1 Introduction

Over the past two decades, better understanding of the immunopathophysiologic basis of various rheumatic diseases led to the discovery of variety of drugs that are now approved and widely used in clinical practice. These drugs are categorized into the following categories: nonsteroidal anti-inflammatory drugs (NSAIDs), synthetic disease-modifying anti-rheumatic drugs (sDMARDs), biological disease-modifying anti-rheumatic drugs (bDMARDs), corticosteroids and drugs used in crystal-induced arthritis. Few other drugs are also used by rheumatologists. These include anti-resorptive drugs and symptom-specific drugs.

2 Learning Objectives

By the end of this chapter, you should be able to:

  • Recall the main drug categories used in the treatment of systemic rheumatic diseases

  • Explain the mechanism of action, dosages, indications, adverse effects, cautions, contraindications and pregnancy category of each drug

3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective anti-inflammatory, antipyretic and analgesic drugs. Although they differ widely in their chemical class, they share the property of blocking the production of prostaglandins (PGs). This is achieved by inhibiting the activity of the enzyme prostaglandin G/H synthase (PGHS), also called cyclooxygenase (COX).

There are two different COX isoforms, COX-1 and COX-2. Inhibition of COX-2 by NSAIDs blocks PG production at sites of inflammation, while inhibition of COX-1 in certain other tissues, most importantly platelets and the gastroduodenal mucosa, can lead to common adverse effects of NSAIDs such as bleeding, bruising and gastrointestinal ulceration [1].

In addition to their use in rheumatoid arthritis and osteoarthritis, NSAIDs are widely used in the symptomatic management of other rheumatic diseases characterized by chronic musculoskeletal pain and diverse forms of acute pain.

NSAIDs are associated with elevated cardiovascular disease risk and risk for gastrointestinal bleeding and ulceration [2, 3]. For that, it is important to identify patients with these risks, and if present, avoiding NSAIDs or using intermittent, low-dose and short half-life drugs is advisable. It is also important to know that use of NSAIDs together with aspirin, which is an NSAID too, can increase gastrointestinal toxicity and lead to aspirin resistance [4].

Patients who take regular doses of NSAIDs should undergo periodic assessment of blood pressure, haemoglobin level, electrolytes and renal and liver function tests.

Complete details about different NSAIDs are shown in Table 4.1

Table 4.1 Nonsteroidal anti-inflammatory drugs (NSAIDs)
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4 Synthetic Disease-Modifying Anti-Rheumatic Drugs (sDMARDs)

This category consists of drugs that have been used as first-line therapies in the majority of systemic rheumatic diseases. Although their precise mechanism of action is still incompletely understood, they have both anti-inflammatory and immunomodulatory effects.

Generally, the choice of a sDMARD therapy should be decided for each patient individually. This should also give attention to patient’s age, fertility plans, comorbid conditions and other concomitant drugs. Adverse effects from sDMARDs may cause significant morbidity and mortality. So, appropriate dosing and monitoring for toxicity are required.

4.1 Methotrexate

Over the past 25 years, methotrexate has become the sDMARD of choice in the treatment of rheumatoid arthritis and is used in many other rheumatic diseases as well (psoriasis, psoriatic arthritis, polymyositis, dermatomyositis, granulomatosis with polyangiitis, giant cell arteritis, subacute lupus erythematosus, scleroderma and vasculitis).

Methotrexate increases the concentration of adenosine, which is a potent inhibitor of inflammation. It also inhibits the enzyme dihydrofolic acid reductase [5].

The effects of methotrexate can be enhanced by using the subcutaneous form instead of the oral form or by splitting the oral dose (within 12-h window) when doses greater than 15 mg weekly are given [6]. Doses should be adjusted based on renal and hepatic function.

A weekly oral dose of folic acid 5–10 mg given 48–72 h post methotrexate dose protects against mucosal ulceration and keeps folic acid levels optimum [7].

4.2 Leflunomide

Leflunomide is approved for the treatment of rheumatoid arthritis. It has both anti-inflammatory and immunomodulatory effects. It inhibits the enzyme dihydroorotate dehydrogenase and pyrimidine synthesis [8].

Loading doses are not used in clinical practice due to gastrointestinal toxicity. Leflunomide is found to have a very long half-life because of its enterohepatic recirculation [9]. It is absolutely contraindicated in pregnancy.

4.3 Azathioprine

It is an imidazolyl derivative of mercaptopurine. It antagonizes purine metabolism and may inhibit the synthesis of DNA, RNA and proteins. It also inhibits cellular metabolism [10].

Azathioprine can be effective as a glucocorticoid-sparing agent in remission maintenance therapy, particularly in systemic lupus erythematosus and necrotizing vasculitis.

