The ongoing challenge of RA treatment

Rheumatoid arthritis follows a progressive course and requires a multidisciplinary approach, writes Damien O’Brien MPSI

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune condition that affects the synovial joints, leading to inflammation, pain, stiffness and joint destruction. It is a chronic inflammatory disorder that involves an interaction between genetic and environmental factors. RA can also cause extra- articular manifestations, including cardiovascular, pulmonary and ocular complications. Without treatment, RA is a progressive disease with significant morbidity and mortality. It can cause substantial disability and greatly impact patients’ quality of life.

RA affects approximately 0.5-to- 1 per cent of the population, with women being two-to-three times more likely to develop RA than men. The complexity of RA management requires a multidisciplinary approach where pharmacists play a vital role in optimising treatment, providing patient education, supporting adherence to treatment, and minimising adverse effects.1,2

Background

The exact aetiology of RA is unclear, but it is accepted that genetic, environmental and hormonal factors play an important role in disease development. The risk of developing RA is linked to the HLA-DR4 and HLA-DR1 genes.

RA results from immune system dysregulation that causes joint inflammation, whereas osteoarthritis arises from mechanical wear-and- tear. The fact that women are two- to-three times more likely to develop RA than men suggests that hormonal factors play a role in the development of the disease. Women are also more likely to have a more aggressive disease course with greater disability.

Cigarette smoking is the strongest environmental risk factor for RA. Smoking increases the body’s oxidative stress, disrupts apoptosis, triggers pro-inflammatory processes, and causes DNA methylation. Exposure to certain infectious agents, silica and asbestos is also a risk factor for developing RA.1,2

The pathophysiology of RA involves complex mechanisms that result in chronic synovial inflammation and joint destruction. An environmental trigger may activate the immune response in genetically susceptible individuals, leading to the loss of immune tolerance and the production of autoantibodies, such as rheumatoid factor and anti-citrullinated protein antibodies (ACPA). This leads to the presence of activated immune cells, such as T cells and B cells, in the synovial membrane, causing the release of pro-inflammatory cytokines like tumour necrosis factor-alpha (TNF-?) and interleukins.

This results in persistent inflammation that can progress to joint deformity and loss of function.

Extra-articular manifestations, including vasculitis and interstitial lung disease, may develop, illustrating the systemic nature of RA.1

RA follows a progressive course, initially having non-specific symptoms such as fatigue, weight loss and malaise, before developing into more distinct joint symptoms. The severity and pattern of symptoms can vary from individual-to-individual, with periods of flare-ups and remission.

The most common symptoms of RA are pain and inflammation that gradually worsen over weeks and months. The pain is typically symmetrical and affects the small joints of the hands and feet. As RA

progresses, it can involve larger joints such as the knees, shoulders and elbows. Joint deformities and loss of function can occur over time due to persistent inflammation and erosion of the cartilage and bone. Morning stiffness lasting more than one hour is a classic feature of RA.

Fatigue, malaise, weight loss and low-grade fever are commonly observed systemic symptoms. Extra-articular manifestations may occur, impacting organs and tissues beyond the joints. These may include rheumatoid nodules, Sjögren syndrome, interstitial lung disease, and cardiovascular complications.1

Diagnosis

The diagnosis of RA is based on a combination of clinical, laboratory, and imaging findings, with early diagnosis important for preventing irreversible joint damage and disability. Clinical features that may be indicative of RA include symmetrical joint involvement, morning stiffness, fatigue, weight loss and inflammation, pain, and warmth in the joints.

Serological testing for the presence of rheumatoid factor or ACPA is useful. RF is present in 80-to-90 per cent of patients with RA, and ACPA is present in 70-to-80 per cent of patients. However, there will be approximately 10 per cent of RA patients with neither RF nor ACPA. Furthermore, the presence of rheumatoid factor is not necessarily diagnostic of rheumatoid arthritis, as it may be present in other conditions such as systemic lupus erythematosus and Sjögren syndrome.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are often elevated in patients with active disease and can be used to assess disease activity. X-rays may be useful to illustrate joint space narrowing and bony erosions, while ultrasound and magnetic resonance imaging (MRI) can be used in early disease to detect synovitis.1

Pharmacological treatment

The objective of pharmacological treatment is to control inflammation and prevent irreversible joint damage. Long-term remission, with the absence of symptoms of inflammatory disease, helps to optimise quality of life. In cases where clinical remission cannot be achieved, low disease activity is the aim.

