**Treatment of Rheumatoid Arthritis with Biological Agents**

Hiroaki Matsuno

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53321

## **1. Introduction**

*Cytokines and Rheumatoid Arthritis*

The term "cytokine" is coined from the combination of "cyto", a prefix which means cell, and "kine", which denotes movement.

Cytokines all have the following features:


For example, both tumor necrosis factor (TNF) and interleukin-6 (IL-6) have synovial prolif‐ eration activity and destroy articular cartilage and bone.

**4.** One cytokine can act on various organs at the same time (pleiotropy).

For example, TNF causes synovial proliferation, destroys articular cartilage, and promotes fever.

**5.** Each cytokine has a specific receptor and acts by binding to that receptor.

Inflammatory cytokines play a central role in rheumatoid arthritis. In the treatment of rheu‐ matoid arthritis with biological agents, the effects of cytokines are suppressed by blocking the cytokine from binding to its specific receptor (Figure 1).

With respect to these cytokines, antibodies and antibody fusion proteins that inhibit the ac‐ tion of IL-1, IL-6, and TNF have already been commercialized, and development of an IL-17 inhibitor is underway (Figure 2,Table 1).

Antibodies for the treatment of rheumatoid arthritis can be divided into three groups: chi‐ meric antibodies, humanized antibodies, and human antibodies. Experimental monoclonal antibodies are usually produced by immunizing a mouse with an antigen, and therefore, the antibody is 100% mouse antibody. When such an antibody is used as a therapeutic agent in humans, it causes a strong anaphylactic reaction. In an effort to reduce as far as possible the content of heterologous proteins, various chimeric antibodies, humanized antibodies, and human antibodies have been developed for the treatment of rheumatoid arthritis.

**Figure 2.** Types of biological agents developed for the treatment of rheumatoid arthritis.

with chimeric antibodies.

production is recommended.

human than adalimumab.

rations being impaired when antibodies to the chimeric antibody are produced.

A chimeric antibody is produced first as a mouse monoclonal antibody by immunizing a mouse with an antigen. Then the antigen binding site is preserved as it is, while the Fc site is artificially replaced with one of human origin such as IgG1 or IgG4. In chimeric antibodies, since about 25% mouse protein remains, anaphylactic reactions still occur about 10% of the time when they are administered. There are also reports of treatment with antibody prepa‐

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A humanized antibody is produced first as a mouse monoclonal antibody, then only the variable parts of the antigen binding site on the heavy chain and light chain of the antibody are left as mouse protein, and the rest is replaced with human protein. Since protein which codes the CDR1, CDR2, and CDR3 regions accounts for about 10% of the total, there is still a small chance of anaphylactic reaction with multiple administrations, though less than that

Human antibodies are fully human antibodies produced by the phage display method. A typical example is adalimumab. This antibody is produced as follows: An antibody light chain and antibody heavy chain, each with a strong affinity for TNF-α, are selected, and then the two are bound together. Therefore, while it is a fully human protein, it is not an antibody that is physiologically produced in humans. Consequently, it is reported that anti‐ bodies against the antibody are detected in 40% of cases or more, reducing the function of the antibody preparation. Combined use of an immunosuppressant to prevent antibody

Another fully humanized antibody on the market is golimumab. This antibody is produced by a method different from that of adalimumab. First, a humanized transgenic mouse is pro‐ duced, the mouse is immunized with TNF, and the antibodies produced are purified and commercialized. This method has made it possible to produce an antibody which is closer to

**Figure 1.** Mechanisms of infliximab and tocilizumab

**Figure 2.** Types of biological agents developed for the treatment of rheumatoid arthritis.

Antibodies for the treatment of rheumatoid arthritis can be divided into three groups: chi‐ meric antibodies, humanized antibodies, and human antibodies. Experimental monoclonal antibodies are usually produced by immunizing a mouse with an antigen, and therefore, the antibody is 100% mouse antibody. When such an antibody is used as a therapeutic agent in humans, it causes a strong anaphylactic reaction. In an effort to reduce as far as possible the content of heterologous proteins, various chimeric antibodies, humanized antibodies, and

human antibodies have been developed for the treatment of rheumatoid arthritis.

96 Innovative Rheumatology

**Figure 1.** Mechanisms of infliximab and tocilizumab

A chimeric antibody is produced first as a mouse monoclonal antibody by immunizing a mouse with an antigen. Then the antigen binding site is preserved as it is, while the Fc site is artificially replaced with one of human origin such as IgG1 or IgG4. In chimeric antibodies, since about 25% mouse protein remains, anaphylactic reactions still occur about 10% of the time when they are administered. There are also reports of treatment with antibody prepa‐ rations being impaired when antibodies to the chimeric antibody are produced.

A humanized antibody is produced first as a mouse monoclonal antibody, then only the variable parts of the antigen binding site on the heavy chain and light chain of the antibody are left as mouse protein, and the rest is replaced with human protein. Since protein which codes the CDR1, CDR2, and CDR3 regions accounts for about 10% of the total, there is still a small chance of anaphylactic reaction with multiple administrations, though less than that with chimeric antibodies.

Human antibodies are fully human antibodies produced by the phage display method. A typical example is adalimumab. This antibody is produced as follows: An antibody light chain and antibody heavy chain, each with a strong affinity for TNF-α, are selected, and then the two are bound together. Therefore, while it is a fully human protein, it is not an antibody that is physiologically produced in humans. Consequently, it is reported that anti‐ bodies against the antibody are detected in 40% of cases or more, reducing the function of the antibody preparation. Combined use of an immunosuppressant to prevent antibody production is recommended.

Another fully humanized antibody on the market is golimumab. This antibody is produced by a method different from that of adalimumab. First, a humanized transgenic mouse is pro‐ duced, the mouse is immunized with TNF, and the antibodies produced are purified and commercialized. This method has made it possible to produce an antibody which is closer to human than adalimumab.


recombinant protein

**Table 1.** Characteristics of various biological agents

**Rheumatoid Arthritis**

tion (Figure 3, Figure. 4) [19].

suppresses bone and joint destruction.

**Figure 3.** Improvement of clinical symptoms with biological agents

**Figure 4.** Suppression of joint destruction with biological agents

[11, 12] SAMURAI[13]

OPTION[14] AIM[15] ATTAIN[16] REFLEX[17] SERENE[18]

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**2. Types of Cytokine Inhibitors (Biological Agents) and their effects on**

Cytokine inhibitors used in the treatment of rheumatoid arthritis are inhibitors of IL-1 (ana‐ kinra), TNF (infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol), and IL-6 (tocilizumab). In addition, biological agents other than cytokine inhibitors used in the treatment of rheumatoid arthritis include abatacept, which inhibits the action of T-cell co-

These drugs each have a stronger effect than methotrexate(MTX), which is considered to be most effective taken orally, and each has strong action to suppress bone and joint destruc‐

Treatment with any biological agent is more effective than MTX monotherapy, and each

stimulatory molecules CD80 and CD86, and rituximab, which targets CD20.

**Representative clinical study**

**Table 1.** Characteristics of various biological agents

**Target** TNF-

98 Innovative Rheumatology

**Non-proprietary**

**Indications**

**Administration**

**Administration interval**

**Representative clinical study**

**Non-proprietary**

**Administration method**

**Administration**

**Product name** Kineret

**Indications** rheumatoid arthritis

**Structure** IL-1 receptor antagonist

Subcutaneous

**Product name** Remicade Enbrel Humira Simponi Cimzia

rheumatoid arthritis, poly juvenile idiopathic arthritis, plaque psoriasis, arthropathic psoriasis, ankylosing spondylitis, Crohn's

disease

Subcutaneous injection

then every 8 wks Every 1–2 wks Every 2 wks Every 4 wks Every 4 wks

DE019[6]

rheumatoid arthritis

CTLA-4–IgG1 fusion

protein Chimeric antibody

injection Drip infusion Drip infusion Drip infusion

**interval** Every 1 or 2 days Every 4 wks Every 4 wks Day 1 and 15, then every 24 wks

protein Human antibody Human antibody

Certolizumab pegol

rheumatoid arthritis, Crohn's disease

Subcutaneous injection

Pegylated humanized antibody

FAST4WARD[9] RAPID2[10]

rheumatoid arthritis, non-Hodgkin's

rheumatoid arthritis

Subcutaneous injection

GO-FORWARD[7] GO-

AFTER[8]

lymphoma

Orencia Rituxan (MabThera)

**name** Infliximab Etanercept Adalimumab Golimumab

rheumatoid arthritis, poly juvenile idiopathic arthritis.

Subcutaneous injection

ATTRACT[1] ASPIRE[2] ERA[3] TEMPO[4] PREMIER[5]

**Target** IL-1Rreceptor IL-6Receptor CD80/86 CD20

Actemra (RoActemra)

**name** Anakinra Tocilizumab Abatacept Rituximab

rheumatoid arthritis, poly juvenile idiopathic arthritis, systemic juvenile idiopathic

arthritis, Castleman's disease

Humanized antibody

rheumatoid arthritis, uveitis, Behcet's disease, plaque psoriasis, pustular psoriasis, arthropathic psoriasis, erythrodermic psoriasis, Crohn's disease, ulcerative

colitis

At wk 0, wk 2, wk 6,

**Structure** Chimeric antibody TNFR–IgG1 fusion

**method** Drip infusion

## **2. Types of Cytokine Inhibitors (Biological Agents) and their effects on Rheumatoid Arthritis**

Cytokine inhibitors used in the treatment of rheumatoid arthritis are inhibitors of IL-1 (ana‐ kinra), TNF (infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol), and IL-6 (tocilizumab). In addition, biological agents other than cytokine inhibitors used in the treatment of rheumatoid arthritis include abatacept, which inhibits the action of T-cell costimulatory molecules CD80 and CD86, and rituximab, which targets CD20.

