Plant parts such as leaves of myrtle (Myrtus), bark of willow tree (Salix), bark of poplar (Populus), and meadow sweet (Spirea) were used in fork medicine for centuries in the treatment of fever, pain, and inflammatory responses (Hedner and Everts, 1998). These medicinal plants represented a primitive form of anti-inflammatory drugs. In the mid-19th century, salicylates were identified as active components of Willow spp. responsible for the anti-inflammatory activity, which laid the foundation for the mass synthesis of acetylsalicylic acid in 1899 (Vainio and Morgan, 1997; Vane, 2000). The progress in chemistry in the 19th–20th centuries promoted the fast development of NSAIDs. Initially, most of NSAIDs were the organic acid, but the non-acidic compounds were also discovered later. With outstanding safety profiles at dose ranges, ibuprofen was the first NSAIDs approved in the United Kingdom (Busson, 1986). After that, pharmaceutical companies began to develop NSAIDs with a series of chemical and biological properties (Rainsford, 2007). Overall, Post-World War II, the development of NSAIDs had experienced two periods: one was the pre-prostaglandin period (∼1970s) and another one was from 1970s to the end of the last century in which drugs were screened and evaluated partially based on their effect on the production of prostaglandin (Rainsford, 2007).

Salicylic acid was synthesized by the Gerland in 1853 for the first time, and acetylsalicylic acid was synthesized by Charles Gerhardt in 1853 (Gerhardt, 1853; Gerland, 1853). Until 1876, salicylic acid was firstly used in clinic for the treatment of rheumatic disorders by two German physicians, Drs Streicher and Reiss (Hedner and Everts, 1998). Acetylsalicylic acid was re-discovered by Hoffman in 1897 (Hoffmann and Förster, 1987), and it became available worldwide in the treatment of rheumatic disorders and pain since then (Hedner and Everts, 1998). Acetyl-salicylate was first used as Aspirin in 1899 (Vainio and Morgan, 1997). The development of aspirin, a prototype of NSAIDs, was a landmark (Vainio and Morgan, 1997), which was followed by the development of phenylbutazone (1946) and indomethacin (1963) (Shen, 1982). The term of ‘non-steroidal anti-inflammatory drug’ was used for the first time when phenylbutazone was introduced 3 years later as an anti-inflammatory agent. Thus, aspirin, phenylbutazone, and indomethacin were founding members of NSAID family.

Non-steroidal anti-inflammatory drugs have the analgesic, antipyretic, and anti-inflammatory effect, frequently used for the treatment of conditions like arthritis and headaches (Rainsford, 2007). NSAIDs relieve pain through blocking cyclooxygenase (COX) enzymes (Simmons et al., 2004). COX promotes the production of prostaglandins, a mediator which causes inflammation and pain (Simmons et al., 2004). Although NSAIDs have different chemical structures, all of them have the similar therapeutic effect, e.g., inhibition of autoimmune inflammatory responses (Rainsford, 2007). In general, NSAIDs can be divided into two broad categories: traditional non-selective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors (Antman et al., 2007).

The traditional non-selective NSAIDs are able to inhibit both COX-1 and COX-2. These drugs also inhibit platelet aggregation and cause significant gastrointestinal disorders such as bleeding, ulcers, and perforation (Fujita et al., 2013). They also induce renal toxicity (Murray and Brater, 1993; Fujita et al., 2013). In contrast, the gastrointestinal adverse effect of selective COX-2 inhibitors is markedly reduced (Dajani and Islam, 2008). However, just like traditional non-selective NSAIDs, selective COX-2 inhibitor still have adverse effects on the cardiovascular system, including congestive heart failure, acute myocardial fraction, and even sudden death (Ray et al., 2002; Hermann and Ruschitzka, 2006).

Methotrexate is an analog and antagonist of folic acid, which was synthesized firstly in 1947 (Swierkot and Szechinski, 2006). Methotrexate was firstly reported to be effective in the treatment of RA in 1962 (Kersley, 1968), and after that it was also widely used as an anti-inflammatory drug for the management of other autoimmune diseases, including psoriasis, CD, and UC (Nathan et al., 2008; Yelamos and Puig, 2015). Methotrexate has been used as the first-line DMARDs since it was developed, due to its long-term effectiveness, satisfying responsive rate, acceptable toxicity profile, and low cost (Visser and van der Heijde, 2009; Favalli et al., 2014). Fundamental mechanisms underlying the therapeutic effect of methotrexate have been elucidated. For example, methotrexate was found to competitively inhibit the activity of folate-dependent enzymes, and synthesis of purine and pyrimidine which are required for DNA and RNA synthesis, and consequently suppress lymphocyte proliferation and production of pro-inflammatory cytokines (Meier et al., 2013). Nevertheless, the methotrexate monotherapy is no longer considered as the gold standard for RA treatment, for the reason that DMARDs combination therapy is more effective (Kremer et al., 2004).

