PATIENTS AND METHODS

Since 1994 we have adopted the policy of treatment with INHP (5 mg/kg/day isoniazid, maximum 300 mg/day and 10 mg/day pyridoxine) for one year of all patients with SLE requiring long term steroids. Patients who started treatment with INHP between January 1994 and December 1999 were studied. At the start all patients underwent a thorough clinical evaluation and chest radiograph to rule out active TB. Patients were evaluated at three to six monthly intervals. Liver function tests (LFT) were carried out during prophylaxis only if liver toxicity was suspected owing to nausea, loss of appetite, and icterus. Only data of those patients who completed the INHP treatment or in whom the drug was withdrawn owing to toxicity have been analysed. The results were compared with the results of our earlier series of patients with SLE who had not received INHP.² The study is divided into two phases. Phase 1 was the period during which the patients received INHP. Patients who completed at least one year's follow up after INHP were included in the phase 2 analysis. The cost effectiveness of the INHP treatment was evaluated.

RESULTS

Ninety seven patients were included in phase 1. Of these, 95 completed one year of INHP. Seventy of these patients were followed up for one further year after completion of the INHP treatment (phase 2). Table 1⇓ gives demographic, clinical, and treatment details.

DISCUSSION

Tuberculosis is common in India.^2,5 Prevalence of radiological disease has been estimated to be 1.3–1.9 %.⁵ A recent study showed an 80% prevalence of latent TB in urban India.⁶ An increased prevalence of active TB has been reported in patients receiving chronic steroid treatment for renal transplantation and asthma.^7,8 We have reported an incidence of 11.6% of TB in patients with SLE receiving steroid treatment.² That study analysed data of 146 patients over a period of five years. Seventeen developed TB with one death. Nine of the 17 (53%) developed TB within the first year of steroid treatment. Four of these 146 patients had received INHP and one of these four patients had developed TB.

TB in adults is due either to reactivation of healed foci or reinfection from an exogenous source. INH prevents reactivation of TB by eradicating the small number of bacilli present in the “healed” foci. Although INHP has been found to be efficacious in AIDS, haematological malignancies,⁹ and renal transplants,¹⁰ there are few data on its use in SLE. A recent study showed that INHP treatment for six months may be effective in systemic rheumatic diseases in countries with a high prevalence of TB.¹¹

INHP has been deemed impractical in the developing countries owing to the already existing high prevalence of INH resistance and extended duration of treatment resulting in non-compliance.¹² There is also a fear of propagating INH resistance.

Despite these misgivings, in view of the high incidence of TB in our patients, we have instituted routine INHP in all patients with SLE requiring long term steroid treatment with or without cytotoxic treatment, with good results. Only 1/97 patients developed pulmonary TB when receiving prophylaxis within a month of starting INHP, and this patient might have been harbouring active disease when treatment with INHP was started; it was a case of inappropriate selection. During further follow up one patient developed TB one month after completion of INHP. He required second line treatment in view of the incorrect treatment given when tuberculosis was diagnosed. There were no deaths due to tuberculosis. Thus in comparison with our previous study the incidence of TB decreased from 11% to 2%, an 82% reduction. Although these two studies were carried out at different times, the odds ratio obtained after combining the results suggests that the risk of TB is six times higher when INHP is not used.

The most important consideration that precludes routine use of INHP is the fear of development of INH resistance. Mycobacterial resistance to INH is linked to large bacterial populations such as those which exist in cavitary lesions.¹³ A healed tuberculous focus, the setting in which INHP is used, contains around 10²–10⁴ bacilli as against cavitary lesions which contain 10⁷–10⁹ bacilli. The only mechanism of development of INH resistance in mycobacteria is by spontaneous mutation.¹⁴ INH resistance occurs at a rate of 3.5 in 10^–8 divisions. A healed focus is highly unlikely to contain INH resistant mutants. Further, INHP acts primarily by prevention of bacillary multiplication. Ferebee has shown that INHP does not result in INH resistance.¹⁵ Nolan et al studied South East Asian refugees in the United States¹⁶ and concluded that INH resistant TB in their patients receiving INHP was more likely to be due to primary drug resistance than due to acquisition of resistance during prophylaxis.

Another fear is that of toxicity, especially peripheral neuropathy and hepatic necrosis. INH induced hepatotoxicity can be fatal.¹⁷ The incidence of INH hepatotoxicity is higher in elderly female patients and close monitoring is advocated.¹⁷ In our series one patient had transient transaminitis. However, a routine LFT was not done in our patients and, possibly, some patients might have had subclinical hepatitis that did not warrant discontinuation of INHP.

To evaluate the cost-benefit ratio of INHP as related to our situation, we compared the present data with those for our series of patients who had not received INHP.² From our earlier data, it can be estimated that about 6% of patients with SLE receiving corticosteroid treatment would develop TB in the first year in the absence of INHP. The cost of drug treatment of TB for these six patients in a group of 100 patients with SLE would be 11 880 rupees (1980 rupees for each patient: HRZE for two months, HR for four months). The cost of provision of INHP to the same group is 36 500 rupees. Addition of the cost of treatment for one patient with presumed INH resistant TB (HRZE for two months, HRE for 10 months) would increase the cost to 40 945 rupees. Thus the cost of prevention of one case of TB in the first year of treatment for SLE is estimated to be around 5800 rupees. This cost is therefore about four times that of treatment of the disease. Though this appears to be high, especially for a developing country like India, it is justified when one considers the protection afforded by INHP in subsequent years. Moreover, it also prevents morbidity, mortality, and transmission of TB in the community.

To conclude, our experience shows that in a situation with a high incidence of TB:

• INHP is safe and effective in patients with SLE receiving steroid treatment

• The fear of INH resistance seems to be misplaced

• Patients chosen to receive INHP treatment should be evaluated carefully to rule out active disease.