These drugs each have a stronger effect than methotrexate(MTX), which is considered to be most effective taken orally, and each has strong action to suppress bone and joint destruc‐ tion (Figure 3, Figure. 4) [19].

Treatment with any biological agent is more effective than MTX monotherapy, and each suppresses bone and joint destruction.

**Figure 3.** Improvement of clinical symptoms with biological agents

**Figure 4.** Suppression of joint destruction with biological agents

## **3. Recommendations for the Use of Biological Agents**

Opinion is divided on which biological agent should be used to start with when active rheu‐ matoid arthritis is diagnosed. Among typical rankings for the use of biological agents, there is the 2012 recommendation of the American College of Rheumatology (Figure 5) [20].

On the other hand, the British National Institute for Health and Clinical Excellence (NICE)

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**Figure 6.** \*1The annual cost of the biological agent is also specified and does not exceed ₤9,295 a year.\*2If certolizu‐ mab pegol is the 1st Bio, there should be a system wherein the manufacturer provides the first 12 weeks for free [23]. \*3If golimumab is used as the 1st Bio, compensation from the manufacturer is necessary so that the drug price of 50 mg and 100 mg is the same [24].\*4Tocilizumab can be used as the 1st Bio with a discount provided by the manufactur‐ er. Therefore, whichever biological agent is used first, the annual cost of any is ₤9,295 or less [27].NICE guidance on

Among TNF inhibitors, there are several biological agents to choose from, with no strict standards for which biological agent to use first in either the United States or the United Kingdom. Most physicians choose one based on their own experience. Recently however,

Regarding efficacy, there is data indicating that etanercept is more effective than infliximab for active rheumatoid arthritis with high levels of anti-cyclic citrullinated peptide antibod‐ ies and rheumatoid factor [28]. In addition, among infliximab, adalimumab, and etaner‐ cept, it is reported that etanercept shows the highest efficacy in patients with high levels of

With respect to adverse reactions, the occurrence of tuberculosis among patients treated with anti TNF agents has been shown to be low for the fusion protein preparation etanercept and high for the antibody preparations infliximab and adalimumab. It has been suggested that the reason for this could be that the antibody preparations, unlike the fusion protein prepara‐

Therefore, from the point of view of adverse reactions, etanercept may be the best choice for

The same could possibly be considered for tocilizumab, an IL-6 inhibitor which does not di‐ rectly suppress macrophage function. A postmarketing survey of tocilizumab as used in a

tion etanercept, simultaneously suppress the function of macrophages [30, 31].

specifies the following guidance on usage (Figure 6) [21–27]:

the treatment of patients with rheumatoid arthritis.

anti-SS-A antibody [29].

**4. Selecting Biological Agents by Efficacy and Safety**

data has begun to accumulate suggesting which usage is best.

rheumatoid arthritis patients with a risk of tuberculosis.

According to this recommendation, in the United States the first biological agent (1st Bio) recommended for treatment of early rheumatoid arthritis with disease duration of less than 6 months is a TNF inhibitor. For treatment of established RA with disease duration of 6 months or more, a TNF inhibitor and abatacept or rituximab are recommended as the 1st Bio.

**Figure 5.** American College of Rheumatology 2012 Recommendation

On the other hand, the British National Institute for Health and Clinical Excellence (NICE) specifies the following guidance on usage (Figure 6) [21–27]:

**3. Recommendations for the Use of Biological Agents**

100 Innovative Rheumatology

**Figure 5.** American College of Rheumatology 2012 Recommendation

Opinion is divided on which biological agent should be used to start with when active rheu‐ matoid arthritis is diagnosed. Among typical rankings for the use of biological agents, there is the 2012 recommendation of the American College of Rheumatology (Figure 5) [20].

According to this recommendation, in the United States the first biological agent (1st Bio) recommended for treatment of early rheumatoid arthritis with disease duration of less than 6 months is a TNF inhibitor. For treatment of established RA with disease duration of 6 months

or more, a TNF inhibitor and abatacept or rituximab are recommended as the 1st Bio.

**Figure 6.** \*1The annual cost of the biological agent is also specified and does not exceed ₤9,295 a year.\*2If certolizu‐ mab pegol is the 1st Bio, there should be a system wherein the manufacturer provides the first 12 weeks for free [23]. \*3If golimumab is used as the 1st Bio, compensation from the manufacturer is necessary so that the drug price of 50 mg and 100 mg is the same [24].\*4Tocilizumab can be used as the 1st Bio with a discount provided by the manufactur‐ er. Therefore, whichever biological agent is used first, the annual cost of any is ₤9,295 or less [27].NICE guidance on the treatment of patients with rheumatoid arthritis.

## **4. Selecting Biological Agents by Efficacy and Safety**

Among TNF inhibitors, there are several biological agents to choose from, with no strict standards for which biological agent to use first in either the United States or the United Kingdom. Most physicians choose one based on their own experience. Recently however, data has begun to accumulate suggesting which usage is best.

Regarding efficacy, there is data indicating that etanercept is more effective than infliximab for active rheumatoid arthritis with high levels of anti-cyclic citrullinated peptide antibod‐ ies and rheumatoid factor [28]. In addition, among infliximab, adalimumab, and etaner‐ cept, it is reported that etanercept shows the highest efficacy in patients with high levels of anti-SS-A antibody [29].

With respect to adverse reactions, the occurrence of tuberculosis among patients treated with anti TNF agents has been shown to be low for the fusion protein preparation etanercept and high for the antibody preparations infliximab and adalimumab. It has been suggested that the reason for this could be that the antibody preparations, unlike the fusion protein prepara‐ tion etanercept, simultaneously suppress the function of macrophages [30, 31].

Therefore, from the point of view of adverse reactions, etanercept may be the best choice for rheumatoid arthritis patients with a risk of tuberculosis.

The same could possibly be considered for tocilizumab, an IL-6 inhibitor which does not di‐ rectly suppress macrophage function. A postmarketing survey of tocilizumab as used in a real-world clinical setting has shown an incidence of tuberculosis of 0.22% [32], which is lower than that of TNF inhibitors.

However, a characteristic effect of IL-6, which is stronger than that of TNF, is the induction of peripheral platelets in bone marrow megakaryocytes. The effect of IL-6 to induce C-reac‐

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When the outcomes of cases in which tocilizumab was selected as the 1st Bio were com‐ pared in rheumatoid arthritis patients stratified by pre-treatment platelet levels, improve‐ ment in rheumatoid activity due to tocilizumab was found to be more marked in patients with high pre-treatment platelet levels (≥400,000 /μL of blood) than in those with normal

From these results, the effects of IL-6 are stronger than the effects of TNF in patients with rheumatoid arthritis of high activity and high platelet levels, which might be a good indica‐ tion for the use of tocilizumab. In SCID-Hu-RA experimented mouse, which is implanted human RA synovium into back of the severe combined immune deficient (SCID) mouse, hu‐ man RA synovium is markedly suppressed by tocilizumab treatment in compared with con‐ trol mouse [36].Tocilizumab not only improves clinical symptoms of rheumatoid arthritis, but is also effective in improving pathological findings in rheumatoid arthritis (Figure 8).

Inflammatory cells in synovial membrane are suppressed by tocilizumab and replaced by fi‐

Biological agents are a very useful treatment for active rheumatoid arthritis, but there are still many problems which must be solved, including their high cost and the problem of ad‐ verse reactions such as infections. As described in the US recommendation and UK guid‐ ance, they should probably be used in patients who do not obtain symptomatic relief

tive protein in hepatocytes is also thought to be stronger than the effect of TNF.

**Figure 8.** Typical changes in synovial membrane seen with tocilizumab treatment

platelet levels (Figure 7).

brous tissue or adipose tissue.

**5. Problems with Biological Agents**

following treatment with DMARDs.

In comparative studies of related biological agents, almost no difference in efficacy was seen between infliximab and abatacept [33] or between adalimumab and abatacept [34]. Howev‐ er, in a study comparing adalimumab and tocilizumab, tocilizumab was shown to be more effective than adalimumab [35] (Table 2).


**Table 2.** Comparative study of related biological agents

Considered this way, the non-TNF cytokine inhibitor (IL-6 inhibitor) tocilizumab could be a biological agent with greater pharmacological effect than TNF inhibitors with fewer adverse reactions due to tuberculosis if used appropriately. Comparison of TNF and IL-6 shows mostly the same pharmacological effects due to cytokine redundancy. Examples of this in‐ clude the induction of synovial proliferation, induction of inflammatory cytokines, and ar‐ ticular destruction.

**Figure 7.** Degree of DAS28 remission with tocilizumab treatment (own data)

However, a characteristic effect of IL-6, which is stronger than that of TNF, is the induction of peripheral platelets in bone marrow megakaryocytes. The effect of IL-6 to induce C-reac‐ tive protein in hepatocytes is also thought to be stronger than the effect of TNF.

When the outcomes of cases in which tocilizumab was selected as the 1st Bio were com‐ pared in rheumatoid arthritis patients stratified by pre-treatment platelet levels, improve‐ ment in rheumatoid activity due to tocilizumab was found to be more marked in patients with high pre-treatment platelet levels (≥400,000 /μL of blood) than in those with normal platelet levels (Figure 7).

From these results, the effects of IL-6 are stronger than the effects of TNF in patients with rheumatoid arthritis of high activity and high platelet levels, which might be a good indica‐ tion for the use of tocilizumab. In SCID-Hu-RA experimented mouse, which is implanted human RA synovium into back of the severe combined immune deficient (SCID) mouse, hu‐ man RA synovium is markedly suppressed by tocilizumab treatment in compared with con‐ trol mouse [36].Tocilizumab not only improves clinical symptoms of rheumatoid arthritis, but is also effective in improving pathological findings in rheumatoid arthritis (Figure 8).

