Abstract

The advent of biologic medication has substantially improved the evolution of juvenile idiopathic arthritis (JIA), producing better social insertion and a clearly superior quality of life. However, there is a possibility of immunological disorders following treatment with biological substances, which may have long-term consequences in treated patients. The extension of clinical trials to pediatric patients has allowed a closer follow-up of both the evolution of the disease under treatment and the consequences of biological treatments. This article aims to analyze this aspect according to studies conducted in many countries by several authors. For each biological agent, the immunological events consisted primarily of the appearance of serious infections, such as tuberculosis, malignancies, response to vaccines, the appearance of autoimmune manifestations, and, last but not least, the appearance of anti-drug antibodies. These studies have shown that there are large differences in side effects between different biological agents, and, therefore, it has been proposed that a dossier be conducted to monitor these side effects. An international pharmacovigilance database called PharmaChild has already been created.

1. Introduction

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. The incidence at a European level is 16 to 150 per 100 inhabitants per year ¹. JIA can cause short and long-term disabilities. JIA is a disease with no apparent cause that lasts more than 6 weeks, with onset at the age of 16 years. The 7 subtypes of JIA differ in genetic susceptibility, distribution in the infant population, and severity of arthritis ². Systemic JIA accounts for up to 17% of all JIA cases. It turned out that this is a totally different disease from the other subtypes, both in its manifestations and in its evolution and response to therapy. In the last decade, legislation has been implemented to encourage controlled clinical trials in children, as well as the introduction of new powerful biologic drugs, which have greatly improved the course of the disease. These biological drugs are produced by biological processes ^{1, 3}.

The American College of Rheumatology mentioned, in 2011, six biological substances in the treatment of JIA. These drugs are TNF-α inhibitors - 3 types: Etanercept, Adalimumab, Infliximab; Immunoglobulins CTLA4, such as Abatacept; Anti-CD20 monoclonal antibodies (mAb), such as Rituximab and an IL-1 antagonist - Anakinra. An IL-6 anti-receptor agent, Tocilizumab, has also been introduced. Difficulties in tracking the biological effects and specific indications of these treatments are related to safety issues, common side effects, small patient populations and too short follow-up time ^{4, 5, 6, 7}.

2. Clinical and Immunological Aspects of Long-term Use of Immunological Therapy in Children with JIA

There are many immunological differences in the actions of these biological substances. Those drugs, which target TNF-α, have a high potency for binding TNF-α and forming complexes. It is interesting to note that among the 3 drugs which bind to TNF-α, Etanercept has a particular action, in the sense that it lacks the first part of the CH1 constant antibody region ^{8, 9}. Due to this particular structure, cytotoxicity does not occur, because the complement does not participate in this type of reaction. Usually, complement 3 (C3) binds to the CH1 portion of the antibody and forms the membrane attack complex. Therefore, the fact that Etanercept does not induce this type of reaction means it has low toxicity. The other 2 drugs, Infliximab and Adalimumab, induce complement-dependent cytotoxicity. Very important for biologics is the half-life, which differs as follows: Adalimumab has a half-life (T1/2) of 2 weeks and Anakinra T1/2 of 4-6 hours, thus it should be injected daily ^{10, 11, 12, 13}.

Very common side effects differ for each agent and mainly refer to lower respiratory tract infections, headaches, etc. The time to assess the effectiveness of the drug is 3-4 months.

If the answer is not appropriate, we should consider changing the medicine. It is important to note that these biological drugs antagonize the cytokines or receptors involved in the immune system. This leads us to think about the possibility of affecting the quality of the immune system and, through this, the emergence of a defective defense mechanism against infections and tumors, ineffective responses to vaccinations, and poor immunoregulation can occur, which can promote autoimmunity or autoinflammation ^{1, 14, 15}. It should be noted that antibodies (Ab) may be produced against the biological drug because it can be recognized as an antigen by the immune system. Some similarities may occur in patients with JIA treated with biological substances and patients with primary immunodeficiency. For this reason, tests for primary immunodeficiency may be performed to estimate possible side effects. Most of the studies analyzed show that bacterial infections are those that require antibiotic therapy and hospitalization. It is also known that Anakinra and Tocilizumab, as well as corticosteroids, can affect body temperature without a patent fever and can also affect the production of acute phase reactants. It has also been found that the two substances can also induce neutropenia. For these reasons, great care must be taken to diagnose an infection during this treatment ^{16, 17, 18}.

