was unremarkable except for fine inspiratory crackles heard bilaterally in the lower zones. Chest radiographs showed small lung fields, no adenopathy, and increased interstitial markings with linear opacifications at the lung bases. Pulmonary function tests confirmed moderate restriction of lung volumes, and reduced transfer factor for carbon monoxide. The erythrocyte sedimentation rate (ESR) was 20 mmh ‘. The full blood count and differential count were normal, as was serum biochemistry. Anti-nuclear factor (ANF) was positive to a titre of l:lOO, rheumatoid factors were absent, and the serum angiotensin converting enzyme value was Received 1994.
31 December
1992 and accepted
in revised form 24 March
To whom correspondence should be addressed at Department of Rheumatology, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa. 0954-6111/95/010063+02
$08.0010
39.6 units (40 & 10). A diagnosis of interstitial lung disease caused by hard metal exposure was made on the basis of history, increased proportions of eosinophils (34%) and neutrophils (12%) in bronchoalveolar These lavage, and open lung biopsy findings. included interstitial fibrosis with extensive desquamation of alveolar lining cells and intra-alveolar macrophage accumulation, and the presence on transmission electron microscopy of multinucleate giant cells of both macrophage and type 2 pneumocyte origin (10). He was treated with azathioprine 200 mg daily and prednisone 20 mg daily. Eight days later he developed over 3-4 days severe myalgia and florid symmetrical polyarthritis of the fingers, hands, elbows, shoulders, knees (with effusions), ankles and feet. There was no skin rash, fever, or lymphadenopathy. Mild muscle tenderness, but no weakness, was present. Respiratory examination was unchanged and further examination was normal. Urinalysis, full blood count and differential count were normal without eosinophilia. The ESR was 55 mmh- ‘. ANF was positive to a titre of 1:500. Repeated investigations for anti-DNA antibodies and rheumatoid factor were negative. Serum biochemistry, including serum urate and creatine kinase, was normal. Synovial fluid microscopy showed numerous polymorphonuclear leucocytes. Crystals were absent. Joint radiographs showed only soft tissue swelling. Azathioprine was withdrawn, prednisone continued, and non-steroidal anti-inflammatory drugs commenced. The arthritis and myalgia resolved completely over the following week. Re-challenge with azathioprine was not performed.
Discussion Details of the eight cases recorded in the WHO Collaborating Centre for International Drug Monitoring data base are given in Table 1. More common are arthralgia and myalgia with 33 cases of each (‘1 1995 W. B. Saunders
Company
Ltd
64 Table
P. I. Pillans 1
et al.
Cases from
Case SIO.
-4s W
WHO
Sex
database
of azdthioprine
Dose of azathioprine
associated Other drugs
1
51
F
U
2
48
M
100 mg daily
3
37
M
U
4
61
F
100 mg daily
Prednisone Excedrin
5
48
M
U
Prednisolone
6
40
F
50 mg daily
I
51
F
U
8
63
M
50 mg daily
U, Unknown;
ADR,
adverse
drug
Prednisolone
Clonidine Bendrofluthiazide Prednisone
-
Prednisolone Disopyramide Salbutamol Beclometasone Acetylcysteine
arthritis Time to onset of symptoms
Outcome
Fever Rash Arthritis
U
Recovered
Fever Arthritis
U
Hepatitis Pruritis Arthritis
U
ADR(s)
Conjunctivitis Arthritis Myalgia Arthritis
24 days 10 days
U Recovered
U Recovered
Arthritis
U
Arthritis
10 days
Recovered
U
Fever Pneumonitis Arthritis
4 days
Recovered Recurrence on rechallenge
reaction.
reported to the WHO. The mean age of patients on azathioprine in whom arthritis was reported was 51 years, with an equal sex incidence. Arthritis was the only symptom reported in two cases, and in the other six cases was associated with such features as fever, rash, myalgias, hepatitis and pneumonitis. The time to onset of symptoms was 4-24 days and in the five cases where outcome was described, all patients recovered. Of note is that in the one patient who was rechallenged, there was recurrence of symptoms. In the one published report of severe polyarthritis and swinging fever in a patient taking azathioprine, recovery occurred on withdrawal, with recurrence of pyrexia of 39°C and severe polyarthritis within 1 h after re-challenge, involving the small joints of the hands and feet as well as the knees and elbows (8). Azathioprine-associated arthritis is rare, may be severe with involvement of small and large joints, and may occur alone or as part of a typical hypersensitivity syndrome. Recovery can be expected if the reaction is recognized and the drug withdrawn. Acknowledgements We thank Mr Sten Olsson for providing the details on cases reported to the WHO drug monitoring programme and Mrs Faldiela Martin for typing the manuscript.