**Figure 8.** Typical changes in synovial membrane seen with tocilizumab treatment

Inflammatory cells in synovial membrane are suppressed by tocilizumab and replaced by fi‐ brous tissue or adipose tissue.

## **5. Problems with Biological Agents**

real-world clinical setting has shown an incidence of tuberculosis of 0.22% [32], which is

In comparative studies of related biological agents, almost no difference in efficacy was seen between infliximab and abatacept [33] or between adalimumab and abatacept [34]. Howev‐ er, in a study comparing adalimumab and tocilizumab, tocilizumab was shown to be more

**ATTEST Study AMPLE Study ADACTA Study**

Abatacept + MTX

Tocilizumab

vs. Abatacept

Adalimumab + MTX

vs.

**Result** −2.88 vs.−2.25 (n.s) 64.8% vs. 63.4% (n.s) −3.3 vs. −1.8 (p < 0.0001)

Considered this way, the non-TNF cytokine inhibitor (IL-6 inhibitor) tocilizumab could be a biological agent with greater pharmacological effect than TNF inhibitors with fewer adverse reactions due to tuberculosis if used appropriately. Comparison of TNF and IL-6 shows mostly the same pharmacological effects due to cytokine redundancy. Examples of this in‐ clude the induction of synovial proliferation, induction of inflammatory cytokines, and ar‐

**Primary endpoint** DAS28(ESR) ACR20 DAS28(ESR) **Study period** 1 year 1 year 24 weeks

lower than that of TNF inhibitors.

102 Innovative Rheumatology

effective than adalimumab [35] (Table 2).

**Agents** Abatacept

**Table 2.** Comparative study of related biological agents

ticular destruction.

vs. Infliximab

**Figure 7.** Degree of DAS28 remission with tocilizumab treatment (own data)

Biological agents are a very useful treatment for active rheumatoid arthritis, but there are still many problems which must be solved, including their high cost and the problem of ad‐ verse reactions such as infections. As described in the US recommendation and UK guid‐ ance, they should probably be used in patients who do not obtain symptomatic relief following treatment with DMARDs.

## **Author details**

Hiroaki Matsuno\*

Address all correspondence to: spr845x9@chime.ocn.ne.jp

Matsuno Clinic for Rheumatic Diseases, Japan

## **References**

[1] Maini, R., St Clair, E. W., Breedveld, F., Furst, D., Kalden, J., Weisman, M., et al. (1999). Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. *Lancet*, 354, 1932-9.

[8] Smolen, J. S., Kay, J., Doyle, M. K., Landewe, R., Matteson, E. L., Wollenhaupt, J., et al. (2009). Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, rand‐ omised, double-blind, placebo-controlled, phase III trial. *Lancet*, 374(9685), 210-21.

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**Author details**

104 Innovative Rheumatology

Hiroaki Matsuno\*

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*Rheum*, 54, 26-37.

Address all correspondence to: spr845x9@chime.ocn.ne.jp

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Matsuno Clinic for Rheumatic Diseases, Japan


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[31] Singh, J. A., Noorbaloochi, S., & Singh, G. (2010). Golimumab for rheumatoid arthri‐

[32] Koike, T., Harigai, M., Inokuma, S., Ishiguro, N., Ryu, J., Takeuchi, T., et al. (2011). Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim

[33] Schiff, M., Keiserman, M., Codding, C., Songcharoen, S., Berman, A., Nayiager, S., et al. (2008). Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in pa‐ tients with rheumatoid arthritis and an inadequate response to methotrexate. *Ann*

[34] Schiff, M., Fleischmann, R., Weinblatt, M., Valente, R., van der Heijde, D., Citera, G., et al. (2012). Abatacept SC versus adalimumab on background methotrexate in RA:

[35] Gabay, C., Emery, P., van Vollenhoven, R., Dikranian, A., Alten, R., Klearman, M., et al. (2012). Tocilizumab (TCZ) monotherapy is superior to adalimumab (ADA) mono‐ therapy in reducing disease activity in patients with rheumatoid arthritis (RA): 24-

[36] Matsuno, H., Sawai, T., Nezuka, T., Uzuki, M., Tsuji, H., Nishimoto, N., et al. (1998). Treatment of rheumatoid synovitis with anti-reshaping human interleukin-6 receptor monoclonal antibody: use of rheumatoid arthritis tissue implants in the SCID mouse

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[18] Emery, P., Deodhar, A., Rigby, W. F., Isaacs, JD, Combe, B., Racewicz, A. J., et al. (2010). Efficacy and safety of different doses and retreatment of rituximab: a rando‐ mised, placebo-controlled trial in patients who are biological naive with active rheu‐ matoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)). *Ann Rheum Dis*,

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[28] Potter, C., Hyrich, K. L., Tracey, A., Lunt, M., Plant, D., Symmons, D. P., et al. (2009). Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour

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106 Innovative Rheumatology


**Chapter 6**

**Perioperative Surgical Site Infections and**

**Not, Clinical Dilemma**

http://dx.doi.org/10.5772/54012

**1. Introduction**

ADL of patients with RA.

Koichiro Komiya and Nobuki Terada

Additional information is available at the end of the chapter

**Complications in Elective Orthopedic Surgery in**

**Patients with Rheumatoid Arthritis Treated with Anti-**

**Tumor Necrosis Factor-Alpha Agents − Discontinue or**

Rheumatoid arthritis (RA) is characterized by the destruction of peripheral joints in which articular cartilage and subchondral bone are destroyed by chronic proliferative synovitis. This damage often leads to significant loss of joint function and impairs the

Most patients with RA are in use of traditional disease modifying antirheumatic drugs (DMARDs) to control disease activity, and among the traditional, non-biological DMARDs (nbDMARDs), methotrexate (MTX) is a first line and an anchor drug for the treatment of RA. Currently introduced biologic agents, especially anti-tumor necrosis factor-alpha (TNFα) agents, have revolutionized the treatment of RA. TNF-α triggers the inflammatory cas‐ cade and stimulates the production of matrix degradable proteinases such as matrix metalloproteinases, which well known to play a major role in the proteolytic degradation of extracellular matrix macromolecules of cartilage and bone, which is a key step in joint de‐ struction in RA. Anti-TNF-α agents are now in routine use for RA patients who have failed to respond to nbDMARDs, and have been demonstrated to improve the clinical symptoms and delay joint destruction dramatically. Unfortunately, despite of the administration of nbDMARDs and/or biologic agents, complete prevention of the destruction of the affected joints is still not achieved. Over the course of their lifetime, many patients with RA may re‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Komiya and Terada; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, **Perioperative Surgical Site Infections and Complications in Elective Orthopedic Surgery in Patients with Rheumatoid Arthritis Treated with Anti-Tumor Necrosis Factor-Alpha Agents − Discontinue or Not, Clinical Dilemma**

Koichiro Komiya and Nobuki Terada

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54012

## **1. Introduction**

Rheumatoid arthritis (RA) is characterized by the destruction of peripheral joints in which articular cartilage and subchondral bone are destroyed by chronic proliferative synovitis. This damage often leads to significant loss of joint function and impairs the ADL of patients with RA.

Most patients with RA are in use of traditional disease modifying antirheumatic drugs (DMARDs) to control disease activity, and among the traditional, non-biological DMARDs (nbDMARDs), methotrexate (MTX) is a first line and an anchor drug for the treatment of RA. Currently introduced biologic agents, especially anti-tumor necrosis factor-alpha (TNFα) agents, have revolutionized the treatment of RA. TNF-α triggers the inflammatory cas‐ cade and stimulates the production of matrix degradable proteinases such as matrix metalloproteinases, which well known to play a major role in the proteolytic degradation of extracellular matrix macromolecules of cartilage and bone, which is a key step in joint de‐ struction in RA. Anti-TNF-α agents are now in routine use for RA patients who have failed to respond to nbDMARDs, and have been demonstrated to improve the clinical symptoms and delay joint destruction dramatically. Unfortunately, despite of the administration of nbDMARDs and/or biologic agents, complete prevention of the destruction of the affected joints is still not achieved. Over the course of their lifetime, many patients with RA may re‐

© 2013 Komiya and Terada; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

quire orthopaedic surgical interventions, such as total joint arthroplasty (TJA), arthrodeis, reconstructive surgeries, cervical stabilization, and so on.

rate [7]. In fact, infections requiring hospitalization were significantly more frequent in RA patients (9.57/100 person-years) than in non-RA patients (5.09/100 person-years) with rate ratio 1.88 (95% CI 1.71-2.07), and SA was also associated with a highest rate ratio of 21.66

Perioperative Surgical Site Infections and Complications in Elective Orthopedic Surgery in Patients with...