It can induce severe myelosuppression in patients with low or absent thiopurine methyltransferase (TPMT) activity that is affected by a polymorphism that can be identified by genetic screening [11]. Severe myelosuppression can also occur in patients with normal TPMT activity, and regular monitoring of white blood cell counts is recommended.

Azathioprine interacts with allopurinol and this can lead to fatal myelosuppression. Concomitant use of these two drugs should be avoided.

4.4 Hydroxychloroquine

It is an anti-malarial drug and a well-tolerated sDMARD that is now used as a cornerstone therapy in patients with systemic lupus erythematosus and in combination therapy regimens for rheumatoid arthritis [12].

Hydroxychloroquine is more commonly used than chloroquine. It has a very long half-life, attributed to its affinity for melanin-containing cells in the skin. Doses of hydroxychloroquine should not exceed 6.5 mg/kg/day in chronic therapy to minimize the risk of retinal toxicity [13]. Although routine laboratory monitoring is not required, ophthalmologic screening is an essential component of toxicity monitoring.

Diabetic patients initiating hydroxychloroquine should be instructed to follow blood sugars closely because of the hypoglycaemic effects of the drug.

Hydroxychloroquine is considered safe in pregnancy; it is recommended that most pregnant patients with SLE remain on the drug to improve pregnancy outcomes.

4.5 Sulfasalazine

It is a sDMARD that has both antimicrobial and anti-inflammatory properties. The exact mechanism of action is unknown. However, it is a 5-aminocyclic acid derivative that inhibits leukotriene synthesis [14].

Sulfasalazine is commonly used as part of combination therapy for rheumatoid arthritis. Its dose should be increased gradually with regular laboratory monitoring to minimize the risk of adverse effects and drug intolerance.

Gastrointestinal intolerance and rash are common side effects. Monitoring complete blood counts, liver transaminases and creatinine levels should be done periodically during therapy [15].

4.6 Mycophenolate Mofetil

It is a powerful inhibitor of lymphocyte proliferation that has a potential glucocorticoid-sparing effect. It is used for the treatment of patients with various rheumatic diseases. It inhibits inosine monophosphate dehydrogenase enzyme which decreases T- and B-cell proliferation and antibody production [16].

Mycophenolate mofetil can be used as a remission induction agent in lupus nephritis and is now increasingly used for remission maintenance treatment of systemic lupus erythematosus and necrotizing vasculitis [17].

It is generally well tolerated, although diarrhoea and leucopenia may necessitate its discontinuation. Complete blood counts should be performed within the first 2 weeks of therapy and then once every 6–8 weeks thereafter if no cytopenia is noted [18].

4.7 Cyclophosphamide

It is an alkylating agent and one of the most potent immunosuppressive therapies available. It is a pro-drug which prevents and inhibits cell division [19].

The indications for its use include induction of remission in lupus nephritis. It is also used to treat rheumatoid vasculitis, interstitial lung disease associated with connective tissue diseases and many types of systemic vasculitides.

Although very effective, it has the potential for devastating toxicity both in the short and long term. Its toxicities include myelosuppression, infection, ovarian failure, haemorrhagic cystitis and malignancy including bladder cancer, especially with high cumulative doses.

The intermittent intravenous doses given every 3–4 weeks are associated with less bladder toxicity compared to oral daily doses [20]. To further minimize bladder toxicity, intravenous fluids, anti-emetics and MESNA (2-mercatpoethanesulfonic acid) may be used.

4.8 Tofacitinib

Tofacitinib is a targeted sDMARD that is now approved for the treatment of rheumatoid arthritis. It inhibits the enzymes janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) and thus prevents the phosphorylation and activation of signal transducers and activators of transcription (STATs), which transmit extracellular information into the cell nucleus, influencing DNA transcription [21].

The most commonly reported adverse effects which occur in less than 5% of patients treated with tofacitinib are upper respiratory tract infections, headache, diarrhoea and nasopharyngitis. Neutropenia and lymphopenia are also reported in less than 1% of patients and laboratory monitoring is recommended.

4.9 Apremilast

This sDMARD is now approved for the treatment of psoriatic arthritis and psoriasis. It is a small molecule inhibitor of phosphodiesterase-4 (PDE4), which breaks down cyclic adenosine monophosphate (cAMP) in inflammatory cells. This results in down-regulation of the expression of a number of the pro-inflammatory factors like tumour necrosis factor alpha (TNFα), interleukin-17, interleukin-23 and many others and up-regulation of the anti-inflammatory interleukin-10.

Headache, back pain, nausea, diarrhoea, fatigue, nasopharyngitis, upper respiratory tract infections and weight loss are common adverse effects and are reported in up to 10% of patients taking apremilast [22].

Complete details about different sDMARDs are shown in Table 4.2.

