Open Access

Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches (Review)

  • Authors:
    • Carolina Negrei
    • Violeta Bojinca
    • Andra Balanescu
    • Mihai Bojinca
    • Daniela Baconi
    • Demetrios A. Spandidos
    • Aristidis M. Tsatsakis
    • Miriana Stan
  • View Affiliations

  • Published online on: February 2, 2016     https://doi.org/10.3892/etm.2016.3045
  • Pages: 1177-1183
  • Copyright: © Negrei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Rheumatic diseases are highly prevalent chronic disorders and the leading cause of physical disability worldwide, with a marked socio-economic impact. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology with an autoimmune pathogenesis, characterised by arthropathy with chronic, deforming, destructive evolution and multiple systemic manifestations. The management of RA has undergone significant changes as far as objectives and approaches are concerned, ending in the current strategy known as ‘treat to target’. The therapeutic array of RA includes several categories of medicinal products, of varying potential. There are several criteria for the classification of medicinal products used against this disease, one of the most important and modern of which divides such substances according to their effects on the progress of the disease: symptom‑modifying antirheumatic drugs (including non-steroidal anti-inflammatory drugs and corticoids), disease-modifying antirheumatic drugs (including various substances, such as gold salts, antimalarials, sulfasalazine, D‑penicillamine; non‑specific immunosuppressive medication, such as methotrexate, cyclophosphamide, azathioprine and leflunomide) and biological therapy is a recent addition, providing new insight into the treatment of this disease. The selection of the optimal therapy for RA should be based on guidelines and recommendations, but also on clinical particular aspects and patient preferences.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology and autoimmune pathogeny, involving the joints and is accompanied by severe deformity and destruction, resulting from inflammation and hypertrophy of the synovial membrane of the diarthrodial joints (synovitis). RA may be complemented with multiple systemic characteristics. The management of RA has undergone significant changes as far as objectives and approaches are concerned, ending in the current strategy known as ‘treat to target’. The primary objective of this in patient treatment is the immediate control of inflammation, through a potentially ‘aggressive’ approach, aiming to prevent progressive structural lesions, maximise the long-term quality of life through symptom control, optimise articular function and improve social inclusion. The treatment of RA involves the use of multiple classes of drugs, each with varying effects (13).

Treatment classification

Non-steroidal anti-inflammatory drugs (NSAIDs)

Currently, in spite of very common use either as continuous or as intermittent treatment, NSAIDSs are no longer indispensable RA medication (1,4). Even though they are used to control joint pain and swelling, NSAIDs are not effective in preventing structural damage; it has thus been determined that the use of NSAIDs in the treatment of RA should be in conjunction with drugs with disease-remitting activity. Nevertheless, the long-term use of NSAIDs is frequent in RA, which is associated with various adverse events and increased morbidity and mortality. The mechanisms of action of NSAIDs are based on the inhibition of cyclooxygenase 1 and 2 and the decrease in prostaglandin production, which accounts for the adverse effects of NSAIDs. These adverse effects most frequently include gastrointestinal symptoms, such as nausea, dyspepsia, heartburn, abdominal pain, gastritis and peptic ulcers with or without perforation or bleeding. Endoscopic gastric and duodenal ulcerations are present in 30–50% of NSAID-treated patients (1,4). The use of NSAIDs should be avoided in patients with active ulcers or gastritis, as is treatment with proton pump inhibitors in patients with a history or increased risk of superior digestive complications [e.g., Helicobacter pylori infection, increased alcohol intake, the concomitant administration of aspirin, clopidogrel, anticoagulants and glucocorticoids (GCs)] (1,4).

As regards long-term treatment with NSAIDs, cardiovascular adverse effects are also prominent, as evidenced by multiple reports of oedema, the aggravation of hypertension and/or heart failure and the increased risk of thrombotic events, including myocardial infarction. In patients with previous, even controlled, cardiovascular problems, with severe cardiovascular disease or risk factors, NSAIDs should be prescribed with caution or even avoided where possible. Chronic kidney disease may also be another complication of long-term NSAID use; the use of these drugs should preferably be avoided or the dose should be adjusted in patients with decreased creatinine clearance (4).