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111

Accumulated data indicate that the risk factors for SA are increasing age, comorbidities (dia‐ betes mellitus, chronic renal failure, chronic cardiac failure), joint prosthesis, skin infection and pre-existing joint damage [1, 8-10], but whether RA treatment with nbDMARDs, corti‐ costeroids and biologics including anti-TNF-α agents increases the risk of SA is still unclear. DMARDs and biologics including anti-TNF-α agents are generally believed to be immuno‐ suppressive and likely to increase the incidence of SA in patients with RA. But the data on these are very limited and sparse. Edwards et al. [1] performed a retrospective study using the United Kingdom General Practice Research Database to analyze the effect of DMARDs on developing SA in patients with RA. There was significantly increased risk of SA in indi‐ viduals with RA prescribed DMARDs compared with those not prescribed DMARDs. The incidence rate ratios (IRR) for developing SA in the patients receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjust‐ ed IRR 2.51, 95% CI 1.29-4.89, *P*=0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04-2.91, *P*=0.03) and prednisolone (adjusted IRR 2.94, 95% CI 1.93-4.46, *P*<0.001) were associated with an increased incidence of SA when compared with receiving no DMARDs [1]. The use of other DMARDs (including MTX) not showed such effect [1]. There was a number of individ‐ uals with RA developed SA without receiving DMARDs, thus they considered that the im‐ mune dysfunction associated with RA and the coexistent joint damage are more important

There is very limited information regarding the effect of anti-TNF-α therapy on the risk of SA. Galloway et al. [11] conducted a prospective observational study to evaluate the risk of SA in patients with RA treated with anti-TNF-α agents. They reported that incidence rates for SA were anti-TNF 4.2/1000/patient years (95% CI 3.6-4.8) and nbDMARDs 1.8/1000/ pa‐ tient years (95% CI 1.1-2.7). The adjusted hazard ratio (HR) for SA in the anti-TNF cohort was 2.3 (95% CI 1.2-4.4). The risk did not differ significantly between the three agents: inflix‐ imab (IFX), etanercept (ETN) and adalimumab (ADA). The hazard for SA in the anti-TNF cohort was greatest in the early months of therapy, as well as data from other cohorts [12], and the risk then decreased steadily over the remainder of the follow-up period [11]. One of the potential explanations for early increased risk is that it may reflect a true reduction in

In summary of this section, patients with RA are at an increased risk of SA irrespective of therapy. Some DMARDs and corticosteroid increase the risk of SA. Exposure to anti-TNF therapy is also associated with an increased risk of SA and this risk was greatest in the first year of treatment. Thus, this increased risk of SA in RA may be due to not only as a conse‐ quence of the disease nature of RA but also treatment with some immunomodulatory agents. Current evidence does not support any one anti-TNF agent having a safer profile

risk factors than immunomodulatory therapies with DMARDs [1].

risk of joint infection in patients who achieve better control of their RA [11].

(95% CI 7.37-257.61)] [4].

with regard to SA.

For orthopaedic surgeons, post-operative surgical site infections (SSI) and delayed wound healing are major concerns, especially in TJA. Prosthetic infection is associated with pro‐ longed antibacterial therapy and hospitalization, functional decline, depression, shorter prosthesis durability, which have great impact on morbidity, mortality and quality of life. The baseline infection risk is increased 13-fold in individuals with RA when compared with the general population [1]. In addition, receiving anti-TNF-α agents showed an increased risk of serious infections. Delayed wound healing or wound dehiscence is also believed to occur more frequently in patients with RA. Patients with RA are already predisposed to im‐ paired wound healing as a result of reduction in skin thickness above that which is due to steroid use. Furthermore TNF-α is required for normal wound healing, and in experimental settings anti-TNF-α has been linked to poor wound healing [2]. Thus careful management of anti-rheumatic agents and their adverse effects in a perioperative period is essential. Among nbDMARDs, only MTX has been investigated prospectively and randomized manner, and demonstrated that continuation of MTX treatment did not increase the risk of either infec‐ tions or surgical complications in elective orthopaedic surgery in patients with RA [3]. As for biologic anti-TNF-α agents, current national guidelines suggested that treatment with bi‐ ologic agents should be discontinued during the perioperative period. Although discontinu‐ ation of anti-TNF-α agents during the perioperative period may have a positive effect on SSI and wound healing rates, but this is at the expense of increased risk of RA flare that could affect postoperative rehabilitation. However, there are no prospective clinical trials and few studies assessing the use of anti-TNF-α agents during the perioperative periods in RA pa‐ tients undergoing elective orthopaedic surgery. In this chapter, we review the available liter‐ ature related to perioperative complications, especially SSI, delayed wound healing and RA flare in elective orthopaedic surgery in patients with RA treated with anti-TNF-α agents, and discuss the perioperative management of anti-TNF-α agents, the clinical dilemma whether discontinue or not.

## **2. Risk of septic arthritis (SA) in RA patients**

Individuals with RA are at an inherently increased risk of infection [1, 4]. Edwards et al. [1] reported that the incidence rate for SA was 12.9 times higher in subjects with RA than those without [95% confidence interval (CI) 10.1-16.5]. Doran et al. [4] performed a retrospective longitudinal cohort study and reported that the overall rate of infection per 100 person-years was higher in RA patients (19.64) than in non-RA patients (12.87), and the rate ratio for de‐ veloping infections in patients with RA was 1.53 (95% CI 1.41-1.65). Infection sites that were associated with the highest rate ratio were the joints (rate ratio for SA 14.89 [95% CI 6.12-73.71]), bone (rate ratio for osteomyelitis 10.63 [95% CI 3.39-126.81]), and skin and soft tissues (rate ratio 3.28 [95% CI 2.67-4.07]) [4]. SA is a serious and severe condition for pa‐ tients that can lead to irreversible joint destruction, and the incidence of SA in the general population is around 4-10/100,000/person-years [5, 6]. SA is lethal around 10% of a death rate [7]. In fact, infections requiring hospitalization were significantly more frequent in RA patients (9.57/100 person-years) than in non-RA patients (5.09/100 person-years) with rate ratio 1.88 (95% CI 1.71-2.07), and SA was also associated with a highest rate ratio of 21.66 (95% CI 7.37-257.61)] [4].

quire orthopaedic surgical interventions, such as total joint arthroplasty (TJA), arthrodeis,

For orthopaedic surgeons, post-operative surgical site infections (SSI) and delayed wound healing are major concerns, especially in TJA. Prosthetic infection is associated with pro‐ longed antibacterial therapy and hospitalization, functional decline, depression, shorter prosthesis durability, which have great impact on morbidity, mortality and quality of life. The baseline infection risk is increased 13-fold in individuals with RA when compared with the general population [1]. In addition, receiving anti-TNF-α agents showed an increased risk of serious infections. Delayed wound healing or wound dehiscence is also believed to occur more frequently in patients with RA. Patients with RA are already predisposed to im‐ paired wound healing as a result of reduction in skin thickness above that which is due to steroid use. Furthermore TNF-α is required for normal wound healing, and in experimental settings anti-TNF-α has been linked to poor wound healing [2]. Thus careful management of anti-rheumatic agents and their adverse effects in a perioperative period is essential. Among nbDMARDs, only MTX has been investigated prospectively and randomized manner, and demonstrated that continuation of MTX treatment did not increase the risk of either infec‐ tions or surgical complications in elective orthopaedic surgery in patients with RA [3]. As for biologic anti-TNF-α agents, current national guidelines suggested that treatment with bi‐ ologic agents should be discontinued during the perioperative period. Although discontinu‐ ation of anti-TNF-α agents during the perioperative period may have a positive effect on SSI and wound healing rates, but this is at the expense of increased risk of RA flare that could affect postoperative rehabilitation. However, there are no prospective clinical trials and few studies assessing the use of anti-TNF-α agents during the perioperative periods in RA pa‐ tients undergoing elective orthopaedic surgery. In this chapter, we review the available liter‐ ature related to perioperative complications, especially SSI, delayed wound healing and RA flare in elective orthopaedic surgery in patients with RA treated with anti-TNF-α agents, and discuss the perioperative management of anti-TNF-α agents, the clinical dilemma

Individuals with RA are at an inherently increased risk of infection [1, 4]. Edwards et al. [1] reported that the incidence rate for SA was 12.9 times higher in subjects with RA than those without [95% confidence interval (CI) 10.1-16.5]. Doran et al. [4] performed a retrospective longitudinal cohort study and reported that the overall rate of infection per 100 person-years was higher in RA patients (19.64) than in non-RA patients (12.87), and the rate ratio for de‐ veloping infections in patients with RA was 1.53 (95% CI 1.41-1.65). Infection sites that were associated with the highest rate ratio were the joints (rate ratio for SA 14.89 [95% CI 6.12-73.71]), bone (rate ratio for osteomyelitis 10.63 [95% CI 3.39-126.81]), and skin and soft tissues (rate ratio 3.28 [95% CI 2.67-4.07]) [4]. SA is a serious and severe condition for pa‐ tients that can lead to irreversible joint destruction, and the incidence of SA in the general population is around 4-10/100,000/person-years [5, 6]. SA is lethal around 10% of a death

reconstructive surgeries, cervical stabilization, and so on.

110 Innovative Rheumatology

whether discontinue or not.

**2. Risk of septic arthritis (SA) in RA patients**

Accumulated data indicate that the risk factors for SA are increasing age, comorbidities (dia‐ betes mellitus, chronic renal failure, chronic cardiac failure), joint prosthesis, skin infection and pre-existing joint damage [1, 8-10], but whether RA treatment with nbDMARDs, corti‐ costeroids and biologics including anti-TNF-α agents increases the risk of SA is still unclear. DMARDs and biologics including anti-TNF-α agents are generally believed to be immuno‐ suppressive and likely to increase the incidence of SA in patients with RA. But the data on these are very limited and sparse. Edwards et al. [1] performed a retrospective study using the United Kingdom General Practice Research Database to analyze the effect of DMARDs on developing SA in patients with RA. There was significantly increased risk of SA in indi‐ viduals with RA prescribed DMARDs compared with those not prescribed DMARDs. The incidence rate ratios (IRR) for developing SA in the patients receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjust‐ ed IRR 2.51, 95% CI 1.29-4.89, *P*=0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04-2.91, *P*=0.03) and prednisolone (adjusted IRR 2.94, 95% CI 1.93-4.46, *P*<0.001) were associated with an increased incidence of SA when compared with receiving no DMARDs [1]. The use of other DMARDs (including MTX) not showed such effect [1]. There was a number of individ‐ uals with RA developed SA without receiving DMARDs, thus they considered that the im‐ mune dysfunction associated with RA and the coexistent joint damage are more important risk factors than immunomodulatory therapies with DMARDs [1].

