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Science

Received 3.21.07 | Revisions Received 3.23.07 | Accepted 3.27.07

Hyperuricemia and Arthralgias During


Pyrazinamide Therapy in Patients With
Pulmonary Tuberculosis
W. Qureshi, MD,1 G. Hassan, MD,2 S. M. Kadri, MPH, WHO FETP,3 G. Q. Khan, MD,2 Bensson Samuel, CT(ASCP),4
Ali Arshad, MBBS1
(1SMHS Hospital, Srinagar, Kashmir, India, 2Department of Medicine, Government Medical College, Srinagar, Kashmir, India,
3Regional Institute of Health and Family Welfare, Directorate of Health Services, Srinagar, Kashmir, India, 4Karol Marcinkowskeigo

University of Medicine, Poznan, Poland)


DOI: 10.1309/7GBYQTY62PFEHDP1

Abstract tuberculosis based on clinical history, physical these cases. Discontinuation of combination
Background: Pyrazinamide (PZA) is used exam findings, and related investigations. therapy and institution of aspirin therapy for 2
frequently in monotherapy or in combination Whole blood samples were obtained from weeks resulted in the return of uric acid levels
therapy with isoniazide and rifampicin in the these patients before, during, and after to the pretreatment levels in these patients.
combination therapy, following discontinuation
management of patients with pulmonary
of combination therapy, and after Conclusion: Significant hyperuricemia, with
tuberculosis (TB). However, hyperuricemia, administration of aspirin. Uric acid was some arthralgia, can occur in TB patients
arthralgia, or symptoms of gout may occur in quantified in serum samples from all patients treated with combination therapy. Pyrazinamide
patients treated long-term with PZA. Typically, using the uricase method in the Hitachi 916 is the most likely component of combination
aspirin therapy is instituted to reduce the chemistry analyzer. The uric acid levels during therapy responsible for these effects. However,
inflammatory pain associated with arthralgia and after discontinuation of combination aspirin therapy is effective in controlling joint
in patients being treated with PZA. The therapy and after initiation of aspirin therapy pain in these patients and in reducing their
authors determined the incidence of were determined. In addition, the authors hyperuricemia to normouricemic levels.
hyperuricemia and arthralgias in TB patients determined the incidence of hyperuricemia and Combination therapy remains a useful
treated with combination therapy and the arthralgia among these patients. treatment in the management of patients with
pulmonary TB, despite the relatively minimal
effect of aspirin therapy on serum uric acid
Results: Combination therapy resulted in side effects caused by PZA.
levels in these patients. progressive hyperuricemia in about 50% of the
patients between the 6th and 8th weeks
Methods: The authors enrolled 50 patients of treatment. Arthralgia occurred in 22% of
categorized as having active pulmonary

Pyrazinamide (PZA) has become an important component therapy.4-6 To further validate these findings, the authors deter-
of short-term, multiple-drug therapy of tuberculosis (TB).1 It is mined the incidence of hyperuricemia and arthralgias in TB pa-
a synthetic analogue of nicotinamide that is only weakly bacteri- tients treated with combination therapy and the effect of aspirin
cidal against extracellular Mycobacterium tuberculosis organisms, therapy on serum uric acid levels in these patients.
but it has potent intracellular bactericidal activity, particularly in
the relatively acidic intracellular environment of macrophages
and areas of acute inflammation. This drug is highly effective
during the initial 2 months of treatment, in which acute inflam- Materials and Methods
matory changes persist, and its use has enabled shorter treatment This study was conducted in accordance with the Institu-
regimens and has reduced the risk of relapse. It is mainly metab- tional Review Board requirements for the conduct of clinical
olized in the liver and is excreted largely in the urine.1,2 studies in the Department of Medicine, Government Medical
Pyrazinamide inhibits renal tubular excretion of urate by College, associated with the SMHS Hospital, Srinagar, Kash-
inhibiting its renal tubular secretion, resulting in some degree of mir, India.
hyperuricemia that is often asymptomatic. Occasionally, how- Patients: The authors recruited 50 patients (22 females and
ever, acute episodes of gout can occur in patients treated with 28 males), ages 15 to 64 years (mean ± SD, 34.8 ± 13.4), with
PZA. In addition, arthralgia may occur in these patients, unre- active pulmonary tuberculosis based on history, clinical examina-
lated to their uric acid level, that is responsive to treatment with tion, and the results of diagnostic and laboratory studies, includ-
analgesics such as aspirin.1-3 Moreover, aspirin is known to pre- ing chest radiography, sputum examinations for acid fast bacilli,
vent hyperuricemia and the arthralgia associated with PZA erythrocyte sedimentation rate (ESR), tuberculin testing,