Glucocorticoids

GCs are hormones acting through complex mechanisms, generating genomic and non-genomic effects (5,6). They are characterised by rapid symptomatic effects, and in association with drugs with disease-remitting activity, they also prevent structural damage in early RA. Typically, small doses are indicated (<7.5 mg prednisone or equivalent/day in the first 6 months of treatment). In remissive patients, the use of GCs should be tapered and terminated where possible, as the long-term use of GCs is associated with multiple adverse effects.

The use of GCs is also indicated in rheumatoid vasculitis or other RA systemic manifestations, as well as in severe active forms of RA, until control by remissive therapy becomes possible. GCs may also be used as local treatment for joints or structures not responsive to systemic treatment. In the case of RA, GCs are used in small doses (≤10 mg/day), average doses (10–30 mg/day), large doses (>30 mg/day) and pulse therapy (>250 mg methylprednisolone/day, via infusion) (5,6).

The use of GCs is associated with the occurrence of various adverse events, which may be classified into preventable and non-preventable events. Preventable adverse effects include heart failure, hypertension, osteoporosis, diabetes mellitus, peptic ulcers, myopathy, as well as sleep and mood disturbances. Non-preventable adverse events include cataract, avascular necrosis, cutaneous modifications, accelerated atherosclerosis, infections and weight gain (5,6). One of the most threatening complications of the use of GCs is osteoporosis, affecting both bone formation (decrease) and bone resorption (increase). The trabecular bone is the first to be involved in these effects (5).

The most important measure for the prevention of these adverse effects of GCs is a decrease in the use of GCs, using them only when they will be truly effective and necessary (according to guidelines), while decreasing the dose until the complete, safe discontinuation of GC treatment can occur.

Disease-modifying antirheumatic drugs (DMARDs) are a very heterogeneous class of medications, able to influence RA pathogenic mechanisms for the reduction of articular and systemic inflammation and the cessation of disease progression, structural damage and disability. It is now generally recognised that, given the intense destructive potential of RA in the first 2 years and the irreversible nature of structural damage, the use of DMARDs should be undertaken as early as possible, from the very first day of the positive diagnosis of RA (1,7). DMARDs for use in RA are classified into conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs).

Conventional synthetic DMARDs

This class includes a wide range of drugs of various chemical structures and different therapeutic action, some of which are still partially unknown. The most commonly used DMARDs are methotrexate (MTX), leflunomide (LEF), sulfasalazine (SSZ) and hydroxychloroquine (HCQ), whereas azathioprine, cyclosporine A, gold salts and cyclophosphamide can also be used in special situations only.

Methotrexate

MTX is the gold standard of RA treatment (13,8,9); however, the mechanisms of action of this drug are still partially unknown in spite of its being in use for over 25 years in the treatment of RA. MTX competitively and irreversibly inhibits dihydrofolate reductase, the enzyme responsible for the conversion of dihydrofolate into tetrahydrofolate (the active metabolite). This is the mechanism by which MTX blocks DNA, RNA and most protein synthesis in fast-dividing cells, such as in gastrointestinal, medullar and neoplastic cells (810). MTX also blocks thymidylate synthase and 5-aminoimidazol-4-carboxamid ribonucleotide transformylase, leading to increased intra- and extracellular adenosine with possible anti-inflammmatory effects. These mechanisms explain only in part the complex effects of MTX in the treatment of RA: the decreased secretion of pro-inflammatory cytokines, such as as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, matrix metalloproteinases, prostaglandins and adhesion molecules (812).

In the treatment of RA, MTX is used in doses between 7.5–25 mg/week, in oral or parenteral administration. The adequate use of MTX in patients with RA is associated with improvement and/or remission, as well as the prevention of structural damage for a significant proportion of patients. In long-term use, MTX treatment in stable doses is generally very well tolerated and safe. The associated administration, not on the same day however, of MTX and folic acid (5–15 mg/week) or folinic acid (leucovorin; 27.5 mg/week), is generally recommended to decrease the adverse events (8). The therapeutic efficacy of MTX may be evaluated by the use of the 1(H) nuclear magnetic resonance metabolomics method (13).

