Οι βιολογικοί παράγοντες ως θεραπεία των χρόνιων φλεγμονωδών αρθροπαθειών
Authors: Παπαδόπουλος Χρήστος 
Published: September 2021

Biological therapies broadened new therapeutic horizons in the treatment of the chronic inflammatory arthropathies. It has been shown that these drugs are effective both for the resistant forms of the rheumatoid arthritis and for the seronegative spondylarthropathies, achieving significant clinical improvement as well as inhibition of radiological lesions’ progression. The aim of the present doctoral thesis was to investigate the long-term efficacy, the safety (toxicity), the residence time (survival) and the reasons of discontinuation of the therapy with biological agents in chronic inflammatory arthropathies. For this purpose, medical records of patients diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), who were under treatment with the anti-TNFa biological agents infliximab, adalimumab and etanercept and were also under the supervision of the Rheumatology Clinic of the University Hospital of Ioannina during a period of 16 years, from October 1999 up to November 2015 were studied. The data related with the parameters of assessment for the effectiveness and safety were collected at determined time points: at baseline, every six months for the first two years of observation and then annually until the completion of an eight-year period for rheumatoid arthritis and a six-year period for spondylarthropathies (PsA and AS). More specifically, at the beginning of the study, the data that are related to the demographic characteristics of the patients (age, sex, etc.) and the nature and severity of the disease (disease duration, less or more destructive disease, presence or not of inflammatory spondylitis, presence or not of positive RF, any prior therapy with other biologic agent or DMARDs etc) were recorded. In each patient's assessment (every 6 months or a year), the dosage of medications, parameters of clinical and laboratory assessment (number of tender and swollen joints, ESR, CRP etc.) as well as specific indices of clinical response which are different for each disease (DAS 28 ESR, DAS 28 CRP, SDAI, ACR 20, 50 and 70 and HAQ for RA; DAS 28 ESR, DAS 28 CRP, SDAI, modified ACR 20, 50 and 70, PsARC and PASI for PsA; BASDAI, BASFI and ASAS for AS) were recorded. Τhe side effects (including allergic reactions) and other adverse events which were possibly related to the biological treatment, disturbances from laboratory tests, appearance of new diseases, surgical operations that were carried out during the biological treatment and any discontinuation or change of the biological agent to another biological agent, including the reasons of this discontinuation or change were also recorded. The primary objective of the present study, as far as the RA patients are concerned, was the calculation of the rate of patients who responded according to the activity index DAS 28, for the PsA patients according to the index PsARC and for the AS patients to the index BASDAI respectively. The results of this study showed that all three biological agents which have been studied (infliximab, adalimumab and etanercept) were proved to be particularly effective in all three diseases (RA, PsA and AS). More particularly, studying RA patients as a whole at first – regardless of the biological treatment they received – a statistically significant reduction was found in both DAS 28 ESR and DAS 28 CRP in the first six months, that was maintained – on both indices – until the end of the follow-up (8 years from the beginning). Studying RA patients separately, per medication, a very good response in all three treatments was observed which was sustained up to a great degree until the end of the study. The response rates according to ACR 20 in the twelve months were 63% for infliximab, 72% for adalimumab and 61,5% for etanercept. The response rates in the eight years period were 17,8%, 32,4% and 65,4% respectively. The good/moderate response according to the DAS28 CRP in the twelve months period was 34,5%/63,8% for infliximab, 42,6%/54,1% for adalimumab and 60%/40% for etanercept. The comparison of the effectiveness of the three drugs, which concerned RA patients for the first eighteen month therapy, did not show superiority of any anti-TNF therapy over the others. After examining PsA patients as a whole – regardless of biological treatment – wefound out, as in the case of RA patients, a statistically significant reduction in both DAS 28 ESR index and DAS 28 CRP in the first six months, which was maintained – on both indices – until the end of the follow-up (6 years after onset). Studying PsA patients separately, per medication, a very good response to all three drugs, which was sustained up to a great degree until the end of the study was observed. The response rates according to the ACR 20 criteria in the twelve months were 73% for infliximab, 71,4% for adalimumab and 88,9%. for etanercept. The response rates for the eight years were 45,9%, 28,6% and 16,7% correspondingly. There was a similar response in the twelve months period according to PsARC: 75,7%, 66,7% and 93,7% respectively. After studying AS patients as a whole – regardless of biological treatment – it was shown that the percentage of the active disease according to the BASDAI index decreased from 75,7% to 22,7% from the first six months of treatment. Gradually, this percentage was further reduced in the six years period until the end of the attendance, where it was zeroed. The response rate according to the BASDAI for the first six months reached 66,7% while in the six years period all patients responded. There was a similar improvement of CRP during the time. Examining AS patients separately, per medication, a similar improvement was observed over time with all three drugs. All three biological treatments were found to have an acceptable safety profile. Studying the total population – regardless of disease – the drug in which most adverse events were remarked was infliximab (96,15% of patients) followed by adalimumab and etanercept with 71,59% and 68,25% respectively. The most frequently occurring adverse event for all the three treatments was infection, with the greater percentage of which to be remarked to infliximab (75%) while the percentage of adalimumab and etanercept was much lower (46,59% and 39,68% correspondingly). The most