Leflunomide was approved for the treatment of RA in the 1998 (Gabriel et al., 2001). Leflunomide is an isoxazole derivative that is capable of blocking the rate-limiting enzyme dihydroorotate dehydrogenase, thereby selectively inhibits the synthesis of de novo pyrimidine ribonucleotides such as rUMP (Fox et al., 1999). Leflunomide is a pro-drug that is metabolized into teriflunomide in vivo (Laev and Salakhutdinov, 2015). Teriflunomide is a potent inhibitor of NF-κB activation, and consequently suppresses the production of pro-inflammatory cytokines. Leflunomide also reduces the production of metalloproteinases in synovial tissue and prevents joint destruction (Laev and Salakhutdinov, 2015). The results of meta-analyses strongly suggest that leflunomide is a DMARDs and effective in the treatment of RA (Osiri et al., 2003). As shown by several studies, the therapeutic effect of leflunomide is comparable to that of methotrexate (Silverman et al., 2005). Leflunomide can improve all clinical outcomes and delay radiographic progression at 6 and 12 months of RA patients (Sharp et al., 2000). Therefore, leflunomide should be considered as first-line therapy if contraindications to methotrexate are present. Furthermore, leflunomide is very useful in the combination therapy (Kalden et al., 2005).

Except for methotrexate and leflunomide, other DMARDs, include gold compounds, sulfasalazine, azathioprine, cyclophosphamide, antimalarials, D-penicillamine, cyclosporine, are all effective in the treatment of autoimmune inflammatory diseases such as RA (Gabriel et al., 2001). The DMARDs commonly used for the treatment of RA include hydroxychloroquine, sulfasalazine, methotrexate and leflunomide, while D-penicillamine, azathioprine, gold compounds, and cyclosporine are used less frequently (Kim et al., 2013).

Parenteral organic gold compounds have been used for RA treatment since 1920s (Simon, 2004), and their effect is comparable with other DMARDs (Meier et al., 2013). Nonetheless, the toxicity of gold compounds, especially the adverse effect on skin and mucosa, is a major concern which limits their clinical application (Bendix and Bjelle, 1996).

Sulfasalazine was initially investigated for the treatment of IBD, including UC and CD (Box and Pullar, 1997). This drug was firstly reanimated in Europe where it has been used in early RA patients. The exact mechanism of sulfasalazine is still unclear, although it inhibits the production of pro-inflammatory cytokines, including TNF and IL-6 (Wahl et al., 1998). The main side effect of sulfasalazine is gastrointestinal upset or rash (Skosey, 1988).

Antimalarial drugs hydroxychloroquine and chloroquine have the capacity to inhibit the clinical progress of several autoimmune diseases, including RA and systemic lupus erythematosus (SLE) (Taherian et al., 2013). Although the exact molecular mechanism of its immunosuppressive effect remains to be fully understood, both drugs can inhibit the activation of T cells, B cells (Taherian et al., 2013) and the production of pro-inflammatory cytokines such as TNF, IL-6, and IL-1β (Jang et al., 2006). Both drugs almost have the same side effects, such as rare irreversible retinopathy and a more rarely form of myopathy (Costedoat-Chalumeau et al., 2015).

Among cDMARDs drug class, the methotrexate is still an ‘anchor drug’ for RA therapy, and the first choice for the most of DMARD-naïve patients (Favalli et al., 2014). However, a considerable proportion of patients do not respond to methotrexate. Either anti-TNF biologics (which will be discussed later) or a combination therapy of cDMARDs should be considered for those patients (van Vollenhoven et al., 2012). Methotrexate has been used in combination with other drugs, including sulfasalazine, sulfasalazine and hydroxychloroquine, cyclosporine and biologic agents such as etanercept and infliximab (Kremer et al., 2004; Swierkot and Szechinski, 2006). For example, the concomitant treatment of methotrexate and leflunomide results in a synergistic effect in the treatment of patients with RA (Boers et al., 1997; Kremer et al., 2004). The triple combination of methotrexate, sulfasalazine and hydroxychloroquine represent an effective therapy regimen since 1996 (Meier et al., 2013), which is more effective and safer than the monotherapy with methotrexate, or methotrexate combination of sulfasalazine, or hydroxychloroquine (ODell et al., 1996, 2002). It has been reported that the combination of methotrexate and cyclosporine, or leflunomide and cyclosporine, are more effective than each drug alone (Karanikolas et al., 2006). However, the toxicity of cyclosporine, including reversible and irreversible renal disease, hypertension and heurism, remains an important issue in the combination therapy (Gabriel et al., 2001). Therefore, the ideal cDMARDs combination therapy should be one that is synergistic in their efficacy while lacking additive effects of toxicity.