As regards the occurrence of various adverse events triggered by the administration of MTX in the context of RA treatment, their vast majority are mild. In that respect, gastrointestinal adverse events are the most frequent (dyspepsia, nausea, vomiting, abdominal pain and anorexia). In rare instances, MTX toxicity produces ulcerative stomatitis or diarrhoea. MTX toxicity is also associated with the occurrence of hepatic fibrosis and cirrhosis (8). Hepatic adverse events are marked by elevations in the levels of liver enzymes [transaminases, gamma-glutamyl transferase (GGT) and alkaline phosphatase]. Patients with mild elevations in the levels of these enzymes [<2× upper limit of normal (ULN)] should be monitored. In the case of significant elevations in these levels (>2–3× ULN), the treatment doses should be reduced or the treatment should be stopped entirely. In such cases, it is important to evaluate the presence of concomitant factors with hepatotoxic potential, such as alcohol, paracetamol, chronic viral B or C hepatitis and other toxic factors. In the majority of patients without additional risk factors, concomitant therapy with folic acid, initial and periodic liver tests and the adjustment of the dose of MTX are sufficient to control liver toxicity (8,14,15). Patients exhibiting persistent and significant modifications in hepatic tests should be referred to a gastroenterologist for specialist evaluation.

Pulmonary adverse events in MTX treatment include acute interstitial pneumonitis, pulmonary fibrosis and non-cardiogenic pulmonary oedema (8). A chest X-ray should be performed at the beginning of the treatment period and periodic evaluation or the evaluation of acute pulmonary symptoms should also be performed during the treatment period. In the case of acute interstitial pneumonitis, the administration of MTX should be terminated. It is important to differentiate MTX-associated pulmonary adverse events from infectious diseases by means of various tests, including bronchoalveolar lavage.

Haematologic adverse events may also occur, such as neutropenia, megaloblastic anaemia, thrombocytopenia and pancytopenia. Folic acid supplements and periodic blood cell counts are the best methods with which to prevent severe haematologic adverse events. An increase in the erythrocyte volume of >100 fl without other hematologic modifications may be the first sign of hematologic toxicity due to MTX. Cutaneous adverse events include rash, itching, alopecia and rare cases of multiform erythema or exfoliative dermatitis.

Infectious diseases with common or opportunistic agents may frequently affect patients with RA on MTX treatment (8). Neurologic adverse events may consist of headaches, dizziness, and speech, sight or cognitive impairments (8). MTX treatment is teratogenic even at low doses (labelled category × by the US Food and Drug Administration), and should not be used during pregnancy; treatment should be terminated at least 1–3 months prior to conception (810). MTX can be used as monotherapy, but also in combination with other csDMARDs or bDMARDs (16,17).

Leflunomide

The therapeutic action of LEF is not yet fully understood. LEF is an isoxazole derivate converted into the active metabolite, A77 1726, in the submucosal wall of the intestinal tract and after the first hepatic passage (18,19). Its active form blocks dihydroorotate dehydrogenase, the enzyme involved in pyrimidine synthesis, an effect leading to the inhibition of tyrosine kinase and nuclear factor (NF)-κB activation, more significant for activated T cells. In the usual 20 mg/day dose, LEF is a very effective treatment for moderate or severe forms of RA, in the early and late stages of the disease (18). It is associated with the improvement and/or remission and prevention of structural damage. LEF can either be used as monotherapy or in association with csDMARDs or bDMARDs (16,18,19).

The adverse events associated with LEF are partially similar to those of MTX. Gastrointestinal adverse events include nausea, vomiting, diarrhoea, abdominal pain and dyspepsia. Diarrhoea usually occurs in the first 3 months of treatment and is mild/moderate, but is sometimes significantly prolonged and is associated with weight loss (18). Hepatic adverse events are more frequent in association with MTX (15). Hematologic adverse events, such as leukopenia, thrombocytopenia and pancytopenia are rare (18). Neurologic adverse events are usually mild and include headaches, dizziness anmd paraesthesia (18).