Early treatment with disease- modifying antirheumatic drugs (DMARDs) is the cornerstone of
RA pharmacological treatment. DMARDs can be classified as biologic or nonbiologic. Nonbiologic agents include methotrexate, leflunomide, sulfasalazine and hydroxychloroquine. Biologic agents are a newer class of medications and offer more targeted therapy. Combination therapy with two or more DMARDs may be more effective than monotherapy, but there is a greater risk of adverse effects, which should be carefully considered.

If RA is not controlled with a nonbiologic DMARD, a biologic DMARD may be considered. Targeted synthetic DMARDs are a final class of drugs that may be used as second-line therapy in RA.1,3

Nonbiologic DMARDs

Methotrexate is a first-line treatment for RA due to its efficacy, safety, low cost and flexibility of administration. It may be used as monotherapy or in combination with other DMARDs. It is an immunosuppressive drug that acts as an antifolate antimetabolite. It inhibits enzymes involved in purine synthesis, which reduces T cell and B cell activity. This reduces the activity of the immune system and thereby reduces inflammation in RA. It is administered once weekly, and in patients who still have disease activity, the dose can be split into twice daily on that day to increase bioavailability.

Subcutaneous injection may be used in patients who do not respond adequately or are intolerant to oral administration. Gastrointestinal issues are the most common adverse effects associated with methotrexate, including nausea, vomiting, pain and ulceration. Other adverse effects include fatigue, alopecia, hepatotoxicity, increased risk of infection, and malignancy. A folic acid dose of at least 5mg once weekly can reduce the risk of adverse effects and toxicity.

Patients on methotrexate require regular blood tests to monitor liver function, renal function and bone marrow deterioration.1,3,4 Leflunomide is a medication that may be used in combination with methotrexate or as an alternative treatment option in patients with poor tolerance to methotrexate.
It inhibits the synthesis of uridine monophosphate pyrimidine and thereby inhibits the reproduction
of lymphocytes, promoting anti- inflammatory and immunomodulatory effects. It is administered orally once daily. It is effective in reducing symptoms and slowing the progression of RA. Common adverse effects include gastrointestinal issues, liver damage, hypertension, and alopecia.4,5,6

Sulfasalazine is a DMARD that can be used as monotherapy or combination therapy in the treatment of RA. The mechanism of action is

not fully understood, but it is thought that it may reduce the secretion of interleukins. It may be useful as monotherapy in patients with low disease activity and who lack poor prognostic features. It is administered orally and generally is quite well tolerated, but should be avoided in individuals with sulfa allergies. Common adverse effects include gastrointestinal problems, rash, urticaria and reversible male infertility.3,4,5

Hydroxychloroquine is an antimalarial drug used in the treatment of RA. It works by decreasing the secretion of proinflammatory cytokines. It is a suitable treatment option for early or less-aggressive RA. It is administered orally and has the benefit of possessing a favourable safety profile, with no myelosuppressive, renal and hepatic adverse effects. Common

adverse effects include gastrointestinal, skin, and ocular problems.3,4,5

Biologic DMARDs

Biologic DMARDs are a newer option for treating RA in cases where nonbiologic medications are ineffective or poorly tolerated. They are effective in slowing the progression of joint damage and provide a direct targeted therapy on the immune system. They are genetically modified molecules that are divided into several classes, based on their mechanism of action.5

TNF-? is a pro-inflammatory cytokine that promotes inflammation in joints. TNF-? inhibitors, including etanercept, infliximab, adalimumab, golimumab and certolizumab pegol, block the action of TNF-? and therefore bring symptom relief.