3. Opportunistic Infections

Opportunistic infections were found in 0.3 per 100 patients with JIA in a cohort of 8,503 children. The responsible pathogens included Coccidioides, Salmonella, and Shigella. In the case of biological treatments, it was found that Etanercept did not cause any serious infections that required hospitalization. Other biologic drugs have caused infections in different percentages, some of them insignificant ^{1, 19}.

4. Tuberculosis

Tuberculosis, which is a serious infection, has occurred in cases treated with Infliximab, even in countries where there is no increased incidence of tuberculosis. For this reason, TNF-α inhibitors should not be used in patients with latent tuberculosis. TB testing is mandatory prior to treatment with TNF-α inhibitors. It is preferable to use more sensitive tests for patients before therapy. One such test would be an immunosorbent assay (IGRA QuantiFERON GOLD).

In 2012, the American College of Rheumatology recommended testing all patients who are treated with biological agents. Studies have shown that for most biological agents, no cases of TB have occurred with treatment ¹.

5. Malignant Diseases

Cases of malignancy have been reported in children and adolescents treated with TNF-α antagonists. In patients treated with TNF-α antagonists, an increased rate of malignancy and, in particular, lymphoproliferative diseases was detected.

Regarding the administration of vaccines to patients with JIA being treated with biologic drugs, it shows that live attenuated vaccines are safe in patients receiving biologic drugs. Methotrexate alone, used in the treatment of JIA, reduces the response to the pneumococcal vaccine, independent of T cells ^{1, 20}.

6. Autoimmune Diseases

The emergence of new autoimmune diseases may be possible during treatment, given the potential of these drugs to create immune system dysfunction. It is known that uveitis can occur in JIA but also in 1.3% of patients with Crohn's disease. Here, it is difficult to interpret whether it is caused by the disease or could be sustained by biological treatment. Several studies have reported the development of demyelinating diseases, especially those with TNF-α inhibitors, which is why warnings and precautions have been sent to TNF-α blockers ^{1, 11}.

7. Conclusions

It is very difficult to assess the incidence of side effects, which are attributed only to biological drugs. However, what we can remember is that these biological drugs, which have brought great changes for the better in the evolution of JIA, should be used with caution in certain categories of patients. We must also be careful about the way these medicines work and to not administer them to those with a potential risk for severe respiratory infections, those with a potential risk for malignancy or latent tuberculosis. We must consider other possible complications and associations, as has been recently described in some patients with JIA, treated with biological agents, the appearance of essential pulmonary hypertension, interstitial lung disease, and alveolar proteinosis.

It seems that these complications are the result of severe uncontrolled systemic activity. We must also take into account the fact that in the treatment of JIA, drug combinations are also used, and in order to appreciate the side effects, we must take into account these combinations. For better management of these adverse side effects, national registries should be created for patients treated with JIA, and side effects should be monitored consistently. In fact, the European Union (EU) funded Pharma Child platform has also been launched, which is, in fact, a web registry that will provide better insights into the real immunological consequences of biologics. The immunological consequences of long-term use of biologic medications differ between the types of medication and their combination. It is known that infections can occur in JIA more frequently even without biological treatment. Malignant tumors may occur more frequently in patients using TNF-α inhibitors. The response to vaccination is good in patients with JIA. Demyelinating diseases have also been described in the peripheral system, so they will have to be recorded in the future as a possibility of autoimmunity, especially in patients treated with TNF-α inhibitors.

References