There is very limited information regarding the effect of anti-TNF-α therapy on the risk of SA. Galloway et al. [11] conducted a prospective observational study to evaluate the risk of SA in patients with RA treated with anti-TNF-α agents. They reported that incidence rates for SA were anti-TNF 4.2/1000/patient years (95% CI 3.6-4.8) and nbDMARDs 1.8/1000/ pa‐ tient years (95% CI 1.1-2.7). The adjusted hazard ratio (HR) for SA in the anti-TNF cohort was 2.3 (95% CI 1.2-4.4). The risk did not differ significantly between the three agents: inflix‐ imab (IFX), etanercept (ETN) and adalimumab (ADA). The hazard for SA in the anti-TNF cohort was greatest in the early months of therapy, as well as data from other cohorts [12], and the risk then decreased steadily over the remainder of the follow-up period [11]. One of the potential explanations for early increased risk is that it may reflect a true reduction in risk of joint infection in patients who achieve better control of their RA [11].

In summary of this section, patients with RA are at an increased risk of SA irrespective of therapy. Some DMARDs and corticosteroid increase the risk of SA. Exposure to anti-TNF therapy is also associated with an increased risk of SA and this risk was greatest in the first year of treatment. Thus, this increased risk of SA in RA may be due to not only as a conse‐ quence of the disease nature of RA but also treatment with some immunomodulatory agents. Current evidence does not support any one anti-TNF agent having a safer profile with regard to SA.

## **3. Risk of SSI in RA patients undergoing TJA**

TJA is a major orthopaedic procedure for destructed joints. In RA, total knee arthroplasty (TKA) and total hip arthroplasty (THA) are the most common, promised surgical interventions for pa‐ tients to recover from painful joints and impaired activities of daily life. However, prosthetic joint infection often requires revision of the infected prosthesis and prolonged intravenous anti‐ microbial therapy, and has a mortality rate of 2.7-18% [13]. Patients with RA have been identi‐ fied to have a higher baseline risk of infectious diseases compared with general population. In addition, the immunosuppressive drugs used in the treatment of RA may further increase the risk of infection. Whether this increased baseline risk of infections in RA patients might influ‐ ence the risk of deep infection after primary TJA is somewhat conflicting.

1.87-16.14), and operation time (HR 1.36 per 60-minitue increase, 95% CI 1.02-1.81) were sig‐ nificant predictors of postoperative prosthetic joint infection. Based on the pharmacokinetic half-life and/or data on the biologic activity of each DMARD, perioperative DMARDs use was judged as either withheld or maintained. DMARDs were withheld perioperatively in 57% of procedures and stopping DMARDs therapy at the time of surgery lowered the risk of prosthesis infection (HR 0.65, 95% CI 0.09-4.95), but this was statistically not significant. There were 3 prosthesis infections in 38 patients who were treated with anti-TNF agents at the time of surgery as compared with no infection in 12 patients who stopped their anti-TNF therapy prior to surgery, but this difference was not statistically significant. Perioperative

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corticosteroid use was not associated with an increased risk of prosthesis infection.

roids was not a significant risk factor.

not analyzed in this study.

Besides DMARDs, the risk of perioperative use of corticosteroids for prosthetic infection in patients with RA is controversial. Berbari et al. [18] conducted a case-control study to deter‐ mine risk factors for the development of prosthetic joint infection. 462 episodes of prosthetic joint infection in 460 patients were used for analysis. Univariate analysis identified that RA, steroid therapy as risk factors for joint prosthetic infection with odds ratio (OR) of 2.0 (95% CI 1.3-3.0) and 2.0 (95% CI 1.3-3.1) respectively. Wilson et al. [19] reported that 67 (1.6%) out of the 4,171 TKA were complicated by infection. The incidence of infection in RA patients (2.2%; 45/2076) was significantly higher than in OA (1%; 16/1857) (*P*<0.0001). Despite the fact that a higher percentage of patients who had RA and infection had used steroids than had those who did not have an infection (75% compared with 46%), a history of oral use of ste‐

While most of papers agreed with increased risk of prosthetic infection in RA patients, da Cunha et al. [20] conducted a retrospective study to compare the incidence of infections be‐ tween RA and OA patients in THA and TKA, and reported that no significant difference was observed between the RA and OA groups regarding the rates of prosthesis infections (TKA 7.1% vs. 0% and THA 2.1% vs. 0%, respectively, both with *P*>0.1), incisional infections (TKA 14.3% vs. 3.3% and THA 4.3% vs. 1.3%, respectively, both with *P*>0.1), and systematic infections (TKA 7.1% vs. 3.6%, *P*=0.92 and THA 4.3% vs. 10.7%, *P*>0.1, respectively). They concluded that RA was not identified as a risk factor for perioperative infections in THA and TKA in their case series. The low incidence of infections in both groups may explain their findings. Although the data on usage and mean dose of DMARDs, biologics and corti‐ costeroids were reported, the association between prosthesis infection and these drugs were

Whether the use of nbDMARDs constitutes an independent risk factor for SSI remains un‐ clear. Among nbDMARDs, only MTX had been investigated in a prospective and random‐ ized study. Grennan et al. [3] reported that signs of infection or surgical complications occurred in two of 88 procedures (2%) in the group of MTX continuation, 11 of 72 proce‐ dures (15%) in the group of MTX discontinuation, and 24 of 228 procedures (10.5%) in the MTX naïve group. Furthermore, accumulated data support the perioperative use of MTX, and international 3E Initiative stated in the recommendation that MTX can be safely contin‐ ued in the perioperative period in RA patients undergoing elective orthopaedic surgery [21].

Wymenga et al. [14] conducted a multicenter prospective study to investigate the association between perioperative factors and SA after TKA and THA. At 1-year follow up, 9/362 pa‐ tients (2.5%) after TKA and 17/2651 patients (0.64%) after THA were completed by SA. They reported that RA was a risk factor for SA for TKA (risk ratio 4.8; 95% CI 1.2-19), but they could not confirm this in THA. Schrama et al. [15] reported a retrospective study using the Norwegian Arthroplasty Register to examine the risk of revision arthroplasty due to infec‐ tion in RA (6,629 procedures) compared with OA patients (102,157 procedures). The inci‐ dence of revision due to infection in TKA and THA were 0.7% (176/24,294 procedures) and 0.6% (534/84,492 procedures), respectively. The risk of revision for infection in RA patients with TKA was 1.6 (95% CI 1.06-2.38) times higher compared to OA patients, but there were no difference in THA. This discrepancy between TKA and THA were also reported by Wy‐ menga et al. [14], and Schrama et al. mentioned that the vulnerable soft tissue envelope around the knee joint could make the TKA in RA patients more susceptible to infection, since the connective tissue disease RA and its potentially immunomodulating medication are risk factors for skin and soft tissue infections. Jamsen et al. [16] analyzed primary (40,135 procedures) and revision (3,014 procedures) knee arthroplasties in a large series of knee ar‐ throplasties from Finnish Arthroplasty Register. In total, 387 reoperations were performed for the treatment of infection (0.90%; 95% CI 0.81-0.99). The adjusted HR for reoperation due to infection in primary and revision TKA in patients with RA were 1.86 (95% CI 1.31-2.63) and 1.01 (95% CI 0.44-2.34) compared with primary OA, respectively. Robertsson et al. [17] also reported using another large series of knee arthroplasties, the Swedish Knee Arthro‐ plasty Register that the risk of revision for infection was significantly higher in RA patients compared to OA patients [risk ratio (RR) 1.4; 95% CI 1.1-1.9]. The data on influences of nbDMARDs on the risk of prosthetic infection in patients with RA were absent in these studies [14-17].

Bongartz et al. [13] conducted a retrospective study using the Mayo Clinic Total Joint Regis‐ try to examine the incidence and risk factors of prosthetic joint infection in RA patients (657 procedures; THA or TKA). 23 (3.7%) joint arthroplasties were complicated by infection. The risk of prosthetic joint infections were increased in RA patients (HR 4.08, 95% CI 1.35-12.33) compared with a matched cohort of OA patients. Revision arthroplasty (HR 2.99, 95% CI 1.02-8.75), previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI 1.87-16.14), and operation time (HR 1.36 per 60-minitue increase, 95% CI 1.02-1.81) were sig‐ nificant predictors of postoperative prosthetic joint infection. Based on the pharmacokinetic half-life and/or data on the biologic activity of each DMARD, perioperative DMARDs use was judged as either withheld or maintained. DMARDs were withheld perioperatively in 57% of procedures and stopping DMARDs therapy at the time of surgery lowered the risk of prosthesis infection (HR 0.65, 95% CI 0.09-4.95), but this was statistically not significant. There were 3 prosthesis infections in 38 patients who were treated with anti-TNF agents at the time of surgery as compared with no infection in 12 patients who stopped their anti-TNF therapy prior to surgery, but this difference was not statistically significant. Perioperative corticosteroid use was not associated with an increased risk of prosthesis infection.

**3. Risk of SSI in RA patients undergoing TJA**

112 Innovative Rheumatology

studies [14-17].

ence the risk of deep infection after primary TJA is somewhat conflicting.