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Discussion
enzyme-linked immunosorbent assay (ELISA) for surface anti-
gens of Mycobacterium tuberculosis, and polymerase chain reac- The trend the authors observed between increasing serum
tion (PCR) for Mycobacterium tuberculosis RNA. All patients UA levels and the number of weeks on combination therapy
underwent combination therapy with isoniazide, rifampicin, and (Table 1) is consistent with the studies by Sharma and
PZA (20 to 30 mg/kg/da) for a minimum of 8 weeks. Ethambu- colleagues,7 Zierski and colleagures,8 Khana and colleagues,9 and
tol, because of its potential to cause hyperuricemia, was excluded Inoue and colleagues10 in which the incidence of hyperuricemia
in the treatment of these patients. All patients were evaluated for
arthralgias based on self-reported signs and symptoms.
Exclusion criteria: Patients with any disease likely to affect Table 1_Time Course of Serum Uric Acid Concentration
serum uric acid levels were excluded from the study, including in Patients (n = 50) With Pulmonary Tuberculosis
those with hypertension, gout, diabetes mellitus, renal disease, Undergoing Combination Therapy With Isoniazide,
hepatobiliary disease, cardiac disease, malignancies, or use of Rifampicin, and Pyrazinamide
drugs that cause hyperuricemia or have a uricosuric effect.
Sample collection, storage, and stability: Venous whole Time Uric Acid Concentration
(mean ± SD), mg/dL
blood specimens were obtained by venipuncture from an antecu-
bital vein at the same time of day (8:00 AM) from all patients. Pretreatment 4.4 ± 0.5
The blood was allowed to clot, the serum was removed and Post-treatment, week
stored at 2°C to 8°C in tightly-capped tubes, and each tube was 2 4.8 ± 0.5
4 5.2 ± 0.6*
thawed once prior to uric acid testing. 6 5.7 ± 0.7**
Serum uric acid determination: Uric acid (UA) was quanti- 8 6.4 ± 0.8**
fied in all serum samples using the uricase method in the Hi-
*p<0.05, compared with pretreatment UA concentration.
tachi 916 automated chemistry analyzer (Hitachi, Japan). The **p<0.005, compared with pretreatment UA concentration.
reference range for this assay is 2.6 to 6.0 mg/dL for females and SD, standard deviation.
3.5 to 7.2 mg/dL for males. The authors defined hyperuricemia
as a serum uric acid concentration greather than the highest
mean uric acid level (6.5 mg/dL) observed after 8 weeks of com- Table 2_Incidence and Location of Joints Affected by
bination therapy. Arthralgia in 11 Patients With Hyperuricemia Following
Distribution of patients: A subset of 13 patients who were 8 Weeks of Combination Therapy
