Difficulties in treating Rheumatoid Arthritis until nowadays

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ACHAIKI IATRIKI | 2025; 44(2):76–83

Review

Alexandra Filippopoulou

Private Medical Practice, 12 Eleftheriou Venizelou St., Amaliada Ileia, Greece

Received: 30 May 2024; Accepted: 07 Oct 2024

Corresponding author: Alexandra Filippopoulou MD, PhD Rheumatologist. 12, Eleftheriou Venizelou St., Amaliada Ileia, Greece, e-mail: alexfilippop@yahoo.com

Key words: Rheumatoid arthritis, difficult-to-treat, high disease activity, complications

 

Abstract

Rheumatoid arthritis (RA), mainly affecting women, is the most frequent rheumatic disease with different phenotypes. In recent years, despite the development of new therapies, clinical remission is not always achieved by all patients. Disease activity remains high or moderate and corticosteroids cannot be tapered, despite the use of conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) and/ or at least two different biologic agents. The difficult to treat RA and the consequent decreased quality of life, remain an intractable problem in everyday clinical practice. Specific genetic factors are reported to be potentially involved, whereas comorbidities, including obesity, osteoarthritis and/or fibromyalgia may aggravate the uncontrolled disease. Moreover, atherosclerosis and malignancies are more frequently presented in cases of refractory RA, often leading to limited therapeutic options. Patients with difficult-to-treat arthritis are additionally prone to infections, occasionally pausing their treatment. Pregnancy and lactation may complicate the disease by imposing specific precautions, also involving the period before conception. Consequently, only allowable therapy is indicated in all cases. Furthermore, several environmental factors, including smoking, coffee consumption and lack of physical exercise, may negatively affect disease activity, despite treatment. Patients’ quality of life may additionally deteriorate because of pharmacologically induced adverse events, such as osteoporosis, particularly following steroids administration. Finally, lower adherence to treatment, frequently related to patients’ lower educational and financial situation, combined with the absence of only one standardized tool for assessing patient’s perception of the severity of their condition, may also lead to difficult-to-treat disease. It is worth noting that the RA population is not treated uniformly worldwide, since drug prescription and administration vary across different areas, according to local economic regulations. For all the above reasons, early recognition of poor prognostic factors is essential to prevent disease flares and hence, therapy escalation, with controversial outcomes.

Abbreviations: RA = Rheumatoid Arthritis, EULAR = European League Against Rheumatism, DMARD = Disease-Modifying Antirheumatic Drugs, csDMARDs = conventional synthetic Disease-Modifying Antirheumatic Drugs, bDMARDs = biologic Disease-Modifying Antirheumatic Drugs, ACPA = Anti- Citrullinated Protein Antibody, DAS-28 = Disease Activity Score-28, TNFi = Tumor Necrosis Factor Inhibitor, BMI = Body Mass Index, tsDMARDs = synthetic targeted Disease-Modifying Antirheumatic Drugs, jakinh = Jak inhibitor, RCT = Randomized Control Trial, TNFa =Tumor Necrosis Factor a, IL 6 = Interleukin 6

Introduction

Rheumatoid arthritis (RA) is one of the most common autoimmune inflammatory diseases, mainly affecting the joints of upper or/and lower extremities in a symmetrical pattern. Extra-articular manifestations, including pleuritis, pericarditis and formation of rheumatoid nodules may also occur. Different phenotypes are not uncommon in everyday clinical practice, since several patients may present with early joint destruction, whereas others exhibit milder symptoms at baseline [5]. Epidemiologically, RA is estimated to affect 1 % of the worldwide population [1,2] with females being twice as likely to be affected, according to most studies [3].

The last decades, the evolution of therapy has been proven to be beneficial for the majority of patients. Clinical remission or low disease activity is achieved through new therapeutic approaches, according to the European League Against Rheumatism (EULAR) recommendations. However, 5- 20% of patients remain difficult to treat, failing to reach treatment targets [4]. Unachievable corticosteroid tapering, usually accompanied by the failure of two or more conventional synthetic Disease-Modifying Antirheumatic Drugs csDMARDs and/or biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) or targeted synthetic DMARDs (tsDAMRDs), also known as Jak inhibitors (Jakinh), is often considered as difficult-to-treat RA. Therefore, despite the treat-to-target strategy, refractory disease is frequently identified [5,6]. Under these circumstances, the concurrent presence of comorbidities, fatigue and /or extra-articular manifestations, is frequent [4]. Additionally, the variant response to treatment, commonly observed in everyday clinical practice, is considered multifactorial.