The use of LEF may also be associated with cardiovascular events, such as the aggravation of pre-existing hypertension more than that of new-onset hypertension (18). Cutaneous adverse reactions occur more frequently in the first months of treatment and include rash, itching, skin dryness and rare cases of Stevens-Johnson syndrome (18).

Infections are more frequent during LEF treatment; however, not all of these infections are severe. An active serious infection is a contraindication for the initiation of LEF treatment and any treatment already being administered should be terminated until the infection has been controlled. LEF should not be used during pregnancy and should be terminated 2 years prior to conception.

The more rapid elimination of LEF and its metabolites is obtained using cholestyramine treatment (8 g 3 times daily for 11 days) (18). To prevent the adverse events associated with LEF, it is important to rule out serious infections and perform blood cell count and liver tests (hepatitis B and C included) both at the beginning of the treatment period and during the treatment period (16,18,19).

Sulfasalazine

SSZ is a combination of sulfapyridine and 5-aminosalicilic acid and is used for the treatment of RA and other inflammatory diseases. The mechanisms of action of SSZ are partially known and involve the production of the decreased synthesis of TNF-α, IL-1 and IL-6, and the decreased activation of NF-κB, the inhibition of T lymphocytes and the decreased production of IgGs and rheumatoid factor by B lymphocytes.

SSZ is used in the treatment of RA at doses of 2–3 g/day, either as monotherapy or in conjunciont with csDMARDs and bDMARDs (10,17,20,21).

Gastrointestinal adverse events are the most common, but are usually mild (nausea, anorexia, dyspepsia). Hepatic adverse events consist of a mild/moderate increase in the levels of liver enzymes, which is usually attenuated by decreasing the dose or by temporary terminating the treatment. The cutaneous adverse events of SSZ treatment may be rash, itching, photosensitivity, rare cases of multiform erythema or Stevens-Johnson syndrome. Neurologic adverse events are anxiety, headaches, sleep disturbances and irritability.

The main hematologic adverse events are lymphopenia and neutropenia (with rare but serious cases of agranulocytosis in the first 6 weeks of treatment) (21) and rare cases of megaloblastic anaemia. Lymphopenia and neutropenia are indications for the discontinuation of treatment. Rare cases of eosinophilic pneumonia have been described during SSZ treatment.

SSZ is safe during pregnancy but may induce oligospermia in males. Caution should be undertaken when breastfeeding (concerning potentially high concentrations of sulfapyridine in breast milk) (21). Initial blood cell count and liver tests and periodic evaluations are usually sufficient for preventing the serious adverse events of SSZ (10,2022).

Hydroxychloroquine

The use of HCQ as monotherapy has moderate efficacy for the treatment of RA. It is usually used in combination with other DMARDs, as ‘triple therapy’: MTX, SSZ and HCQ (21). Common adverse reactions are gastrointestinal (nausea, anorexia), cutaneous (rash), ocular retinopathy, although rare, but require screening in susceptible patients) (21).

Biologic therapy for RA

The better understanding of the immunopathogenic mechanisms involved in the genesis of RA (pro-inflammatory cytokines, costimulation between antigen-presenting cells and T cells, involvement of B cells) has contributed to the development of novel therapeutic agents, known as bDMARDs (23). These are classified into cytokine inhibitors (anti-TNF-α, anti-IL-6 and anti-IL-1 agents) and non-cytokine agents (anti-CD20 receptor on B cells and anti costimulation between antigen-presenting cells and T cells). All biologic agents have demonstrated their efficacy in clinical and functional improvement, in reduced radiographic damage and an improved quality of life for patients with RA.

Anti-TNF-α agents

TNF-α is one of the pivotal inflammatory cytokines, found in increased levels in the synovia and synovial fluid of patients with RA and it is involved in immune response, inflammation, cell infiltration, angiogenesis, and bone and cartilage destruction (2426). This cytokine also plays important physiologic roles, particularly in relation to anti-tumour and anti-mycobacterial protection. TNF-α plays a major role in the formation of granuloma in tuberculosis (TB). TNF-α blockade may favour a new BK virus infection or reactivation of latent infection, which renders the rationale for very strict TB screening before beginning treatment with anti-TNF-α agents. Anti-TNF-α agents are either monoclonal antibodies (infliximab, adalimumab, golimumab, certolizumab) or soluble receptors (etanercept).