treated with combination therapy for 8 weeks were discontinued
on this therapy and begun on aspirin therapy (2.4 g/day in di- Location of Affected Joints Number of Casesa (%)
vided doses for 2 weeks). Knee 4 (8.0)
Statistical Analysis: The data was analyzed using a paired Shoulder 2 (4.0)
Student’s t-test and a chi-square test. A p-value less than 0.05 Wrist and interphalanges 2 (4.0)
was considered statistically significant. Vertebral column 1 (2.0)
Ankle 2 (4.0)
Total 11 (22.0)
aN = 50
Results
The serum uric acid level in all patients (n = 50) prior to
the initiation of combination therapy ranged from 2.6 mg/dL Table 3_Incidence of Hyperuricemia Among 13 Patients
to 5.4 mg/dL (mean ± SD, 4.4 ± 0.5 mg/dL). Moreover, who Received Aspirin Therapy After Discontinuation
of Combination Therapy
there was a progressive increase in serum UA concentration
over the 8-week period of combination therapy in all Specimen Type Number of Patients With
patients, with levels rising significantly between weeks 4 and Uric Acid Concentration, mg/dL
8 compared with pretreatment levels of UA (Table 1). <6.5 >6.5
Among these patients, the prevalence of hyperuricemia was
Pretreatment 13 0
48.0% (24 of 50). One patient had hyperuricemia (UA con- Post-CT for 8 wk 0 13
centration = 7.1 mg/dL) after the 4th week of combination Post-DC of CT + ASA therapy for 2 wk 13 0
therapy. At the end of the 8-week period of combination
CT, combination therapy, DC, discontinuation; ASA, acetylsalicylic acid (aspirin)
therapy, 11 of the 50 (22%) patients complained of arthral-
gias, especially in the knee (Table 2). In the patients (n = 13)
who were treated with combination therapy for 8 weeks and
Table 4_Serum Uric Acid Concentration in 11 Patients
then discontinued on this therapy and begun on aspirin ther- Before and After Discontinuation of Combination
apy for 2 weeks, the serum UA levels in all of these patients Therapy
returned to normouricemic levels (ie, < 6.5 mg/dL), consis-
tent with their pretreatment levels, from their hyperuricemic Time Uric Acid Concentration, mg/dL
levels (> 6.5 mg/dL) at the end of 8 weeks of combination Mean ± SD Range
therapy (Table 3). Moreover, in patients (n = 11) treated with
Pretreatment 4.4 ± 0.5 3.5-5.2
combination therapy for 8 weeks and subsequently discontin- Post-treatment, 8 weeks 7.2 ± 0.2* 6.8-7.4
ued on this therapy for 2 weeks, UA levels were significantly After discontinuation of treatment, 2 weeks 4.5 ± 0.3 4.0-5.0
higher at 8 weeks post-therapy versus pretreatment levels and
*p<0.001, compared with pretreatment value
returned to pretreatment levels after discontinuation of this SD, standard deviation
therapy (Table 4).