Interleukin (IL) 6 inhibitors, such as tocilizumab, and IL-1 inhibitors, such as anakinra, have a similar mechanism of action. They work by blocking the action of interleukins, cytokines that are involved in persistent inflammation. Abatacept is a T cell co- stimulation inhibitor that modulates T cell activation to reduce inflammation.1

Biologics are immunomodulators that target the disease-causing mechanism and have been used more in treating RA in recent years. They can have a significant positive impact on disease activity and a good safety profile. They can be used as first-line treatment for severe RA, but are more commonly used if other conventional treatments are ineffective or not tolerated.

Biologics tend to be expensive, and they also have a risk of serious adverse effects. Due to their immunosuppressive nature, they increase the susceptibility to infection. Patients therefore require screening before initiation of therapy, and monitoring while taking the medication. Other adverse effects include fatigue, fever, increased risk of malignancy, and increased risk of multiple sclerosis. They are often used in combination with nonbiologic DMARDs, particularly methotrexate.

Biologics are typically administered by either intravenous infusion or subcutaneous injection, with the dosing schedule varying between the different medications.1,3,4,5

Targeted synthetic DMARDs

Targeted synthetic DMARDs are not biologics, but may be useful in the second-line treatment of RA if other therapies have failed. Janus kinase (JAK) inhibitors, such as tofacitinib, inhibit intracellular signalling pathways involved in cytokine production, thereby reducing inflammation. Tofacitinib is orally administered twice daily, as monotherapy or in combination with MTX. It should not be used in combination with biologic medications.

Common adverse effects include upper respiratory tract infections, hypertension, gastrointestinal issues, and hyperlipidaemia, while more serious adverse effects include malignancy and opportunistic infections.1,5

Non-steroidal anti- inflammatory drugs (NSAIDs) and corticosteroids Pharmacological management of RA may involve the use of NSAIDs and corticosteroids for controlling pain and inflammation. These should only be used in the short-term treatment of RA, with DMARDs the preferred therapy for long-term management.

NSAIDs work by blocking the cyclooxygenase enzymes, thereby inhibiting the synthesis of prostaglandins, which are mediators involved in inflammation and pain.

NSAIDs do not possess disease- modifying effects, but may be effective in relieving symptoms of inflammation and pain.

Aspirin and ibuprofen are examples of NSAIDs available over-the-counter, with celecoxib, etoricoxib, diclofenac, meloxicam, naproxen, dexketoprofen and mefenamic acid available on prescription. The adverse effects of NSAIDs include gastrointestinal discomfort, gastrointestinal
bleeding, hepatotoxicity, reduced kidney function, hypertension, and thromboembolic events.1,3

Corticosteroids are also effective in reducing inflammation and pain in RA. Corticosteroids have two main indications in RA — used as bridging therapy for DMARDs until their effects start, and as adjuncts
to treatment in exacerbations. Long-term use of corticosteroids is discouraged due to their adverse effect profile. Potential adverse effects include immunosuppression, reduced bone mass density, weight gain, and diabetes. Corticosteroids should not be abruptly withdrawn, as this can lead to adrenal insufficiency and flares of RA.4

Non-pharmacological treatment

Non-pharmacological management of RA is important in addition to pharmacological therapy, with the objective of improving patients’ quality of life and slowing disease progression.

Smoking cessation and maintaining a healthy weight are important lifestyle modifications that can
help reduce disease activity. A diet high in omega fatty acids, including docosahexaenoic acid (DHA)

and eicosapentaenoic acid (EPA), may reduce inflammation and be beneficial in RA. Physiotherapy and occupational therapy may also be effective in reducing inflammation and improving joint function. Joint surgery is an option for individuals with severe RA, which may provide pain relief and improve joint function.5

Role of the pharmacist

Pharmacists play an integral role in the multidisciplinary care of RA patients, offering expertise in medication management, patient education,

and medication adherence support. Pharmacists are important in optimising medication regimens for patients with RA, ensuring appropriate drug selection, dosing and monitoring. They can also identify and reduce the incidence of adverse effects and drug interactions.

Pharmacists can educate patients on the importance of medication adherence to ensure optimal clinical outcomes. Furthermore, they can provide counselling on correct administration techniques for injectable medications.

In conclusion, pharmacists are accessible and knowledgeable healthcare professionals, and can collaborate with other healthcare providers to reduce symptoms and enhance the quality of life for individuals living with RA.