Anergy and immunosuppression in patients with rheumatoid arthritis

The management of autoimmune diseases has experienced a surprising evolution, as our knowledge about the underlying immunity of the various diseases has improved. Immunomodulation therapies manage to control the activity of the disease and patients have a greater chance to achieve early remission, avoid pathological damage to the different organs, particularly the joints, hence preventing disability and improving quality of life.¹ However, this improvement is usually at the expense of an increased risk of infections. Such infections may be trivial, or may be life-threatening for the patient.

We still have limited clinical tools to establish the effect of medications on the immune system. Though some tests are able to quantify the number of lymphocytes, our ability to measure lymphocyte activity is limited. The T CD4+ lymphocyte count in clinical practice has been helpful in HIV patients, but its use in autoimmune diseases has been limited and rather disappointing.² This fact is clinically relevant since being able to predict the risk of infection or reactivation of infection in patients receiving immunomodulatory therapy is certainly of interest.

The effect on the immune system and the risk of infection varies significantly with the treatment selected: non-steroidal disease modifying drugs seem to have a low risk of infection,^3,4 while those with steroids have increasing infection rates, associated with the dose administered. Even low dose steroids may have an immunosuppressor effect, though the exact cutoff point seems to be controversial. A systematic review of the literature identified one study showing an increased infection risk with prednisone doses of less than 5 mg/day, with a relative risk of 1.3 (95% CI: 1.06–1.63), and an increased risk of 1.95 (95% CI: 1.53–2.43) when the doses were increased to between 6 and 9 mg/day.⁵

Typically, steroid-associated immunosuppression has been considered when the dose exceeds 20 mg/day, particularly in chronic use. Traditionally, it was thought that the patient became immunosuppressed as a result of medication use, when the accumulated dose exceeded 600 mg (20 mg/day in one month). However, it is now evident that even lower doses are associated with a higher risk of infection, compared to individuals with no medication. To further complicate our understanding about this issue, live virus vaccines (although attenuated) have been administered to patients with juvenile rheumatological conditions, receiving up to 20 mg of prednisone per day,⁶ with immune response to the immunization and no adverse effects, such as disseminated vaccine-associated infection.

Finally, the introduction of biologic therapy has been clearly associated with an increased risk of infection, which in some cases may hinder its use, or at least postpone therapy. The CORRONA registry, developed in North America, assessed the rates of infection adjusted for exposure in around 8000 patients and found that the risk per 100 persons/year was as follows: for disease modifying drugs not including biologics, 24.5 (95% CI: 21.8–27.5); for methotrexate, 30.9 (95% CI: 29,2–37,2); for methotrexate in combination with biologics, 37.1 (95% CI: 34.9–39.3), and Anti-TNF drugs, 40.1 (95% CI: 37.0–43.4).⁷ The addition of steroids increased the incidence of infections by about 63% (95% CI: 20-22,1%), and if the doses were above 10 mg/day, the increase was of around 30% (95% CI: 11–53%). As a whole, these data show an increased risk with the use of steroids and biologics.

One of the most feared complications with the use of immunomodulatory therapy is tuberculosis. TB may develop via 2 mechanisms: reactivation of an old infection focus or de novo presentation. Given the high incidence of tuberculosis in our environment (compared to the United States or to some European countries), both mechanisms are feasible. In order to identify the first mechanism, various tests have been suggested to show whether the individual has been exposed to the mycobacteria: the traditional tuberculin, a mixture of soluble antigens from Mycobacterium tuberculosis cultures which, notwithstanding its technical name of purified protein derivative (PPD), contains several protein and lipid fractions; and the most modern tests based on memory lymphocyte production of interferon that recognize antigens of the mycobacteria.

This is an important test because it allows for the identification of patients at risk of disease reactivation. A study in Spain ― a country with an incidence of tuberculosis similar to that reported in Colombia ― showed that the use of biologics was associated with an over 60-fold increased frequency of tuberculosis,⁸ and that a strategy based on the identification of patients with latent TB (through tuberculin) and its treatment with isoniazid, decreased the risk of TB infection during treatment with these medications.⁹

This issue of the COLOMBIAN JOURNAL OF RHEUMATOLOGY features the study by Vallejo et al., measuring the ability of a group of patients with rheumatoid arthritis and different treatment regimens, to respond to 2 stimuli: the tuberculin test and tetanus toxoid inoculation.¹⁰ The purpose of the study was to identify the proportion of patients with anergia, i.e., failure to generate a lymphocytic response, evidenced by failure of the individual to respond to these 2 stimuli. With these 2 simple tests, the research team found 9% anergia in a population comprising 104 patients with rheumatoid arthritis and different treatment regimens, predominantly methotrexate and leflunomide.

Only13% had a positive tuberculin test, which is low considering the prevalence of the disease in the country,¹¹ but the test was done just once. Moreover, biologic therapy is not administered as a routine in the country to patients with a positive test, or it is only administered following treatment with isoniazid or other anti-TB medications.

The data in this study indicate that as a routine, the tuberculin test should be done with a booster; hence, in those cases in which the test results are negative, a second test should be done over the next few weeks (1–4 weeks later). This limits the possibility to administer immune therapy to individuals wrongfully classified as negative for latent tuberculosis. The next step is to establish the approach for this group of patients, since on the one hand, treatment with isoniazid or other drugs is efficient in reducing the risk of active tuberculosis,¹² but on the other hand, the treatment is associated with adverse effects and may delay the administration of the required immunomodulatory regimen.

Probably another important message is routine tuberculin testing in patients who will be receiving chronic steroid therapy, since once the treatment is established, it is very difficult to identify the presence of latent tuberculosis and the benefit of the corresponding therapy.

Notwithstanding the improved socioeconomic conditions in our country, tuberculosis is still a public health issue and should be considered, not just by rheumatologists and infectious disease specialists, but also by physician assessing patients receiving immunosuppressants, both for their previous identification (as latent tuberculosis prior to immunomodulatory therapy), and for a timely diagnosis of patients receiving immunosuppressants for a rheumatological condition of for other reasons.