TJA is a major orthopaedic procedure for destructed joints. In RA, total knee arthroplasty (TKA) and total hip arthroplasty (THA) are the most common, promised surgical interventions for pa‐ tients to recover from painful joints and impaired activities of daily life. However, prosthetic joint infection often requires revision of the infected prosthesis and prolonged intravenous anti‐ microbial therapy, and has a mortality rate of 2.7-18% [13]. Patients with RA have been identi‐ fied to have a higher baseline risk of infectious diseases compared with general population. In addition, the immunosuppressive drugs used in the treatment of RA may further increase the risk of infection. Whether this increased baseline risk of infections in RA patients might influ‐

Wymenga et al. [14] conducted a multicenter prospective study to investigate the association between perioperative factors and SA after TKA and THA. At 1-year follow up, 9/362 pa‐ tients (2.5%) after TKA and 17/2651 patients (0.64%) after THA were completed by SA. They reported that RA was a risk factor for SA for TKA (risk ratio 4.8; 95% CI 1.2-19), but they could not confirm this in THA. Schrama et al. [15] reported a retrospective study using the Norwegian Arthroplasty Register to examine the risk of revision arthroplasty due to infec‐ tion in RA (6,629 procedures) compared with OA patients (102,157 procedures). The inci‐ dence of revision due to infection in TKA and THA were 0.7% (176/24,294 procedures) and 0.6% (534/84,492 procedures), respectively. The risk of revision for infection in RA patients with TKA was 1.6 (95% CI 1.06-2.38) times higher compared to OA patients, but there were no difference in THA. This discrepancy between TKA and THA were also reported by Wy‐ menga et al. [14], and Schrama et al. mentioned that the vulnerable soft tissue envelope around the knee joint could make the TKA in RA patients more susceptible to infection, since the connective tissue disease RA and its potentially immunomodulating medication are risk factors for skin and soft tissue infections. Jamsen et al. [16] analyzed primary (40,135 procedures) and revision (3,014 procedures) knee arthroplasties in a large series of knee ar‐ throplasties from Finnish Arthroplasty Register. In total, 387 reoperations were performed for the treatment of infection (0.90%; 95% CI 0.81-0.99). The adjusted HR for reoperation due to infection in primary and revision TKA in patients with RA were 1.86 (95% CI 1.31-2.63) and 1.01 (95% CI 0.44-2.34) compared with primary OA, respectively. Robertsson et al. [17] also reported using another large series of knee arthroplasties, the Swedish Knee Arthro‐ plasty Register that the risk of revision for infection was significantly higher in RA patients compared to OA patients [risk ratio (RR) 1.4; 95% CI 1.1-1.9]. The data on influences of nbDMARDs on the risk of prosthetic infection in patients with RA were absent in these

Bongartz et al. [13] conducted a retrospective study using the Mayo Clinic Total Joint Regis‐ try to examine the incidence and risk factors of prosthetic joint infection in RA patients (657 procedures; THA or TKA). 23 (3.7%) joint arthroplasties were complicated by infection. The risk of prosthetic joint infections were increased in RA patients (HR 4.08, 95% CI 1.35-12.33) compared with a matched cohort of OA patients. Revision arthroplasty (HR 2.99, 95% CI 1.02-8.75), previous prosthetic joint infection of the replaced joint (HR 5.49, 95% CI Besides DMARDs, the risk of perioperative use of corticosteroids for prosthetic infection in patients with RA is controversial. Berbari et al. [18] conducted a case-control study to deter‐ mine risk factors for the development of prosthetic joint infection. 462 episodes of prosthetic joint infection in 460 patients were used for analysis. Univariate analysis identified that RA, steroid therapy as risk factors for joint prosthetic infection with odds ratio (OR) of 2.0 (95% CI 1.3-3.0) and 2.0 (95% CI 1.3-3.1) respectively. Wilson et al. [19] reported that 67 (1.6%) out of the 4,171 TKA were complicated by infection. The incidence of infection in RA patients (2.2%; 45/2076) was significantly higher than in OA (1%; 16/1857) (*P*<0.0001). Despite the fact that a higher percentage of patients who had RA and infection had used steroids than had those who did not have an infection (75% compared with 46%), a history of oral use of ste‐ roids was not a significant risk factor.

While most of papers agreed with increased risk of prosthetic infection in RA patients, da Cunha et al. [20] conducted a retrospective study to compare the incidence of infections be‐ tween RA and OA patients in THA and TKA, and reported that no significant difference was observed between the RA and OA groups regarding the rates of prosthesis infections (TKA 7.1% vs. 0% and THA 2.1% vs. 0%, respectively, both with *P*>0.1), incisional infections (TKA 14.3% vs. 3.3% and THA 4.3% vs. 1.3%, respectively, both with *P*>0.1), and systematic infections (TKA 7.1% vs. 3.6%, *P*=0.92 and THA 4.3% vs. 10.7%, *P*>0.1, respectively). They concluded that RA was not identified as a risk factor for perioperative infections in THA and TKA in their case series. The low incidence of infections in both groups may explain their findings. Although the data on usage and mean dose of DMARDs, biologics and corti‐ costeroids were reported, the association between prosthesis infection and these drugs were not analyzed in this study.

Whether the use of nbDMARDs constitutes an independent risk factor for SSI remains un‐ clear. Among nbDMARDs, only MTX had been investigated in a prospective and random‐ ized study. Grennan et al. [3] reported that signs of infection or surgical complications occurred in two of 88 procedures (2%) in the group of MTX continuation, 11 of 72 proce‐ dures (15%) in the group of MTX discontinuation, and 24 of 228 procedures (10.5%) in the MTX naïve group. Furthermore, accumulated data support the perioperative use of MTX, and international 3E Initiative stated in the recommendation that MTX can be safely contin‐ ued in the perioperative period in RA patients undergoing elective orthopaedic surgery [21].

In summary of this section, most of studies support the increased prevalence of TJA infec‐ tion in RA patients. Among nbDMARDs, only MTX had been intensively investigated the influences of the perioperative use on the risk of SSI, and accumulated data support the safe‐ ty of perioperative continuation of MTX undergoing elective orthopaedic surgery. We should be aware that TJA in RA patients is high-risk in infection and sufficient antibiotic prophylaxis should be taken with a careful follow-up.

an increase in SSI rates (OR 1.5, 95% CI 0.43-5.2, *P*=0.43). However, wound dehiscence occur‐ red more frequently in patients that continued anti-TNF compared to patients that tempora‐

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Bongartz et al. [13] conducted a retrospective, single-center, double cohort study that includ‐ ed all patients with RA who underwent THA or TKA at the Mayo Clinic Rochester between January 1996 and June 2004. 657 surgeries in 462 patients with RA were identified. There were 3 prosthesis infections in 38 patients who were treated with anti-TNF agents at the time of surgery as compared with no infection in 12 patients who stopped their anti-TNF

Secondary, we take up 7 studies which compare the perioperative risk of infection between

Bibbo et al. [25] reported a 12-month prospective study that compared foot and ankle sur‐ gery in 16 RA patients (mean age 50 years) on TNF blockers (group 1) (IFX; 5, ETN; 11) com‐ pared with 15 controls (mean age 60 years) on nbDMARDs (group 2). Patients on TNF blockers discontinued treatment prior to surgery (ETN; mean 2.6 days, IFX; mean 20.2 days) and resumed treatment postoperatively. Infectious complications occurred in two patients: one case of a superficial infection in a group 1 patient and one case of a deep infection (os‐ teomyelitis) in a group 2 patient. Delayed wound healing occurred in three patients, all oc‐ curred in group 2. Bone healing complications occurred in three patients, all in group 2, comprised of two nonunions and one delayed union. When considered individually, the oc‐ currence of an infectious or healing complication proved to be statistically similar between groups 1 and 2. However, when complications summed (infectious and healing complica‐ tions), group 2 demonstrated a statistically higher overall complication rate (*P*=0.033, Fish‐ er's exact test). They concluded that the use of TNF blockers may be safely undertaken in the perioperative period without increasing the risk of infectious or healing complications in the

Hirano et al. [26] performed retrospective cohort study where adverse events of surgical wounds were compared between patients treated with TNF blockers (n=39) (IFX; 24, ETN; 15) and those on nbDMARDs (n=74). TKA is the commonest surgery followed by THA. Ad‐ ministration of TNF blockers was stopped prior to surgeries (IFX; mean 29.8 days, ETN; mean 9.6 days) and restarted after surgical wounds were completely healed. Adverse events of surgical wounds occurred after two operations in the TNF group (5.1%) and five opera‐ tions in the nbDMARDs group (6.8%), which was not statistically significant difference by Fisher's exact test (*P*=1.0000). OR was 0.7459 (95% CI 0.1380-4.0336). Although most of ad‐ verse events of surgical wounds were wound dehiscence and continuation of discharge, postoperative infection occurred in one TKA in the TNF group. They concluded that the use of anti-TNF agents dose dot cause specific adverse events on surgical wounds after elective

Kawakami et al. [27] performed a retrospective case-control study to identify perioperative complications associated the use of TNF blockers. RA patients on anti-TNF (64 procedures/49 patients) were compared to those on nbDMARDs (64 procedures/63 patients).

therapy prior to surgery. However, the result did not reach statistical significance.

rily discontinued anti-TNF treatment (OR 11.2, 95% CI 1.4-90).

patients on TNF blockers and those on nbDMARDs.

patients with RA undergoing elective foot and ankle surgery.

orthopedic surgeries in RA patients.

## **4. Risk of SSI in RA patients treated with anti-TNF-α agents undergoing orthopaedic surgery**

The information about the risk of SSI in RA patients treated with anti-TNF-α agents undergoing orthopedic surgery is very limited, and to date, there are only 14 studies on this matter.

We at first take up 4 studies those analyzed whether continuation of TNF blockers in perio‐ perative period increases the risk of SSI in patients on anti-TNF therapy.

Talwalker et al. [22] performed a small retrospective study. 16 procedures in 11 patients (RA; n=10, psoriatic arthritis; n=1) on anti-TNF undergoing elective joint surgery were reviewed. TNF blockers were continued in group A (4 procedures), while in group B (12 procedures), they were withheld before surgery and restarted after the procedure. In group A, IFX was used in one operation, the patient receiving the injection 3 days before surgery while ETN was used in three patients. In group B, IFX was stopped nearly 4 weeks before surgery, whereas ADA and ETN was stopped at 2 weeks. The timings for restarting the drug were variable. Postoperative‐ ly, none of the patients in either group developed serious wound and systematic infections, but one flare up occurred in a patient receiving ETN in group B.