Main text

Genetic risk factors may lead to the presence of heterogeneous clinical phenotypes; however, no specific genetic factor has been strongly associated with a better response to treatment [4]. Positivity for various alleles, such as HLA DR1 and HLA DR4, is prone to the development of RA [6]. Anti–citrullinated protein antibodies (ACPAs), the most specific autoantibodies for the disease [7,6], are more frequently present in HLA DR1 positive patients. Therefore, radiological damage, accompanied by higher inflammatory markers in sera and more swollen joints in clinical examination, is often observed [7-9]. According to De Rooy et al, the presence of SNPs located near TNF receptor-associated factor 1 (TRAF1) is highly associated with aggravation of radiographic damage, indicating that SNPs may play an important role in difficult to treat RA cases [10]. Conigliaro et al report that exacerbation of RA is associated with several SNPs, such as PSORS1C (psoriasis susceptibility 1 candidate 1, PTPN2 (protein tyrosine phosphatase non-receptor type 2, FOXO3A (Forkhead Box O3A) [4]. The methylation of DNΑ may also affect the synovium cells of the joint and is frequently associated with the development of a more severe and aggressive RA phenotype and consequently more difficult to treat [4,11]. The last decades the use of DMARDs, and more specifically of bDMARDs, aiming at better management and treatment of RA, is proven to be promising [15]. On the other hand, bDMARDs are not always successful, despite their increased use. According to Schipper et al, positive predictors for rapid reach of low disease activity include male gender, younger age and low Disease Activity Score-28 (DAS28) at baseline [12]. These predictors often require early diagnosis. Unfortunately, delays in identifying RA are not uncommon. It is reported that the time lag between onset of symptoms and diagnosis ranges from one month to ten years [58], increasing the risk for a more difficult to treat disease. However, refractory RA is frequently associated, not only with delayed diagnosis, but also with the presence of comorbidities. Despite the use of biologic agents and more specifically Tumor Necrosis Factor inhibitors (TNFi), disease remission may not occur, as revealed by an Italian cohort of 308 patients [13,14]. Generally, clinical outcomes in RA are often influenced by the presence of comorbidities; hence it is highly recommended that patients should be monitored for co- or pre- existing comorbidities [26]. Among them, obesity plays an important role in difficult to treat patients. Concurrent osteoarthritis, in conjunction with depression, is often associated with exacerbation of fibromyalgia and consequently chronic pain, have a negative impact on clinical remission [16]. The assessment of DAS28 score, widely used for the estimation of disease activity in RA, may not be accurate in cases of obesity, since obese patients are frequently considered to have more swollen joints during clinical examination. For that reason, the use of ultrasound (not available in all rheumatology outpatient clinics) may be beneficial in patients with a higher BMI (Body Mass Index) [17]. Furthermore, obesity is also associated with a worse clinical response to treatment with TNFi, when compared to patients with normal BMI [18,19]. Therefore, non-TNFi administration, including abatacept or tocilizumab, is considered to be more beneficial in overweighed RA subjects, whose sera have higher amounts of IL 6, frequently resulting in exacerbation of inflammation [20-22]. The pro- inflammatory cytokine IL 6, especially in high levels, is also associated with cardiovascular diseases and atherosclerosis. Many studies report that RA patients have an increased risk for cardiovascular events, especially in high levels of inflammation [23-25].

According to an observational cohort-study with combinatorial data from Norway and Sweden, the increased RA disease activity is correlated with higher risk for acute coronary syndrome. These results indicate the imperative need for close monitoring of these patients, who are prone to remain in a continuous non-remission state, despite treatment [25]. Additionally, Oral Surveillance survey revealed an increased risk for major adverse cardiovascular events (MACE), also concerning malignancies, in RA patients under treatment with tofacitinib (the first approved jak inhibitor in RA), compared to subjects under TNFi administration [58]. The survey results raise suspicions for the safe use of Jak inhibitors (jakinh) in RA, and inflammatory diseases in general. Consequently, the use of jakinh is recommended after risk assessment [59] and as a result, several patients may be excluded from this kind of therapeutic options by their rheumatologists. Nonetheless post hoc analysis did not reveal significant danger for these events after jakinh administration [60], indicating that there is no real contraindication for their use. However, it is worth noting that comorbidities, including cardiovascular disease, may lead to contraindications concerning the use of several approved for RA drugs, resulting in a sustainable active disease.