Infliximab is a recombinant chimeric antibody that is generated by mouse myeloma cells. The structure of infliximab contains a constant sequence of human IgG1 and variable regions of murine, which is specific for all forms of TNF in human and chimpanzees, and effectively blocks the binding of TNF to its soluble and membrane receptors (Monaco et al., 2015). The maximum serum concentration of infliximab can be reached within 1 h by intravenous administration (Atzeni et al., 2005), and the half-life is approximately 8–10 days (Chatzantoni and Mouzaki, 2006). After that, infliximab can be maintained by dosing every 8 weeks. Infliximab is capable of mediating both complement-dependent and antibody-dependent cytotoxicity on a cell line overexpressing TNF (Tracey et al., 2008). Infliximab is initially approved for the treatment of Crohn’s disease by the US Food and Drug Administration (FDA) and later also for RA. It was further approved for the treatment of AS, PsA, UC, CD, and chronic plaque psoriasis (Atzeni et al., 2005).

Etanercept comprises soluble TNF receptor 2 and Fc portion of IgG1, which is a human recombinant protein (Kerensky et al., 2012). After subcutaneous administration, etanercept has a half-life of 3–3.5 days (Chatzantoni and Mouzaki, 2006). Etanercept binds to and inactivates soluble form and membrane form of TNF and lymphotoxin, by blocking their interaction with the receptors (Tracey et al., 2008). Similar as infliximab, etanercept alleviate the signs and symptoms of arthritis and inhibits progress of RA in patients (Moreland et al., 1999). Furthermore, it is more effective when combined with methotrexate (Emery et al., 2008). Etanercept is also approved by FDA for the treatment of juvenile rheumatoid arthritis and PsA, RA, PP, and AS (Kerensky et al., 2012).

Adalimumab is a fully humanized IgG1 monoclonal antibody, which can specific block human TNF binding to its receptors (Atzeni et al., 2005). Adalimumab needs a less frequent subcutaneous injection because of its relative longer half-life which is about 2 weeks (Simon, 2004). Furthermore, adalimumab shows the lower immunogenicity than infliximab (Rau, 2002).

Adalimumab is effective in alleviating the signs and symptoms of moderate to severe RA patients (van de Putte et al., 2004). Adalimumab is also effective in the treatment of patients with CD, with good tolerance and minimal immunogenicity, thus can be used in patients with allergic reactions to infliximab (Sandborn et al., 2004). Adalimumab has been approved by FDA for the treatment of autoimmune diseases including RA, PsA, AS, and CD (Lapadula et al., 2014).

Golimumab is also a fully humanized IgG1 monoclonal antibody, which has a high affinity and specificity for human TNF (Shealy et al., 2007). As shown by the preclinical data, golimumab has higher affinity and is more effective in the neutralization of soluble and trans-membrane forms of TNF, as compared with infliximab and adalimumab, thus it can potently neutralize TNF biological activity (Shealy et al., 2010). The half-life of golimumab is about 7–20 days (Zhou et al., 2007). Golimumab was approved by the FDA in 2009 for the treatment of moderate-to-severe RA when administrated in combination with methotrexate (Mazumdar and Greenwald, 2009). It was also approved for UC treatment by FDA and European Medicines Agency (EMA) in 2013 (Lowenberg and D’Haens, 2013).

Certolizumab pegol (CDP870) is a humanized monoclonal antibody with the structure of polyethylene glycolated Fab fragment, which is a novel TNF inhibitor with a distinct mechanism of action compared with other TNF inhibitors (Pasut, 2014). The unique structure might be an explanation for certolizumab pegol with higher efficiency in comparison with other TNF inhibitors (Desai et al., 2012). PEGylation of certolizumab pegol improves its half-life to 2 weeks which may contribute to its high concentration in the inflamed tissues (Keystone et al., 2008).