frequently occurring infections were, in descending order, upper respiratory system infection/common cold, urinary tractinfection, gastrointestinal infection, skin mycosis, cold sores, pneumonia, herpes zoster, sinusitis, and pharyngitis. The systemic allergic reactions were more frequent to infliximab (33,33%) and much less frequent to adalimumab and etanercept (2,27% and 1,59% respectively). Especially for RA patients, the results were similar to those of the total population. The greater percentage of the patients who had experienced at least one adverse event was under the treatment with infliximab and it was a high one (98,65%). The most frequently reported adverse event for all three drugs was the infection, whose highest rate was observed in infliximab again (70,27%) and having a statistically significant difference from the other two regimens. However, there was not any statistical difference among the three drugs as far as the occurrence of serious infections is concerned. The systemic allergic reactions were significantly more frequent in infliximab with a fairly high percentage (39,19%), a rare one in adalimumab (2,67%) while in etanercept no allergic reaction was observed, neither systemic nor local. In the samples of PsA and AS patients, the most common adverse event for all three drugs was also infection. Λnfliximab, as far as the appearance of systemic allergic reactions and other events during infusion (except for allergies) is concerned, appeared to be much better tolerated in AS patients than in RA and PsA patients (systemic allergic reactions in RA and PsA: approximately 40% while in AS: 17,78%; other events during infusion in RA and PsA: about 10% while in AS: 2,22%). Both adverse events in general and infections and systemic allergic reactions in particular have been occurred more frequently during the first year of the biological treatment. This fact requires more attention by physicians during this period. As predisposing factor for the significantly more frequent occurrence of the infections was found to be the steroids’ intake but only for RA patients and only for those who were under the treatment with infliximab. For the PsA and AS patients – but not for the RA ones – the occurrence of allergic reactions in women in comparison with men was significantly more likely to appear. Six incidents with TB infection were recorded (5 of pulmonary TB and 1 of extrapulmonary). From all these, 4 appeared in infliximab, 2 in adalimumab, including extrapulmonary TB and none in etanercept. Also, 3 malignant lymphomas appeared (2 in infliximab and 1 in adalimumab), 1 incident of multiple sclerosis (infliximab), 1 incident of optic neuritis (adalimumab), 1 incident of aggravation of heart failure (etanercept) and 1 incident of reactivation of hepatitis B (infliximab). Studying the survival of anti-TNFα treatment in all three diseases for the whole population – regardless of the administered drug – a survival rate of 31,8% for RA (at the end of the 8-year period) was found while the respect rates for PsA and AS were 50% and 60,8% (at the end of the 6-year period). From the survival curves it seemed that AS patients had a relatively higher survival rate but the difference with the other two diseases was not statistically significant. Examining the survival for three biological treatments in all patients – regardless of disease – a survival rate of 36,6% for infliximab, 39,7% for adalimumab and 60,5% for etanercept was observed. The survival time was on average significantly lower for the case of infliximab in comparison with the survival time of adalimumab and etanercept, between which there was no a statistically significant difference. Finally, while studying the survival from the point of view of the treatment for each disease separately, the highest survival rate for etanercept in the AS patients was recorded (88,9%) whereas the lower survival rate in RA patients using infliximab was also recorded (20%). Particularly in RA, it was also shown that the survival for the infliximab was significantly lower in comparison with the two other treatments that were not statistically different between them (p=0,089). Also RA patients, as independent prognostic factors which influence the survival time with statistical significance, were found to be the number of failed DMARDs and the co-administration of methotrexate as well. More specific, itseemed that the survival for those who had failed to > 3DMARDs and those who had not received MTX was significantly lower. In the case of PsA and AS, it didn’t seem to be statistically significant differences in the survival among the three drugs nor independent factors that can significantly affect the survival time. The most common reasons for the discontinuation of the biological treatment for the whole population were ineffectiveness (12,7% of the original patient sample) andfollowed by systemic allergic reaction (11,7%) and adverse event (9,4%). The above three reasons were also the most common for all combinations between treatment and disease. In the total population, the most common adverse event which resulted in the discontinuation of the biological therapy was tuberculosis infection, followed by pneumonia and psoriasiform rash. In conclusion, it was shown that all three biological agents that have been studied (infliximab, adalimumab and etanercept) are particularly effective for the three diseases (RA, PsA and AS). In a significant percentage of patients, improvement occurred since the first six months of the treatment and it was maintained until the end of the surveillance (8 years for RA, 6 years for PsA and AS). The comparison of the effectiveness of the three drugs, which concerned RA patients for the first eighteen month therapy, did not show superiority of any anti-TNF therapy over the others. All three drugs showed an acceptable safety profile. In rheumatoid arthritis, both adverse events in general and infections and systemic allergic reactions in particular were significantly more frequent in infliximab. However, for serious infections, a statistically significant difference between the three drugs was not found. Survival for all three treatments was satisfactory but in infliximab, in patients with rheumatoid arthritis, was found to be significantly lower compared with adalimumab andetanercept, which had not any difference between them statistically.