Infliximab

Infliximab is a chimeric monoclonal antibody combining the constant region of human IgG1 with the variable murine Fv region. The usual dose in the treatment of RA is 3 mg/kg via intravenous infusion at weeks 0, 2 and 6, and every 8 weeks thereafter. The dose may be increased to 7–10 mg/kg or the interval between infusions may be shortened to 4–6 weeks.

The Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study demonstrated that infliximab in combination with MTX is more effective than MTX alone in decreasing clinical signs and symptoms, in improving physical function and the quality of life, as well as in reducing structural damage (27,28). These results have been validated by numerous studies that confirmed the long-term positive results of treatment with infliximab (2830).

Adalimumab

Adalimumab is a fully human IgG1 monoclonal anti-TNF-α antibody which is administered subcutaneously at the dose of 40 mg every 2 weeks.

The anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Rheumatoid Arthritis (ARMADA) study demonstrated the favourable effects of treatment with adalimumab in combination with MTX concerning all clinical and radiological variables (10). Other studies have also demonstrated the same favourable clinical and radiological effects and the safety of the use of adalimumab + MTX (or other DMARDs) for the treatment of RA in the advanced and early stages, for short-term (24 weeks) or long-term follow-up (3135).

Golimumab

Golimumab is a fully human monoclonal anti-TNF-α antibody which is administered subcutaneously at the dose of 50 mg once a month. The evaluatoin of golimumab has been very complex, involving patients who are DMARD-naïve to insufficient responders to MTX treatment and anti TNF-α treatment failures. Golimumab has been shown to have the ability to improve the symptoms associated with RA and physical function, as well as to attenuate short- and long-term structural damage (36,37).

Certolizumab

Certolizumab is derived from a human monoclonal anti-TNF-α antibody, only retaining the latter's Fab fragment of an IgG molecule, and is polyethylene glycol (PEG)-coated. Certolizumab is administered subcutaneously at the dose of 200 mg every 2 weeks. The pegylated molecule of certolizumab offers important biological properties: a greater molecular weight with a prolonged half-life, the decreased penetration to normal tissue and the increased penetration to inflamed tissue, the inhibition of mast cell degranulation, the reduction of injection site-related adverse events and no placenta passage (38).

RAPID I and RAPID II studies have demonstrated the clinical and radiological efficacy of certolizumab in patients with RA who are unresponsive to MTX (39,40). In addition, it has been demonstrated that certolizumab can be effective as a monotherapy for RA (41).

Etanercept

Etanercept is a recombinant molecule generated through the fusion of 2 identical chains of TNF-α receptors (p75-type II receptor) with a Fc fragment of an IgG1 human molecule. Etanercept is administered subcutaneously at the dose 50 mg once a week.

Etanercept is a binding soluble TNF-α, which blocks the interaction of TNF-α with specific receptors on target cells. Etanercept only binds circulating TNF-α and not the TNF-α membrane, resulting in milder TNF blockade. Etanercept also binds to TNF-β (monoclonal anti-TNF-α antibodies only bind to TNF-α). Etanercept has undergone extensive study, and has proven to be effective in combination with MTX or as monotherapy for the treatment of early-stage RA, and in MTX-naïve and in patients with RA who are unresponsive to MTX treatment. The TEMPO study (trial of etanercept and MTX with radiographic patient outcomes) demonstrated good clinical and radiological efficacy in combination with MTX (4244).

The overall safety of anti-TNF therapy is considered satisfactory, with the most important adverse events including: i) an increased risk of infections (TB is of most concern); ii) an increased risk of cancer (however, clinical studies and registry data have indicated a similar cancer risk in patients with RA on anti-TNF treatments as compared to cancer risk in all patients with RA, with a possibly slight increase in the risk of lymphoma); iii) the aggravation of heart failure, anti-TNF treatments being contraindicated in patients with heart failure [New York Heart Association (NYHA) classes III and IV]; iv) demyelinating diseases (rare); v) the development of anti-dsDNA antibodies and even lupus-like syndrome; vi) allergic reactions; and vi) immunogenicity, with the development of anti-drug antibodies (45,46).