Certolizumab pegol monotherapy could effectively control the symptoms of patients with RA (Choy et al., 2002). It is also effective the treatment of patients with moderate to severe CD (Schreiber et al., 2005). Certolizumab pegol has been approved for the treatment of CD and PsA by FDA (Deeks, 2016).

Biosimilar has been defined as a biological medicinal product that has the similar quality, safety, and efficacy with the already approved biological medicine (Fiorino and Danese, 2014). Anti-TNF biosimilars that are extensively developed in recent years will help reduce the cost of anti-TNF treatment. To date, a number of anti-TNF biosimilar products (summarized in Table 1) have been marketed (Dorner and Kay, 2015). CT-13 is the first biosimilar monoclonal antibody against TNF. Comparing with the original TNF inhibitor infliximab, CT-13 is equally effective and safe (Yoo et al., 2013). It is approved in European for the treatment of RA, AS, PsA, PS, CD, and UC (Dorner et al., 2016).

Although anti-TNF biologics are generally effective in the treatment of patients with different autoimmune inflammatory diseases (Willrich et al., 2015), not all patients respond equally well to the treatment. Up to 40% of patients have no response to anti-TNF treatment (Roda et al., 2016). Furthermore, several types of adverse effects have been associated with anti-TNF biologics.

It was reported recently that PBMCs isolated from patients responding to the treatment of adalimumab and etanercept can produce higher levels of TNF and soluble TNFR2 (sTNFR2) than those from patients responding to infliximab, and PBMCs isolated from patients who do not respond to infliximab produce higher levels of TNF and sTNFR2 than those from patients responding to infliximab (Gibellini et al., 2016). Therefore, anti-TNF biologics may have major and different effects on TNF expression and soluble TNFR2 levels in patients. It was reported that the TNF gene polymorphism (TNF-alpha 308G > A) is association with patients who do not respond to anti-TNF therapy (Wijnen et al., 2014). Furthermore, the polymorphism of tumor necrosis factor receptor superfamily member 1B, a gene encoding TNFR2 protein, is able to predict responses of patients with autoimmune diseases to anti-TNF therapy (Chen W. et al., 2015). Thus, aberrant expression of TNF and TNFR2, and their responses to TNF blockade, is responsible at least partially for the outcome of anti-TNF therapy.

TNF plays a crucial role in host defense to invading pathogens (Pfeffer, 2003). Anti-TNF biologics can inhibit IFN-γ expression in the blood (Wallis, 2007). In addition, TNF is a good inducer of nitric oxide (NO) in macrophage, and TNF also synergizes with IFN-γ in inducing inducible nitric oxide synthase (iNOS) (Vila-Del Sol et al., 2007), while iNOS is able to synthesize antimicrobial nitric oxide (Fang, 1997). This can explain why infections, such as tuberculosis and pneumonia, are common adverse event of patients treated with anti-TNF biologics (Antoni and Braun, 2002).

There is also some evidence that anti-TNF treatment is associated with increased risk of malignancy (Bongartz et al., 2006). However, this is not supported by the more recent studies (Minozzi et al., 2016; Shelton et al., 2016). In fact, the underlying inflammatory condition is likely to promote the development of cancer, while anti-inflammatory treatment has the beneficial effect in inhibition of malignancy (Lasry et al., 2016). For example, patient with RA and CD has a higher risk of lymphoma compared with the general population (Antoni and Braun, 2002). Therefore, patients with malignancy after treatment with anti-TNF biologics should be more carefully studied.

Anti-TNF treatment has been tried in patients with congestive cardiac failure, since the high levels of circulating TNF was found in such patients. However, infliximab, adalimumab, and etanercept have deleterious, rather than beneficial, effects on congestive cardiac failure patients (Balakumar and Singh, 2006). Anti-TNF biologics have been reported to have side effects on the neurological system. For example, anti-TNF treatment exacerbated diseases in almost all multiple sclerosis (MS) (Robinson et al., 2001). Paradoxically, some new autoimmune diseases can be de novo induced by anti-TNF therapy. For example, psoriasis can be induced in IBD patients treated with anti-TNF biologics (Guerra et al., 2012). Therefore, more effective and safer TNF-targeting treatment needs to be developed. Thorough understanding of the fundamental biology of TNF and it receptors is a prerequisite to reach this goal.