Table 4.2 Synthetic disease-modifying anti-rheumatic drugs (sDMARDs)
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5 Biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs)

The bDMARDs target specific components of the immune response that are dysregulated and are thought to be the cause of the disease process. These components are called pro-inflammatory cytokines. Tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6) and others are the pro-inflammatory cytokines found in the rheumatoid synovium. Few other bDMARDs target B and T cells. These agents have considerable efficacy in the treatment of patients with rheumatoid arthritis and other systemic inflammatory disorders.

5.1 TNF-α Blockers

Five TNF-α inhibitors are approved for the treatment of selected rheumatic disease by the United States Food and Drug Administration. These are adalimumab, etanercept, infliximab, golimumab and certolizumab.

A 2008 systematic review of synthetic and biologic DMARD therapy for rheumatoid arthritis concluded that anti-TNF monotherapy was similar in efficacy to treatment with methotrexate alone, while the combination of an anti-TNF agent with methotrexate reduced disease activity more and slowed radiographic progression to a greater extent than did anti-TNF monotherapy or methotrexate alone [23].

Most patients with rheumatoid arthritis respond to treatment with TNF inhibitors, with significant improvements in signs and symptoms of disease, significant decrease in radiographic damage and significant improvement in quality of life and functional status.

They have also proved to be highly effective in treating patients with ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease and juvenile idiopathic arthritis. However, they were ineffective in patients with scleroderma or vasculitis.

5.2 Rituximab

Rituximab is a chimeric monoclonal antibody that binds to CD20 antigen and leads to B-cell inhibition [24]. It is an effective biologic therapy for rheumatoid arthritis with a greatest benefit in seropositive patients. If given as two infusions of 1 gram each, it slows the radiographic progression in rheumatoid arthritis.

Rituximab is considered as a safe drug in rheumatoid arthritis, but infusion reactions can occur; most are mild to moderate. Pre-medication with methylprednisolone, diphenhydramine and acetaminophen can reduce these reactions.

Rituximab therapy carries a risk of hepatitis B reactivation amongst patients who have positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc). All patients should be screened for HBsAg and anti-HBc prior to starting treatment [25].

5.3 Abatacept

It is a fully human fusion protein that inhibits co-stimulation (an essential step in the induction of adaptive immune responses) and inhibits T-cell activity [26].

Abatacept can be used when sDMARDs and/or other biologic drugs have failed to control inflammatory arthritis. Infection risk with abatacept is higher compared to other biologics [26].

It is administered as a 30-min intravenous infusion that is usually achieved without complications. Subcutaneous administration is equally effective and is now approved.

Abatacept is used to treat rheumatoid arthritis and polyarticular juvenile idiopathic arthritis. Clinical trials on abatacept in psoriatic arthritis and scleroderma have shown promising results [27].

5.4 Tocilizumab

It is a humanized monoclonal antibody that antagonizes the cytokinetic effect of IL-6. It has been approved for treatment of rheumatoid arthritis [28] and systemic onset juvenile idiopathic arthritis. It was recently granted a breakthrough designation status by the United States Food and Drug Association for giant cell arteritis based on positive results from a phase 3 clinical trial [29].

A dose of 4 mg/kg is started initially and then increased to 8 mg/kg based on clinical response. It is administered intravenously every 4 weeks. Administration through the subcutaneous route is also available. It may cause dyslipidemia but is generally well tolerated. Periodic monitoring of lipid profile along with other routine investigation is required.

5.5 Ustekinumab

Ustekinumab is a humanized monoclonal antibody that binds to and interferes with the biological effects of IL-12 and IL-23. It is approved for the treatment of psoriatic arthritis and moderate to severe plaque psoriasis [30].

It is administered at a dose of 45 mg subcutaneously at week zero, followed by a second dose at week 4 and then every 12 weeks. Nasopharyngitis, upper respiratory tract infections and nausea are common side effects.

5.6 Secukinumab

Secukinumab is a humanized IgG1 monoclonal antibody that selectively binds to IL-17A and inhibits its pro-inflammatory action. It is approved for the treatment of active ankylosing spondylitis, psoriatic arthritis and moderate to severe plaque psoriasis [31].

Nasopharyngitis, upper respiratory tract infections and diarrhoea are common side effects. If administered with a loading dose, 150 mg subcutaneously is given at weeks 0, 1, 2, 3 and 4 followed by 150 mg every 4 weeks. Without a loading dose, 150 mg subcutaneously is administered every 4 weeks.

Complete details about different bDMARDs are shown in Table 4.3.

Table 4.3 Biological disease-modifying anti-rheumatic drugs (bDMARDs)
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6 Glucocorticoids

Glucocorticoids exert both anti-inflammatory and immunosuppressive effects. They inhibit prostaglandin and leukotriene synthesis, reduce macrophage phagocytosis and inhibit the release of collagenase and lysosomal enzymes [32].