In spite of the excellent overall efficacy of anti-TNF treatment, 35–40% of patients with RA are not responsive to this therapy and should be treated using biologic drugs with different actions.

IL-6 blockade

IL-6 is a pro-inflammatory cytokine with an important role in local and systemic RA pathogenic mechanisms. IL-6 stimulates the activation, differentiation and proliferation of B lymphocytes, IgG synthesis, lymphocyte T helper and cytotoxic differentiation and IL-17 production, and is also involved in acute and chronic inflammation, and prolonged immune response. As regards joints, IL-6 contributes to synovial cell proliferation, angiogenesis, the formation of articular pannus, bone and cartilage destruction. IL-6 systemic effects are also important in RA: the stimulation of the hepatic production of acute phase reactants, anaemia by the stimulation of hepatic hepcidin production (with the subsequent blockade of iron in macrophages), fatigue by affecting the hypothalamus-hypophysis system, increased cardiovascular risk through alterations in lipid metabolism and pro-inflammatory effects.

Tocilizumab

Tocilizumab is a monoclonal anti-IL-6 receptor antibody. By binding the Il-6 receptor, it blocks the effects of IL-6. Tocilizumab is administered by intravenous infusion at the dose of 8 mg/kg, once a month. Tocilizumab has been proven to be effective in various clinical trials on patients who are MTX-naïve, MTX-resistant and unresponsive to anti-TNF therapy. In combination with MTX and also as a monotherapy, treatment with tocilizumab leads to an improvement in the clinical symptoms, also halting radiologic progression, thus rendering biologic therapy with the strongest evidence of efficacy in monotherapy (4750). The main adverse events of tocilizumab treatment include infections, diverticulitis, dyslipidemia, elevations in hepatic enzyme levels and neutropenia.

IL-1 blockade

IL-1 is a pro-inflammatory cytokine with many effects similar to those of TNF-α. Currently, only one IL-1 blocker has been approved for the treatment of RA, namely anakinra, an IL-1 receptor antagonist. Although currently it is less commonly used due to its lower efficacy as compared to anti-TNF therapy, anakinra is administered via daily subcutaneous injections, which is highly unpopular with patients (51). The adverse events of IL-1 inhibitors include injection site reactions and possible infections (of the upper airways) (52).

Non-cytokine biologic agents
T lymphocyte blockade

Full T cell activation requires the costimulatory molecules, CD80/86 from antigen-presenting cells and CD28 from T lymphocytes. The binding of CD80/86 to CD28 leads to the activation of T lymphocytes and the binding of CD80/86 to the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor leads to the inhibition of T lymphocytes.

Abatacept is a soluble fully humanised recombinant receptor, formed by the fusion of the extracellular domain of CTLA-4 with a Fc fragment of human IgG1. Abatacept binds to CD80/86 from antigen-presenting cells, with greater affinity than to CD28, also blocking the costimulation and activation of T lymphocytes. The complex activity of T lymphocytes is not completely blocked, as by selectively binding CD80/86, abatacept allows other approaches for T lymphocyte activation, which makes it the first biologic therapy able to modulate T lymphocyte activity. Abatacept is administered via intravenous infusion (500–1,000 mg at weeks 0, 2 and 4, and monthly thereafter) and via subcutaneous injection (125 mg, once a week). Randomised clinical trials have demonstrated that, in combination with MTX, abatacept is very effective in the short- and long-term treatment of patients with RA who are MTX-naïve and who are resistant to MTX, and that treatment with abatacept improves clinical manifestations and blocks structural destruction in a manner comparable with anti-TNF therapy (53,54,55). The main adverse events associated with abatacept are infusion-related reactions, susceptibility to infections and a reduced protective humoral response to vaccines (53).