References 1. Saway PA, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity. Case report and review of the literature. Am J Med 1988; 84: 960-964. 2. Goldenberg DL, Stor RA. Azathioprine hypersensitivity mimicking an acute exacerbation of dermatomyositis. J Rheumatol 1975; 2: 346349. CC, Lessner HE, Larsen WE. Azathioprine 3. Corley therapy of autoimmune diseases. Am J Med 1966; 41: 404412. to azathio4. King JO, Laver MC, Fairley KF. Sensitivity prine. Med J Aust 1972; 2: 9399941. 5. Farthing MJG, Coxon AY, Sheaff PC. Polyneuritis associated with azathioprine sensitivity reaction. BMJ 1980; 280: 367. 6. Van de Walle JGJ, Donckerwoicke RAMG. Association of fever, nasal decongestion and rise in serum creatinine with azathioprine therapy. Paediatr Nephrol 1990; 4: 67-68. I. Zaltzman M, Kallenbach J, Shapiro T et al. Lifethreatening hypotension associated with azathioprine therapy. A case report. S Afr Med J 1984; 65: 306. 8. Weisenburger D. Interstitial pneumonitis associated with azathioprine therapy. Am J Clin Path01 1978; 69: 181-185. 9. Hershfield NB. Reaction to azathioprine. Can Med Assoc J 1973; 10% 1082. 10. Davidson AG, Haslam PL, Corrin B et al. Interstitial lung disease and asthma in hard-metal workers: bronchoalveolar lavage, ultrastructural, and analytical findings and results of bronchial provocation tests. Thorax 1983; 38: 119-128.
Medicine
(1995) 89, 63-64
Acute polyarthritis associated with azathioprine for interstitial lung disease P. I. PILLANS*,
A. F. R. Toomt~,
E. D. BATEMAN$
AND G. M. AINSLIE~
Departments of *Pharmacology, TRheumatology, IMedicine, and GRespiratory Clinic, University of Cape Town Medical School and Groote Schuur Hospital, Cape Town, South Africa
Introduction Hypersensitivity reactions to azathioprine are uncommon, and may be associated with fever, rash, myalgia, arthralgia, hypotension, interstitial nephritis, jaundice and pneumonitis (l-8). To our knowledge only one case of florid azathioprine-associated arthritis has been described in the medical literature (9). We report on a case of acute polyarthritis in a man taking azathioprine for interstitial lung disease, and describe the features of another eight cases reported to the World Health Organisation (WHO) Collaborating Centre for International Drug Monitoring. Case Report A 54-year-old male power-tool mechanic whose work regularly involved grinding of hard metals presented with a 2 yr history of progressive exertional dyspnoea, an unproductive cough, episodes of left pleuritic chest pain, and mild arthralgias of fingers, wrists and shoulders, without features of arthritis. He had a 37 pack-year cigarette-smoking history. Examination was unremarkable except for fine inspiratory crackles heard bilaterally in the lower zones. Chest radiographs showed small lung fields, no adenopathy, and increased interstitial markings with linear opacifications at the lung bases. Pulmonary function tests confirmed moderate restriction of lung volumes, and reduced transfer factor for carbon monoxide. The erythrocyte sedimentation rate (ESR) was 20 mmh ‘. The full blood count and differential count were normal, as was serum biochemistry. Anti-nuclear factor (ANF) was positive to a titre of l:lOO, rheumatoid factors were absent, and the serum angiotensin converting enzyme value was Received 1994.
31 December
1992 and accepted
in revised form 24 March
To whom correspondence should be addressed at Department of Rheumatology, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa. 0954-6111/95/010063+02
$08.0010
39.6 units (40 & 10). A diagnosis of interstitial lung disease caused by hard metal exposure was made on the basis of history, increased proportions of eosinophils (34%) and neutrophils (12%) in bronchoalveolar These lavage, and open lung biopsy findings. included interstitial fibrosis with extensive desquamation of alveolar lining cells and intra-alveolar macrophage accumulation, and the presence on transmission electron microscopy of multinucleate giant cells of both macrophage and type 2 pneumocyte origin (10). He was treated with azathioprine 200 mg daily and prednisone 20 mg daily. Eight days later he developed over 3-4 days severe myalgia and florid symmetrical polyarthritis of the fingers, hands, elbows, shoulders, knees (with effusions), ankles and feet. There was no skin rash, fever, or lymphadenopathy. Mild muscle tenderness, but no weakness, was present. Respiratory examination was unchanged and further examination was normal. Urinalysis, full blood count and differential count were normal without eosinophilia. The ESR was 55 mmh- ‘. ANF was positive to a titre of 1:500. Repeated investigations for anti-DNA antibodies and rheumatoid factor were negative. Serum biochemistry, including serum urate and creatine kinase, was normal. Synovial fluid microscopy showed numerous polymorphonuclear leucocytes. Crystals were absent. Joint radiographs showed only soft tissue swelling. Azathioprine was withdrawn, prednisone continued, and non-steroidal anti-inflammatory drugs commenced. The arthritis and myalgia resolved completely over the following week. Re-challenge with azathioprine was not performed.