Malignacies are another major problem in RA patients. An increased rate of lymphoma and lung cancer is observed among them [62-64], due to immune dysregulation and/or chronic inflammation, that often result in cell proliferation, mutagenesis, oncogene activation and angiogenesis [65]. Although it was initially believed that bDMARDs, and mainly TNFi, were potentially involved in carcinogenesis, meta-analyses, observational studies and post marketing surveillance, indicated that early use of these drugs is safe, not increasing the overall risk for malignancies [66]. Data remain controversial, reporting that patients receiving treatment for RA, especially rituximab, have a greater risk for all cancers, compared to general population [67]. The recent ORAL surveillance study also detected an increased risk for carcinogenesis after tofacitinib (jakinh) administration compared to TNFi [58]. Burmester et al, however, did not report a higher risk of malignancy, excluding NMSC, in RA patients after a 5.45 year administration of another jak inhibitor, upadacitinib [69].

Nonetheless, managing patients with RA and concurrent cancer is a non-rare complex problem for both rheumatologists and oncologists, often resulting in a difficult to treat disease. In patients with a history of malignancy, bDMARDs, and specifically TNFi, are not commonly preferred as therapeutic tools, while an increased use of rituximab is noticed in most cases [68]. Nowadays, treatment with TNFi in patients with prior cancer (except in cases of lymphoma or melanoma), is considered to be safe after a mean follow-up of five years, since no significant cancer recurrence is reported, under these circumstances [70]. However, since no robust data from randomized clinical trials (RCTs) exist, the therapeutic management of RA patients during the first five years after malignancy diagnosis still remains an ongoing question.

An increased rate of infections (both outpatient and those requiring hospitalization), is observed in patients with refractory disease [28]. Serious infections, especially under treatment with bDMARDs or jakinh, are common in RA population with high disease activity, especially during the first year after treatment initiation [27,72]. Bacterial infections are more commonly observed in these patients. Interestingly, in case of sepsis, a lower risk of death is noted in subjects treated with bDMARDs, compared to subjects, who are on therapy with conventional synthetic DMARDs (csDMARDs) (71). CsDMARDs, initially administered after the diagnosis of RA and frequently in combination with low daily doses of glucocorticosteroids (5–7.5 mg), are generally considered safe [71-74]. Risk factors for severe infections among RA patients include older age (> 65 years), high disease activity and disability score (as defined by DAS-28 and HAQ score, respectively), presence of comorbidities (chronic lung or kidney disease), higher doses of glucocorticoids (> 7.5 mg/day), history of previous serious infections and previous DMARDs failures and, finally, current immunosuppressive therapy [71]. Infectious complications should be taken into consideration, because in case of infection, according to general recommendations in everyday clinical practice, patients with autoimmune diseases, including RA, are advised to temporarily suspend their immunosuppressive therapy. This practice, however, often results in a non remission state, especially when pausing is frequent.

Pregnancy is another factor that may cause difficulties in treating RA. Since women are mainly affected by the disease, the periods of pregnancy and puerperium, especially with concomitant lactation, are critical. Although 60 % of pregnant RA women (particularly without positive RF and/or ACPAs in the serum) are reported to be in remission during pregnancy [29-30], treatment in this period remains challenging. Contraindications for the use of several drugs are the major problem for rheumatologists. Methotrexate, the basic and most widely used DMARD in rheumatology, is known for its teratogenic effects on the fetus. The drug is also combined with an increased rate of abortion [31]. Generally, for safety reasons, the discontinuation of methotrexate is recommended, three months prior to scheduled conception [34,35].

Taking into consideration that 40% of pregnancies are unintended worldwide [32], women diagnosed with RA in their reproductive age, should be advised for contraception measures, and if they still express the desire to conceive in near future, only conventional medications can be prescribed, including: glucocorticoids (prednisolone is particularly selected, since, due to its lower transpacental transfer, earlier fetal lung maturation is avoided), hydroxychloroquine, azathioprine, cyclosporine and sulfasalazine [4,33]. Those drugs are also compatible with breastfeeding, except from sulfasalazine that is not recommended in case of premature or ill infants [34]. However, several of them are occasionally proven to be inadequate in controlling disease activity and therefore bDMARDs should be used. During pregnancy the most widely used bDMARD is certolizumab pegol, a PEGylated, Fc‐free anti‐TNF agent with a high safety profile. In 1,137 prospectively reported pregnancies with maternal exposure to the drug, neither teratogenesis, nor increased rate of fetal death was found [35]. Data from gastroenterology indicate that adalimumab may also be a safe choice for pregnant patients with autoimmune diseases [37]. Additionally, there are no reports linking etanarcept to unfavorable outcomes during pregnancy and lactation, indicating that etanercept may be administered, if necessary [39].

Congenital abnormalities are not referred to in cases of compatible TNFi administration during the first half of pregnancy [4]. However, there are several concerns about the potential affection of infants’ immune system after birth, and consequently live vaccines are contraindicated for the first 12 months of life [38]. As far as the newer therapies with targeted synthetic therapies (tsDMARDs or jakinh) are concerned, no clear evidence to this date exist regarding their safety during pregnancy. Due to their small size, these molecules are considered capable of crossing the placenta; therefore, their use is not indicated in pregnant women [40].