Generally, five types of glucocorticoids are used in rheumatology daily practice. These are hydrocortisone, prednisolone, methylprednisolone, triamcinolone and dexamethasone. They differ considerably in potency and biologic half-life as shown in Table 4.4. They are used in the majority of systemic rheumatic diseases.

Table 4.4 Glucocorticoids
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The chronic use of low-dose glucocorticoids can cause multiple adverse events [33]. For that, the dose of glucocorticoids should be tapered as quickly as possible to the lowest effective dose when chronic use is anticipated. Serum glucose, lipid profile and bone mineral density to prevent glucocorticoid-induced osteoporosis should be performed to monitor toxicity. Patients should also be screened frequently for polydipsia, oedema and shortness of breath, visual changes, weight gain and changes in blood pressure during therapy.

Complete details about different glucocorticoids are shown in Table 4.4.

7 Anti-Resorptive Drugs

7.1 Bisphosphonates

Alendronate, risedronate, ibandronate and zoledronic acid are effective for the treatment of osteoporosis. These drugs inhibit bone resorption, increase bone mass and reduce the incidence of fractures. They are considered as first-line therapy for osteoporosis in postmenopausal women and men because of their efficacy, favourable cost and the availability of safety data. For those who cannot tolerate oral bisphosphonates; who have difficulty with dosing requirements, including the inability to sit upright for 30–60 min; or who have relative contraindications to bisphosphonates (achalasia, scleroderma oesophagus, oesophageal strictures), intravenous zoledronic acid is the choice of therapy. Bisphosphonates should be avoided in renal impairment. They are also avoided in women of childbearing age due to foetal risk. Bisphosphonates cross the placenta and accumulate in the foetal bones [34].

7.2 Raloxifene

It is a selective oestrogen receptor modulator that inhibits bone resorption and reduces the risk of vertebral fracture. It is suggested for those who cannot tolerate or are not candidates for bisphosphonate therapy [35]. It is also usually chosen for osteoporosis when there is an independent need for breast cancer prophylaxis.

7.3 Teriparatide

It is a recombinant formulation of endogenous parathyroid hormone. It stimulates osteoblast function, increases gastrointestinal calcium absorption and increases renal tubular reabsorption of calcium. In postmenopausal women, teriparatide has been shown to decrease osteoporosis-related fractures. This drug is also suggested for those who cannot tolerate or are not candidates for bisphosphonates therapy [36].

7.4 Denosumab

It is a fully human monoclonal antibody that specifically binds to receptor activator of nuclear factor kappa B ligand (RANKL). It reduces the formation, function and survival of osteoclasts, which results in decreased bone resorption and increased bone density. It is suggested for those who cannot tolerate or are not candidates for bisphosphonate therapy [37].

Complete details about different anti-resorptive drugs are shown in Table 4.5.

Table 4.5 Anti-resorptive drugs
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8 Drugs Used in Crystal Arthropathy

8.1 Colchicine

It is a uricosuric agent that prevents activation, degranulation and migration of neutrophils associated with mediating some gout symptoms. It can be used for both acute flare and prophylaxis against recurrent attacks of gouty arthritis [38].

Common adverse effects of colchicine may include diarrhoea and abdominal cramping. It is contraindicated in severe renal or hepatic impairment. Colchicine treatment may also benefit patients with acute episodes of pseudogout and arthritis due to other crystals.

8.2 Allopurinol

It is a xanthine oxidase inhibitor that inhibits its conversion to uric acid. It is considered as the first-line urate-lowering agent for the treatment of chronic gout. The dose of allopurinol should be adjusted based on the stage of renal disease. Febuxostat is another urate-lowering agent that can be used if allopurinol is to be avoided [39]. Allopurinol decreases the metabolism of azathioprine.

Complete details about different drugs used in crystal arthropathy are shown in Table 4.6.

Table 4.6 Drugs used in crystal arthropathy
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9 Symptom-Specific Drugs

Systemic rheumatic diseases are multi-system diseases that can affect different body organs. These disease cause symptoms that can be either due to the immunopathologic changes or adverse effects from the DMARD therapy. Most of these rheumatic symptoms are effectively treated with different DMARDs. However, few other symptoms require additional specific drugs. For example, Raynaud’s phenomenon, fatigue, generalized aches and pains and acid reflux are common symptoms that patients describe to their rheumatologists. Table 4.7 provides a list of common symptom-specific medications that rheumatologists prescribe during their daily clinical practice. Table 4.8 defines the pregnancy categories for pharmacological agents.

Table 4.7 Common symptom-specific drugs
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Table 4.8 Pregnancy category definitions
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