Discussion Details of the eight cases recorded in the WHO Collaborating Centre for International Drug Monitoring data base are given in Table 1. More common are arthralgia and myalgia with 33 cases of each (‘1 1995 W. B. Saunders
Company
Ltd
64 Table
P. I. Pillans 1
et al.
Cases from
Case SIO.
-4s W
WHO
Sex
database
of azdthioprine
Dose of azathioprine
associated Other drugs
1
51
F
U
2
48
M
100 mg daily
3
37
M
U
4
61
F
100 mg daily
Prednisone Excedrin
5
48
M
U
Prednisolone
6
40
F
50 mg daily
I
51
F
U
8
63
M
50 mg daily
U, Unknown;
ADR,
adverse
drug
Prednisolone
Clonidine Bendrofluthiazide Prednisone
-
Prednisolone Disopyramide Salbutamol Beclometasone Acetylcysteine
arthritis Time to onset of symptoms
Outcome
Fever Rash Arthritis
U
Recovered
Fever Arthritis
U
Hepatitis Pruritis Arthritis
U
ADR(s)
Conjunctivitis Arthritis Myalgia Arthritis
24 days 10 days
U Recovered
U Recovered
Arthritis
U
Arthritis
10 days
Recovered
U
Fever Pneumonitis Arthritis
4 days
Recovered Recurrence on rechallenge
reaction.
reported to the WHO. The mean age of patients on azathioprine in whom arthritis was reported was 51 years, with an equal sex incidence. Arthritis was the only symptom reported in two cases, and in the other six cases was associated with such features as fever, rash, myalgias, hepatitis and pneumonitis. The time to onset of symptoms was 4-24 days and in the five cases where outcome was described, all patients recovered. Of note is that in the one patient who was rechallenged, there was recurrence of symptoms. In the one published report of severe polyarthritis and swinging fever in a patient taking azathioprine, recovery occurred on withdrawal, with recurrence of pyrexia of 39°C and severe polyarthritis within 1 h after re-challenge, involving the small joints of the hands and feet as well as the knees and elbows (8). Azathioprine-associated arthritis is rare, may be severe with involvement of small and large joints, and may occur alone or as part of a typical hypersensitivity syndrome. Recovery can be expected if the reaction is recognized and the drug withdrawn. Acknowledgements We thank Mr Sten Olsson for providing the details on cases reported to the WHO drug monitoring programme and Mrs Faldiela Martin for typing the manuscript.
References 1. Saway PA, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity. Case report and review of the literature. Am J Med 1988; 84: 960-964. 2. Goldenberg DL, Stor RA. Azathioprine hypersensitivity mimicking an acute exacerbation of dermatomyositis. J Rheumatol 1975; 2: 346349. CC, Lessner HE, Larsen WE. Azathioprine 3. Corley therapy of autoimmune diseases. Am J Med 1966; 41: 404412. to azathio4. King JO, Laver MC, Fairley KF. Sensitivity prine. Med J Aust 1972; 2: 9399941. 5. Farthing MJG, Coxon AY, Sheaff PC. Polyneuritis associated with azathioprine sensitivity reaction. BMJ 1980; 280: 367. 6. Van de Walle JGJ, Donckerwoicke RAMG. Association of fever, nasal decongestion and rise in serum creatinine with azathioprine therapy. Paediatr Nephrol 1990; 4: 67-68. I. Zaltzman M, Kallenbach J, Shapiro T et al. Lifethreatening hypotension associated with azathioprine therapy. A case report. S Afr Med J 1984; 65: 306. 8. Weisenburger D. Interstitial pneumonitis associated with azathioprine therapy. Am J Clin Path01 1978; 69: 181-185. 9. Hershfield NB. Reaction to azathioprine. Can Med Assoc J 1973; 10% 1082. 10. Davidson AG, Haslam PL, Corrin B et al. Interstitial lung disease and asthma in hard-metal workers: bronchoalveolar lavage, ultrastructural, and analytical findings and results of bronchial provocation tests. Thorax 1983; 38: 119-128.