INTRODUCTION – PREVALENCE AND PATHOPHYSIOLOGY OF RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) used to be a crippling disease for many of the affected patients until the late 20th century. However, an intense improvement and an expansion of the therapeutic armamentarium, especially during the past two decades, made it possible that the percentage of RA patients that suffer from immobility has been shrunken dramatically.
This is also reflected by the fact that the frequency of orthopaedic surgeries in RA in the past 13 years.[1]
This review will focus on the clinical manifestations and the pathophysiology of RA and highlight the therapeutic options.
RA is an autoimmune disease that occurs in any age of adulthood. A peak has been described around the age of 55 years, in the elderly, the disease has been named late-onset RA.[2]
Juvenile forms are referred to as an own disease i.e., juvenile idiopathic arthritis and differ from RA both with regards to the course of the disease and with respect to the therapeutic agents.[3]
Females are around four times more frequently affected from RA than males which led to the hypothesis that hormonal factors might play a role in the pathogenesis of the disease. The prevalence of the disease varies according to the literature and can be estimated between 0.5% and 1%.[4]
The pathogenesis of RA despite excessive investigations still remains not fully understood.[5,6] Generally and most likely in most of the hypotheses, there is an autoantigen at the beginning of the cascade which kicks off the inflammatory process. Briefly, the antigen-presenting cells then activate T-cells which then lead to a vicious cycle with monocyte activation, secretion of proinflammatory cytokines and B-cell activation.
The effects of this process are reflected by synovial inflammation, pannus formation, cartilage and bone destruction, which are the leading pathophysiological correlates of the disease.
This process is likely to be driven by also by genetic an environmental factors.
CLINICAL FEATURES AND LABORATORY FINDINGS
Regarding the clinical manifestations, one of the first symptoms is morning stiffness mainly in the fingers and toes but also less frequent in the wrists, ankles and knees, which can last several hours. One of the hallmarks of RA is the synovial swelling which occurs primarily in the pmetatarsophalangeal joints, the proximal interphalangeal joints, wrists and also the metatarsophalangeal joints. However, also knees, wrists, shoulders and hips can be affected. In contrast, RA never affects the distal interphalangeal joints, where osteoarthritis but also psoriatic arthritis can lead to inflammation. Those two diseases represent the most relevant differential diagnoses.
Moreover, most of the patients suffer from fatigue but also weight loss and depression can be observed.
With respect to relevant laboratory tests, there exists no marker which is specific for RA. However, the majority of patients exhibit slightly to extensively elevated parameters of inflammation, mainly measured with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) but also fibrinogen, leucocytes and thrombocytes can be increased.
First described in 1948 by Rose and Ragan[7] rheumatoid factor (RF) represents an antibody against RF[8] and is positive in the serum of approximately 69% of all RA patients.[9] It is important to note that in early RA, only 33% of the patients have been shown to be RF positive indicating that a large proportion of patients exhibit a conversion of the RF during the course of disease. However, very important for clinical daily routine, RF can also be found in healthy patients or in other diseases. Moreover, RF has also been found more frequently in the elderly population not suffering from RA.
Another marker that is known to be more specific for RA are the antibodies against citrullinated peptide (ccP). These have been described around 20 years ago and differ in dependency of the stage of RA.[10,11] It also was described that healthy individuals that are anti-ccP positive have a higher probability to develop RA. A positive anti-ccP status has been shown to be associated with a more severe course of the disease and radiographic progression.
DIAGNOSIS AND TREATMENT
To facilitate and standardise the diagnosis of RA, joint classification criteria of the European League Against Rheumatism (EULAR) and the American College of Rheumatism have been published [Table 1].[16]
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Table 1: 2010 EULAR/ACR classification criteria (16)
Once the diagnosis has been performed, early treatment is regarded to be crucial. The long-term clinical outcome and the radiographic progression are driven by an early effective treatment.
Besides the effective reduction of pain and swelling, halt or inhibition of the radiographic progression, remains the goal of therapy.