Environmental factors may also play an important role in unsuccessful treatment in RA. Smoking increases the risk of ACPA-positive RA [41]. Seropositive RA (as defined by positive ACPA and/ or RF in patients’ serum) is known to be more severe than seronegative disease and therefore more difficult to treat. The administration of the most widely used bDMARDs, such as TNFi, is negatively correlated with smoking [46]. Smoking is also associated with radiographic progression in RA. According to Rydell et al, other risk factors for rapid joint destruction are seropositivity, presence of erosions, and high disease activity at baseline; maintenance of active disease at one year after diagnosis is additionally considered dangerous for the development of novel erosions [47]. Therefore, cigarette smoking may be related to a more severe and often refractory disease, with limited response to treatment options.

Coffee consumption is also associated with higher risk for RA development and mainly for a seropositive, and consequently more difficult to treat, disease [42]. However, inflammatory responses are influenced by caffeine and its metabolite paraxanthine. Caffeine has been shown to suppress chemotaxis of monocytes and neutrophils, as well as the production of pro – inflammatory cytokines, including TNFα [49], indicating the existence of contradictory data concerning caffeine consumption in RA patients [4]. The lack of physical exercise may also exacerbate disease activity. Due to inflammatory mechanisms, lower bone mineral density and aggravation of joint mobility may occur [43]. More specifically, Th1 cell production is reported to be decreased after physical activity. IL 6 is also secreted inducing the production of anti- inflammatory cytokines, including IL 1ra, IL 10 and TNF receptor (TNF-R) [48]. Furthermore, lack of physical activity may also increase the cardiovascular risk. Patients with RA, due to uncontrolled systemic inflammation, are prone to atherosclerotic cardiovascular diseases [50], as already mentioned. Consequently, they are advised for a healthier way of living, including aerobic exercise, as well as strength and resistance training, as a main part of their therapy, according to EULAR recommendations published in 2018, concomitantly aiming at a better quality of life [44,45,51]. However, nowadays, the maintenance of good physical condition is limited by the new way of urban living. The concurrent long-term use of steroid agents may also easily lead to muscle weakness and osteoporosis [4]. Systemic inflammation, as observed in RA, is often associated with bone loss. Osteoclastic activity may also be activated, resulting in a reduced bone mineral density (BMD) [52]. Osteoporosis is estimated to be found in 30–50% of patients with RA, mainly in cases of high disease activity [53]. However, the prolonged use of corticosteroids, a major cornerstone in the treatment of RA patients, may increase the risk for bone loss and, consequently, fractures. As a result, anti-osteoporotic treatment is also recommended in RA patients, contributing to polypharmacy and frequently poor treatment compliance [53,54].

Considering all the above, the use of several commonly preferred drugs for RA treatment, may be present challenges and, therefore, inevitably not prescribed for several patients. Comorbidities and adverse drug reactions may not be compatible with the administration of DMARDs, leading to refractory disease, difficult to treat [55]. Furthermore, lower adherence to treatment in RA is mainly observed in patients with higher disease activity. in addition, factors such as lower education level and worse financial situation of several patients further result in non- compliance and, therefore, poor disease outcomes [54]. In order to calculate disease activity, several tools are often used, taking into consideration the Patient Global Assessment (PGA), too. PGA is a widely used self-report measure reflecting patients’ own assessment of the severity of their condition. However, since many versions of PGA world widely exist, its standardization remains a major problem, indicating the necessity for validity and reliability [56]. Since patients’ lives are undoubtedly affected by the disease in every aspect of their everyday activities, the development for new patient – centered tools, capable of incorporating the symptoms and consequences is imposed.

Finally, the high cost of several treatment options (especially bDMARDs) may influence the physician’s prescription. Rheumatologists should lean on robust data for better disease control, but financial obstacles may influence the therapy that is administered in their patients [61], especially in different regions with different economic laws.

Conclusion

Despite the treat-to-target strategy in combination with novel drugs in RA, some patients may still fail to respond. Difficult-to-treat RA remains a major problem in everyday clinical life of rheumatologists, indicating the need for early recognition of poor prognostic factors in order to avoid disease flares and hence therapy escalation, resulting in controversial outcomes. Refractory disease may require better management of comorbidities and environmental factors, which, combined with the different pathways, molecules, and cells involved in the pathogenesis of RA, may in part justify the lack of response of some patients.

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare.

Author contributions

AF was responsible for the conception, research, writing and the final draft of this review.

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