Wendling et al. [23] conducted a retrospective study with a sample size of 50 surgical proce‐ dures (foot and ankle; 13, hand and wrist; 11, TJA; 12, others; 14) in 30 patients with RA treated with TNF blockers. TNF blockers at the time of surgery was IFX (n=26), ETN (n=13), ADA (n=11), with a mean exposure of 12.1 months (range 1-42). TNF blockers were with‐ held before surgery in 18/50 patients, and for the rest, surgery was performed between two TNF blocker injections. Postoperatively, no infections occurred in either group whether TNF blocker was discontinued or not, but RA flares were observed in 6 cases (12%) and signifi‐ cantly associated with anti-TNF interruption before surgery (5 interruptions/6 cases of flare vs. 13 interruption/44 surgical procedures without flare; Fisher's exact value=0.02).

Den Broeder et al. [24] performed a large retrospective study. Two parallel cohorts were de‐ fined: cohort 1 did not use anti-TNF, cohort 2 used anti-TNF but had either stopped (2A) or continued anti-TNF preoperatively (2B), the cutoff point being set at 4 times the half-life time of the drug. In total, 1,219 procedures were performed (wrist/hand; 317, ankle/foot; 280, knee; 195, hip; 172, shoulder; 114, elbow; 102, other; 39). Crude infection risk in cohorts 1, 2A, and 2B were 4.0% (41/1023), 5.8% (6/104), and 8.7% (8/92), respectively. History of prior SSI or skin infection was found to be the strongest predictor for SSI (OR 13.8, 95% CI 5.2-36.7, *P*<0.0001), but perioperative use of anti-TNF was not significantly associated with an increase in SSI rates (OR 1.5, 95% CI 0.43-5.2, *P*=0.43). However, wound dehiscence occur‐ red more frequently in patients that continued anti-TNF compared to patients that tempora‐ rily discontinued anti-TNF treatment (OR 11.2, 95% CI 1.4-90).

In summary of this section, most of studies support the increased prevalence of TJA infec‐ tion in RA patients. Among nbDMARDs, only MTX had been intensively investigated the influences of the perioperative use on the risk of SSI, and accumulated data support the safe‐ ty of perioperative continuation of MTX undergoing elective orthopaedic surgery. We should be aware that TJA in RA patients is high-risk in infection and sufficient antibiotic

**4. Risk of SSI in RA patients treated with anti-TNF-α agents undergoing**

The information about the risk of SSI in RA patients treated with anti-TNF-α agents undergoing

We at first take up 4 studies those analyzed whether continuation of TNF blockers in perio‐

Talwalker et al. [22] performed a small retrospective study. 16 procedures in 11 patients (RA; n=10, psoriatic arthritis; n=1) on anti-TNF undergoing elective joint surgery were reviewed. TNF blockers were continued in group A (4 procedures), while in group B (12 procedures), they were withheld before surgery and restarted after the procedure. In group A, IFX was used in one operation, the patient receiving the injection 3 days before surgery while ETN was used in three patients. In group B, IFX was stopped nearly 4 weeks before surgery, whereas ADA and ETN was stopped at 2 weeks. The timings for restarting the drug were variable. Postoperative‐ ly, none of the patients in either group developed serious wound and systematic infections, but

Wendling et al. [23] conducted a retrospective study with a sample size of 50 surgical proce‐ dures (foot and ankle; 13, hand and wrist; 11, TJA; 12, others; 14) in 30 patients with RA treated with TNF blockers. TNF blockers at the time of surgery was IFX (n=26), ETN (n=13), ADA (n=11), with a mean exposure of 12.1 months (range 1-42). TNF blockers were with‐ held before surgery in 18/50 patients, and for the rest, surgery was performed between two TNF blocker injections. Postoperatively, no infections occurred in either group whether TNF blocker was discontinued or not, but RA flares were observed in 6 cases (12%) and signifi‐ cantly associated with anti-TNF interruption before surgery (5 interruptions/6 cases of flare

Den Broeder et al. [24] performed a large retrospective study. Two parallel cohorts were de‐ fined: cohort 1 did not use anti-TNF, cohort 2 used anti-TNF but had either stopped (2A) or continued anti-TNF preoperatively (2B), the cutoff point being set at 4 times the half-life time of the drug. In total, 1,219 procedures were performed (wrist/hand; 317, ankle/foot; 280, knee; 195, hip; 172, shoulder; 114, elbow; 102, other; 39). Crude infection risk in cohorts 1, 2A, and 2B were 4.0% (41/1023), 5.8% (6/104), and 8.7% (8/92), respectively. History of prior SSI or skin infection was found to be the strongest predictor for SSI (OR 13.8, 95% CI 5.2-36.7, *P*<0.0001), but perioperative use of anti-TNF was not significantly associated with

vs. 13 interruption/44 surgical procedures without flare; Fisher's exact value=0.02).

orthopedic surgery is very limited, and to date, there are only 14 studies on this matter.

perative period increases the risk of SSI in patients on anti-TNF therapy.

one flare up occurred in a patient receiving ETN in group B.

prophylaxis should be taken with a careful follow-up.

**orthopaedic surgery**

114 Innovative Rheumatology

Bongartz et al. [13] conducted a retrospective, single-center, double cohort study that includ‐ ed all patients with RA who underwent THA or TKA at the Mayo Clinic Rochester between January 1996 and June 2004. 657 surgeries in 462 patients with RA were identified. There were 3 prosthesis infections in 38 patients who were treated with anti-TNF agents at the time of surgery as compared with no infection in 12 patients who stopped their anti-TNF therapy prior to surgery. However, the result did not reach statistical significance.

Secondary, we take up 7 studies which compare the perioperative risk of infection between patients on TNF blockers and those on nbDMARDs.

Bibbo et al. [25] reported a 12-month prospective study that compared foot and ankle sur‐ gery in 16 RA patients (mean age 50 years) on TNF blockers (group 1) (IFX; 5, ETN; 11) com‐ pared with 15 controls (mean age 60 years) on nbDMARDs (group 2). Patients on TNF blockers discontinued treatment prior to surgery (ETN; mean 2.6 days, IFX; mean 20.2 days) and resumed treatment postoperatively. Infectious complications occurred in two patients: one case of a superficial infection in a group 1 patient and one case of a deep infection (os‐ teomyelitis) in a group 2 patient. Delayed wound healing occurred in three patients, all oc‐ curred in group 2. Bone healing complications occurred in three patients, all in group 2, comprised of two nonunions and one delayed union. When considered individually, the oc‐ currence of an infectious or healing complication proved to be statistically similar between groups 1 and 2. However, when complications summed (infectious and healing complica‐ tions), group 2 demonstrated a statistically higher overall complication rate (*P*=0.033, Fish‐ er's exact test). They concluded that the use of TNF blockers may be safely undertaken in the perioperative period without increasing the risk of infectious or healing complications in the patients with RA undergoing elective foot and ankle surgery.

Hirano et al. [26] performed retrospective cohort study where adverse events of surgical wounds were compared between patients treated with TNF blockers (n=39) (IFX; 24, ETN; 15) and those on nbDMARDs (n=74). TKA is the commonest surgery followed by THA. Ad‐ ministration of TNF blockers was stopped prior to surgeries (IFX; mean 29.8 days, ETN; mean 9.6 days) and restarted after surgical wounds were completely healed. Adverse events of surgical wounds occurred after two operations in the TNF group (5.1%) and five opera‐ tions in the nbDMARDs group (6.8%), which was not statistically significant difference by Fisher's exact test (*P*=1.0000). OR was 0.7459 (95% CI 0.1380-4.0336). Although most of ad‐ verse events of surgical wounds were wound dehiscence and continuation of discharge, postoperative infection occurred in one TKA in the TNF group. They concluded that the use of anti-TNF agents dose dot cause specific adverse events on surgical wounds after elective orthopedic surgeries in RA patients.

Kawakami et al. [27] performed a retrospective case-control study to identify perioperative complications associated the use of TNF blockers. RA patients on anti-TNF (64 procedures/49 patients) were compared to those on nbDMARDs (64 procedures/63 patients). TKA is the commonest surgery followed by THA. TNF blockers (IFX; 35 and ETN; 29) were withheld 2-4 weeks prior to surgery according to the British Society for Rheumatology and the Japan College of Rheumatology guidelines (2-4 weeks for ETN, 4 weeks for IFX). Multi‐ variate logistic regression analysis identified the use of TNF blockers (OR 21.80, 95% CI 1.231-386.1, *P*=0.036), prednisone dosage (OR 1.433, 95% CI 1.007-2.040, *P*=0.046), and dis‐ ease duration (OR 1.169, 95% CI 1.030-1.326, *P*=0.015) as a risk factors for SSI. SSIs were de‐ veloped 12.5% (8/64) in the anti-TNF group, whereas 2% (1/64) in the nbDMARDs group (*P*=0.016), but there was no delayed wound healing occurred in either groups. RA flare-ups during the perioperative periods were found in 17.2% (11/64) of anti-TNF group. These flare-ups were significantly increased in ETN group (31.0%, 9/29) compared with the IFX group (5.7%, 2/35) (*P*=0.009). Multivariate logistic regression analysis also revealed that the use of TNF blockers was the only risk factors for DVT (OR=2.83, 95% CI 1.10-7.25, *P*=0.03) in their study. DVT were developed 51% (23/45) in the anti-TNF group, whereas 26% (12/45) in the nbDMARDs group (*P*=0.015). They concluded that TNF blockers were likely cause SSI and DVT in RA patients undergoing elective orthopaedic surgery.

arthroplasty in RA patients on anti-TNF therapy was more than twofold greater compared