B lymphocyte blockade

B lymphocytes are crucial for the pathogenic mechanisms of RA, acting as producers of cytokines and autoantibodies, and also of antigen-presenting cells and activators of T lymphocyte (54). CD20 is a receptor found on B lymphocyte membrane, but not on stem cells and plasmocytes. Treatment with monoclonal anti-CD20 antibody leads to a depletion of peripheral B lymphocytes by cytotoxicity, complementing activation and inducing apoptosis (56).

Rituximab

Rituximab is a chimeric monoclonal anti-CD20 antibody initially used in the treatment of non-Hodgkin lymphoma. Clinical trials have proven that rituximab is highly effective in combination with MTX in the treatment of RA by improving clinical manifestations and blocking radiological progression (5759). Rituximab is administered via intravenous infusion, and one treatment cycle consisting of two 1,000 mg infusions at 2-week intervals, repeated after at least 6 months.

The rituximab safety profile is very good, the most frequent adverse events being related to infusion reactions and a slight increase in the number of infections (44). Guidelines indicate rituximab as second-line biologic treatment for patients with RA who are unresponsive to anti-TNF therapy; however, in particular clinical situations (recent lymphoma, latent TB with contraindication of prophylaxis with isoniazid) rituximab may be used as first-line biologic treatment (50).

The European League Against Rheumatism (EULAR) guidelines for the treatment of RA recommend biologic treatment with TNF-α blockers, tocilizumab or abatacept for patients who are unresponsive to at least one DMARD. In the case of ineffective first-line biologic treatment, this should be changed to another biologic medication of the same or different class.

New emerging therapies are represented by kinase inhibitors. Tofacitinib (Xeljanz) is a JAK inhibitor with comparable efficacy to TNF blockers (60). The associated adverse reactions are gastrointestinal and infections (an increased risk of herpes zoster infection).

Conclusions

The treatment of RA may be a challenge due to the complexity of the disease, the presence of comorbidities in the majority of patients, the duration of treatment and the frequency of adverse reactions of the drugs. The selection of the optimal treatment for RA should be based on guidelines and recommendations, but also on clinical particular aspects and patient preferences. RA requires aggressive therapies and the ‘treat to target’ strategy is effective in controlling the disease and achieving remission. At the same time, pharmacological interventions have a tremendous impact on the disease and on patients. Patients must be monitored with caution in clinical, biologic and imagistic aspects. The evaluation of periodic liver function (including serologic markers for viral hepatitis), renal evaluation, pulmonary evaluation with the Quantiferon TB Gold Test and radiologic imaging must be a rule in the evaluation of RA treatment. The aggravation of heart failure and demyelinating diseases, as well as the possibility of an increased risk of cancer during biologic therapy (although unconfirmed by registry data) are important issues which require in-depth investigations.

The use of biologic agents on wide scale has significantly changed the evolution of RA, but has also led to a brand new pathology. There are currently novel therapeutic targets under investigation, as there are still unmet needs in the management of RA, both in terms of efficacy and in reducing adverse events.

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April-2016
Volume 11 Issue 4

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Spandidos Publications style
Negrei C, Bojinca V, Balanescu A, Bojinca M, Baconi D, Spandidos DA, Tsatsakis AM and Stan M: Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches (Review). Exp Ther Med 11: 1177-1183, 2016
APA
Negrei, C., Bojinca, V., Balanescu, A., Bojinca, M., Baconi, D., Spandidos, D.A. ... Stan, M. (2016). Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches (Review). Experimental and Therapeutic Medicine, 11, 1177-1183. https://doi.org/10.3892/etm.2016.3045
MLA
Negrei, C., Bojinca, V., Balanescu, A., Bojinca, M., Baconi, D., Spandidos, D. A., Tsatsakis, A. M., Stan, M."Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches (Review)". Experimental and Therapeutic Medicine 11.4 (2016): 1177-1183.
Chicago
Negrei, C., Bojinca, V., Balanescu, A., Bojinca, M., Baconi, D., Spandidos, D. A., Tsatsakis, A. M., Stan, M."Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches (Review)". Experimental and Therapeutic Medicine 11, no. 4 (2016): 1177-1183. https://doi.org/10.3892/etm.2016.3045