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was 43.4%, 56.0%, 73.7%, and 86.3%, respectively, in patients improvement of the signs and symptoms of arthralgia. Because
treated with combination therapy or PZA alone. In similar stud- PZA therapy does not lead to either severe intolerable joint
ies by others, the incidence of hyperuricemia following PZA manifestations or irreversible sequelae, and aspirin is effective in
therapy alone was as high as 100%.4,11 Such differences in the reducing the pain associated with arthralgia in patients undergo-
the prevalence of hyperuricemia following combination therapy ing this therapy, discontinuation of PZA therapy, either alone or
is probably attributable to rifampicin. Raghupati and as part of combination therapy, does not seem warranted. LM
colleagues12 have shown previously that rifampicin enhances the
renal excretion of UA regardless of the presence or absence of
PZA as a component of the combination therapy used in the 1. Mandell GL, Petri WA Jr. Antimicrobial agents: Drugs used in chemotherapy
treatment of patients with TB. In the authors’ study, the rela- of tuberculosis, Mycobacterium avium complex and leprosy. In: Hardman JG,
tively lower prevalence (48.0%) of hyperuricemia was probably Limbird LE, Molinoff PB, et al, eds. Goodman & Gilman’s—The
related to the uricosuric effect of rifampicin. Exclusion of etham- Pharmacological Basis of Therapeutics, 9th ed. McGraw Hill: New York;
1155–1174.
butol in the authors’ study might also have been responsible for
2. World Health Organization. Treatment of Tuberculosis: Guideline for National
the lower frequency of hyperuricemia, since this drug is known Programmes; 3rd ed. 2003:87–104.
to increase serum UA levels.13 3. Cullen JH, Early LJA, Fiore JM. The occurrence of hyperuricemia during
Among a subset of patients (n = 11) who developed hyper- Pyrazinamide therapy. Am Rev Tuberc Pulm Dis. 1956;74:289–292.
uricemia, the joints most affected were the knees, shoulders, and 4. Shapiro M, Hyde L. Hyperuricemia due to Pyrazinamide. Am J Med.
ankles (Table 2); however, radiologic studies did not reveal any 1957;23:596–599.
abnormality. This finding suggests that the arthralgia reported by 5. Iyer KN, Srinivasan P. Effect of aspirin in the control of hyperuricemia and
these patients was non-deforming and non-erosive. Similar find- arthralgia due to pyrazinamide therapy. Indian J Tuberc. 1987;25:197–198.
ings were observed in the studies by Khana and colleagues9 and 6. Petty TL, Dalrymple VG. Inhibition of pyrazinamide hyperuricemia by small
doses of acetylsalicylic acid. Ann Int Med. 1964;60:898–899.
Sharma and colleagues.7 In these studies, the severity of arthal-
7. Sharma TN, Jian NK. Hyperuricemia and arthralgia due to pyrazinamide
gias was not severe enough to warrant termination of therapy therapy. Indian J Tubercle. 1981;28:92–97.
and none of their patients developed frank arthritis. Horsefall 8. Zierski M, Bek E. Side effects of drug regimens used in short course
and Plummer14 also noted involvement of big joints during chemotherapy for pulmonary tuberculosis: A controlled clinical study. Tubercle.
PZA therapy; however, Zierski and colleagues8 and Cullen and 1980;60:44–48.
Levine15 did not observe any joint involvement despite develop- 9. Khana BK, Kumar J. Hyperuricemic effect of ethambutol and pyrazinamide
ment of hyperuricemia in their patients.12 The frequency of administration concomitantly. Indian J Tuberc. 1991;38:21–24.
arthralgias reported among studies of patients undergoing com- 10. Inoue T, Ikeda N, Kurasawa T, et al. Hyperuricemia and athralgia during
pyrazinamide treatment. Nihon Kokyuki Gakkai Zasshi. 1999;37:115–118.
bination therapy or therapy with PZA alone varies widely from
13.0% to 66.6%.7,10,16,17 11. Gutman AB, Yu TF, Berger I. Estimation of tubular secretion and reabsorption
of uric acid by use of Pyrazinamide. Am J Med. 1969;47:575–592.
The authors’ study demonstrated no direct relationship be-
12. Raghupati SG, Acharyulu GS, Kannapiran M. Role of rifampicin in arthralgia
tween the level of serum UA concentration and the severity of induced by pyrazinamide. Tubercle. 1983;64:93–100.
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symptoms are not directly related to serum UA levels in patients 14. Horsfall PAL, Plummer J, Allan WGL, et al. Double blind controlled
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study, serum UA levels returned to normal in all patients who arthralgia during pyrazinamide administration. Tubercle. 1979;60:13–24.
were given 2 weeks of aspirin therapy (Table 3) or in those in 15. Cullen JH, Levine M. Studies of hyperuricemia produced by Pyrazinamide.
Am J Med. 1957;23:587–598.
whom PZA therapy was discontinued (Table 4). Moreover, simi-
16. McDermott W, Tompsett R. Activation of pyrazinamide and nictotinamide in
lar to the findings reported by Sherma and colleagues,7 all of acidic environments in vitro. Am Rev Tuberc. 1954;70:740–754.
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