This was an observational, prospective, multicentre study of a cohort of patients with RA treated with their first TNF antagonist in standard clinical practice within the Andalusian Health Services. The registry included 90 % of prescriptions of biologic agents issued in this community. We observed differences in the characteristics of patients who received their first TNF antagonist in monotherapy or in combination with csDMARDs, and found that prescriptions were largely influenced not only by accessibility to biological drugs within the health system, but also by the clinical characteristics of the patients, particularly comorbidities and drug intolerance, and by the previous experience of the rheumatologist .
Patients in the three groups had differences in the type and number of comorbidities. As we know since the time of Hippocrates, there are patients, not diseases, and this is the art of medicine reflected in DMARDs prescription patterns, in spite of treatment schedules that are defined in Spain in summaries of product characteristics and their respective Clinical Practice Guidelines [1, 2], (https://www.nice.org.uk/guidance/cg79/chapter/Recommendations#pharmacological-management), [3, 19]. The data are in agreement with data recently reported by other registries and publications [5, 8–14].
In our study, before initiation of their first TNF antagonist, only 1 % of patients had not received GCs, MTX, LFN, SSZ, and/or CLQ/HCLQ. PDN, either as monotherapy or in combination with other csDMARDs was the most commonly prescribed drug (78 %), followed by MTX (50 %), and LFN (44 %); SSZ (21 %) was only used in a small number of cases. Rheumatologists prefer combinations of csDMARDs with PDN, and the most frequently prescribed for combination therapy is MTX [4–7, 12–15]. This high level of prescription of PDN at low or very low doses, in monotherapy or in combination with csDMARDs or a TNF antagonist, is a consequence of the effectiveness of this drug for reducing signs and symptoms of the disease. The advantages of PDN include improved patient-reported outcomes and lower disease activity levels, its benefit on radiological evidence of disease progression, and its very favourable efficacy/toxicity ratio producing very low rates of serious adverse events, and no serious adverse events related to this low or very low dose.
According to the literature, low or very low doses of steroids are used the same way as any other csDMARDs, and should be considered as such [8–12, 16, 17]. The frequency of baseline use of steroids found in several registries of patients with RA receiving bDMARDs are the following: 27 % in the Swiss Registry , 22 % in the Danish Registry , and in accordance with a review including various countries , figures range from 38 % to 84 % in Germany (84 %), Spain (52 %), Sweden (51 %), UK (44 %), and USA (38 %) (CORRONA database). Considering these data, TNF antagonists are not really given in monotherapy, due to the high frequency of GC use in patients treated with TNF antagonists in monotherapy. Unfortunately, this study did not include data on radiographic progression, so the real value of GCs as csDMARDs cannot be assessed.
The low use of SSZ in Spain may be explained by the enteric coating of the formulation. This is different from the coating used in other European countries, and its efficacy is lower than that reported in studies conducted in Northern Europe. As a consequence, SSZ is only used after other csDMARDs, namely MTX, LFN, and CLQ/HCLQ . Our results may be influenced by our requirement that during the period in which the study was conducted, patients had to have failed to respond to at least two csDMARDs in order to be prescribed a bDMARD [3, 19]. A lack of efficacy, followed by mild csDMARD toxicity (30–40 %), were the primary reasons for the participating rheumatologists to request bDMARDs. Severe toxicity was very infrequent (< 3 %).
With regard to GCs and csDMARDs prescription patterns, at the time of initiation of the first TNF antagonist most patients were receiving monotherapy or combination therapy with MTX, followed by PDN, LFN, and SSZ. The decreased frequency of GC treatment, from 78 % to 45 %, needs to be emphasized. Only 15 % of patients received the first TNF antagonist without concomitant csDMARDs or GCs. Almost one third (27 %) of patients who received their first TNF antagonist in monotherapy were being treated with PDN as the sole medication. Again, the data show that low or very low doses of PDN were a commonly used treatment at the time of initiation of the first TNF antagonist. GC, MTX, and LFN doses were similar to those recorded in other registries and observational studies [5, 8–12, 14]. It should be noted that a smaller subgroup of patients (those who received their first TNF antagonist plus two or more csDMARDs) were treated with different GCs, and csDMARD combinations. The most commonly used regimen was combination treatment with PDN plus one or more csDMARDs.
It should be emphasized that patients achieved adequate responses irrespective of the treatment they received. There were no differences between groups in improvement in disease activity after starting the biologic agent, but poorer levels of physical function were observed in the baseline and final assessments of those patients treated with the first TNF antagonist plus two or more csDMARDs. After adjustment for potential confounders, the survival analysis showed the best survival rates in the group treated with the first TNF antagonist plus one csDMARD.
This study had advantages that should also be pointed out. First, the study was based on data from standard clinical practice that included 90 % of biologic drug prescriptions. This prospective study was conducted in the setting of specialized rheumatology care and was specially designed to determine prescription patterns of GCs, csDMARDs, and the first TNF antagonist. Furthermore, patients’ clinical characteristics were similar to those observed in other European registries of patients with RA.
Unfortunately, due to the large number of patients lost to follow up, effectiveness data should be viewed with reservation, even though no statistically or clinically relevant differences were found in a comparison of sociodemographic and RA disease characteristics between patients lost to follow up vs. patients who continued (data not shown). The different statistical techniques used to handle missing values also showed different results. We know that the effectiveness data are not fully robust, as they might reflect a cohort of survivors. Another limitation is that, currently, many of these patients who cannot receive csDMARDs are treated with TCZ; thus, the external validity of the data is limited to patients who cannot receive TCZ. The third handicap is the lack of evaluation of radiographic outcome.