Since the millennium, the available therapeutic options have been dramatically improved.
The agents used for the treatment of RA can be divided into conventional synthetic (cs) disease-modifying drugs (DMARDs), biologic (b) DMARDs and targeted synthetic (ts) DMARDs which are (currently) similar to Janus kinase (JAK) inhibitors [Table 2].
Table 2: Overview of the most commonly used drugs in RA
CsDMARDs have been long in use and methotrexate (MTX), which has been approved by the Food and Drug Administration in the 1980s, still represents the anchor drug of RA therapy and should be initially administered if there are no contraindications existing.
Moreover, the current guidelines recommend short-term glucocorticoid treatment at the very beginning of the RA treatment in order to dampen the disease activity. However, during the course of treatment, glucocorticoids ideally should be avoided indicating that an efficacious therapy does not require co-medication with glucocorticoids. This is an important aspect since glucocorticoids are known for their side effects if given over a longer period.
Other csDMARDs are sulfasalazine, which in contrast to MTX could also be given before and during pregnancy as well as lactation. Leflunomide can also be given to patients with impaired renal function.
The bDMARDs that are in use in RA therapy are tumour necrosis factor-alpha (TNF) blockers, the IL-6 receptor antagonist tocilizumab and the co-stimulation antagonist abatacept. These agents represent antibodies or receptor antagonists against TNF or the other above-mentioned cytokines and are administered intravenously or subcutaneously in distinct intervals.
The most recent expansion of therapeutic agents are the JAK inhibitors. These orally administered drugs aim at the signal transduction casacade, which is driven by JAK. There are 4 JAK inhibitors existing (JAK 1–3 and Tyrosine Kinase 1 = Tyk1) and currently, 4 JAK inhibitors have been approved for RA treatment. Those four agents inhibit the different JAK inhibitors to different extent [Table 2]. Several phase 3 studies indicate higher remission rates for patients treated with JAK inhibitors when compared to those performed with TNF blockers, although these were no head-to-head studies. Moreover, for baricitinib and upadacitinib superiority against the most common TNF blocker adalimumab in combination with MTX could be shown in direct comparison.[12,13]
Since many years, the EULAR publishes treatment recommendations for RA which are updated every few years according to recent scientific insights. Briefly, RA patients immediately after diagnosis should receive a therapy with MTX accomplished by short-term glucocorticoids to dampen inflammatory activity rapidly. If this therapy fails after 3–6 months, a therapy with either bDMARDs or JAK inhibitors is recommended when diagnostic unfavourable factors (erosions, positive anti-ccP/RF or increased parameters of inflammation) are present. TNF blockers usually should be combined with MTX, since it has been shown that this improves their efficacy, whereas JAK inhibitors and anti-IL-6 blockade can also been administered as monotherapy showing good efficacy. [Table 2] gives an overview of the immunomodulating therapies used in RA.
Before starting a therapy, it is important to explain the patient the possible side effects associated with the disease as well as an awareness for infections. Distinct laboratory parameters should be checked depending on the drug prescribed.
In daily clinical routine, disease activity is measured using validated composite scores which include swollen joint count, tender joint count, parameters of inflammation as well as the patients rating of his pain. Among those, DAS28 (CRP or ESR),[14] CDAI and SDAI[15] are the most common instruments.
Around a decade ago, the 'treat to target' principle has emerged, which is meanwhile state of the art in several inflammatory rheumatic diseases.[16] Briefly, the target of treatment is to reach remission as measured by the distinct composite scores. If this is not possible, due to several reasons, the goal should be at least low disease activity. The level of disease activity should be assessed every 3 months and if a therapy fails, it should be switched after 3–6 months.
Several studies have shown that a treatment strategy aiming for rapid depletion of disease activity is associated with a better outcome on the long term.
CONCLUSION
Taken together, RA represents the most common inflammatory rheumatic disease that nowadays can be effectively treated in many patients. The diagnosis, however, can be challenging. Treatment should be initiated rapidly according to the EULAR criteria and the treat to target principle to optimise the outcome.
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
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