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Kubota et al. [30] performed a retrospective study to analyze the influence of biological agents on delayed wound healing and the postoperative SSI in RA patients. The patients were divided into two groups, those treated with biologics (bio group; 276 joints) and not treated with biologic agents (non-bio group; 278 joints). Biologics administered in the bio group were IFX (n=14), ETN (n=236), ADA (n=8), and TCZ (n=18), and these agents were withheld 2-4 weeks before surgery. TKA is the commonest surgery followed by THA. In the bio group, postoperative superficial and deep infection developed in one and two joints, re‐ spectively. In the non-bio group, superficial infection developed in one joint, and deep infec‐ tion was not observed. The incidence of SSIs did not differ significantly between the two groups (Mann-Whitney *U*-test, *P*=0.31251). Delayed wound healing occurred in 15 joints (5.4%) in the bio group (all the patients were treated with ETN), and 12 joints (4.3%) in the non-bio group, but the difference was not statistically significant (Mann-Whitney *U*-test, *P*=0.522). They concluded that the use of biologics may not affect the incidence of postopera‐

Hayata et al. [31] performed a retrospective study to investigate the complications of ortho‐ peadic surgery for RA patients treated with IFX (52 patients). Commonest surgery was ar‐ throscopic synovectomy (n=30), followed by TJA (n=16). The mean timing of surgery after infusion of IFX was 4 weeks. There were two cases (3.8%) of superficial wound infection (one case was foot arthroplasty and the other was spine surgery), but there was no deep wound infection. Furthermore, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, rheumatoid arthritis particle-ag‐ glutination (RAPA) and the period until surgery after IFX infusion. They concluded that IFX did not increase the risk of either infection or surgical complications occurring in patients

Thirdly, we take up 3 studies which compare the patients with postoperative infection and those without, to identify the association between anti-TNF therapy and the risk of infection.

Gilson et al. [32] carried out a retrospective case-control study using French RATIO registry to analyze the risk factors for TJA infections in patients receiving TNF blockers. 20 patients (18 with RA) treated with TNF blockers (IFX; 7, ETN; 5, ADA; 8) and presented with TJA infections were compared to controls (40 patients) without TJA infections on TNF blockers. TJA infections concerned principally the knee (n=12, 60%) and the hip (n=5, 25%). 8 cases (40%) versus 5 controls (13%) had undergone primary or revision TJA for the joint subse‐ quently infected during the previous year (*P*=0.03). Of these procedures, TNF blockers were continued in 5 cases compared to 1 in the control group (*P*=0.08). Multivariate analysis dem‐ onstrated that the predictors of infection were primary TJA or TJA revision for the joint sub‐ sequently infected within the last year (OR 88.3, 95% CI 1.1-7071.6, *P*=0.04) and increased daily steroid intake (OR 5.0 per 5 mg/day increase, 95% CI 1.1-21.6, *P*=0.03). They concluded that TJA infection was rare but potentially severe in patients receiving TNF blockers. Impor‐ tant risk factors were primary TJA or TJA revision for the joint subsequently infected within

with those treated with nbDMARDS.

tive adverse events related to SSI and wound healing.

with RA within 1 year of orthopeadic surgery.

Momohara et al. [28] performed a retrospective study to identify risk factors for acute SSI after TJA (THA; 81, TKA; 339) in RA patients treated with biologics (48 patients, THA; 11, TKA; 37) and nbDMARDs (372 patients). In the biologics group, 19 (4.5%) received IFX, 23 (5.5%) received ETN, two (0.5%) received ADA, and four (1.0%) received tocilizumab (TCZ). Of the patients undergoing THA or TKA, 24 cases (5.7%) developed a superficial incisional SSI requiring the use of antibiotics and the three cases (0.7%) developed an organ/space SSI necessitating surgical treatment to remove the artificial joint prosthesis. Multivariate logistic regression analysis revealed that the use of biologics (OR=5.69; 95% CI 2.07-15.61, *P*=0.0007) and longer RA duration (OR=1.09; 95% CI 1.04-1.14, *P*=0.0003) were the only significant risk factors for acute SSI. Furthermore, multivariate logistic regression analysis of individual medication (nbDMARDs and biologics) adjusted for disease duration indicated that TNF blockers increased the risk of SSI (IFX OR=9.80; 95% CI 2.41-39.82, *P*=0.001; ETN OR=9.16; 95% CI 2.77-30.25, *P*=0.0003). They found that the use of biologics (IFX or ETN) and longer disease duration were associated with an increased risk of acute SSI in RA patients.

The Committee on Arthritis of the Japanese Orthopedic Association [29] investigated the prevalence of postoperative complications in patients with RA in teaching hospitals in Ja‐ pan. The number of surgical procedures under treatment with biologic agent was 3,468 (IFX; 1,616, ETN; 1686, ADA; 41, TCZ; 102, abatacept; 23) and the prevalence of infection was 1.3% (46 procedures). For IFX, ETN, and TCZ, the mean times of withdrawal before surgery were 26.4, 14.1, and 19.8 days, respectively. The prevalence of infection was 1.0% (567 procedures) in 56,339 procedures under treatment with nbDMARDs. There were no significant differen‐ ces between biologics and nbDMARDs groups with respect to the prevalence of infections (OR 1.32, 95% CI 0.98-1.79, *P*=0.07). In the joint arthroplasty group, the prevalence of infec‐ tion was 2.1% (34/1,626 procedures) in biologics group and 1.0% (298/29,903 procedures) in nbDMARDs group. There was a significant difference between biologics and nbDMARDs groups (OR 2.12, 95% CI 1.48-3.03, *P*<0.0001). They concluded that the infection risk of joint arthroplasty in RA patients on anti-TNF therapy was more than twofold greater compared with those treated with nbDMARDS.

TKA is the commonest surgery followed by THA. TNF blockers (IFX; 35 and ETN; 29) were withheld 2-4 weeks prior to surgery according to the British Society for Rheumatology and the Japan College of Rheumatology guidelines (2-4 weeks for ETN, 4 weeks for IFX). Multi‐ variate logistic regression analysis identified the use of TNF blockers (OR 21.80, 95% CI 1.231-386.1, *P*=0.036), prednisone dosage (OR 1.433, 95% CI 1.007-2.040, *P*=0.046), and dis‐ ease duration (OR 1.169, 95% CI 1.030-1.326, *P*=0.015) as a risk factors for SSI. SSIs were de‐ veloped 12.5% (8/64) in the anti-TNF group, whereas 2% (1/64) in the nbDMARDs group (*P*=0.016), but there was no delayed wound healing occurred in either groups. RA flare-ups during the perioperative periods were found in 17.2% (11/64) of anti-TNF group. These flare-ups were significantly increased in ETN group (31.0%, 9/29) compared with the IFX group (5.7%, 2/35) (*P*=0.009). Multivariate logistic regression analysis also revealed that the use of TNF blockers was the only risk factors for DVT (OR=2.83, 95% CI 1.10-7.25, *P*=0.03) in their study. DVT were developed 51% (23/45) in the anti-TNF group, whereas 26% (12/45) in the nbDMARDs group (*P*=0.015). They concluded that TNF blockers were likely cause SSI

Momohara et al. [28] performed a retrospective study to identify risk factors for acute SSI after TJA (THA; 81, TKA; 339) in RA patients treated with biologics (48 patients, THA; 11, TKA; 37) and nbDMARDs (372 patients). In the biologics group, 19 (4.5%) received IFX, 23 (5.5%) received ETN, two (0.5%) received ADA, and four (1.0%) received tocilizumab (TCZ). Of the patients undergoing THA or TKA, 24 cases (5.7%) developed a superficial incisional SSI requiring the use of antibiotics and the three cases (0.7%) developed an organ/space SSI necessitating surgical treatment to remove the artificial joint prosthesis. Multivariate logistic regression analysis revealed that the use of biologics (OR=5.69; 95% CI 2.07-15.61, *P*=0.0007) and longer RA duration (OR=1.09; 95% CI 1.04-1.14, *P*=0.0003) were the only significant risk factors for acute SSI. Furthermore, multivariate logistic regression analysis of individual medication (nbDMARDs and biologics) adjusted for disease duration indicated that TNF blockers increased the risk of SSI (IFX OR=9.80; 95% CI 2.41-39.82, *P*=0.001; ETN OR=9.16; 95% CI 2.77-30.25, *P*=0.0003). They found that the use of biologics (IFX or ETN) and longer

disease duration were associated with an increased risk of acute SSI in RA patients.

The Committee on Arthritis of the Japanese Orthopedic Association [29] investigated the prevalence of postoperative complications in patients with RA in teaching hospitals in Ja‐ pan. The number of surgical procedures under treatment with biologic agent was 3,468 (IFX; 1,616, ETN; 1686, ADA; 41, TCZ; 102, abatacept; 23) and the prevalence of infection was 1.3% (46 procedures). For IFX, ETN, and TCZ, the mean times of withdrawal before surgery were 26.4, 14.1, and 19.8 days, respectively. The prevalence of infection was 1.0% (567 procedures) in 56,339 procedures under treatment with nbDMARDs. There were no significant differen‐ ces between biologics and nbDMARDs groups with respect to the prevalence of infections (OR 1.32, 95% CI 0.98-1.79, *P*=0.07). In the joint arthroplasty group, the prevalence of infec‐ tion was 2.1% (34/1,626 procedures) in biologics group and 1.0% (298/29,903 procedures) in nbDMARDs group. There was a significant difference between biologics and nbDMARDs groups (OR 2.12, 95% CI 1.48-3.03, *P*<0.0001). They concluded that the infection risk of joint

and DVT in RA patients undergoing elective orthopaedic surgery.

116 Innovative Rheumatology

Kubota et al. [30] performed a retrospective study to analyze the influence of biological agents on delayed wound healing and the postoperative SSI in RA patients. The patients were divided into two groups, those treated with biologics (bio group; 276 joints) and not treated with biologic agents (non-bio group; 278 joints). Biologics administered in the bio group were IFX (n=14), ETN (n=236), ADA (n=8), and TCZ (n=18), and these agents were withheld 2-4 weeks before surgery. TKA is the commonest surgery followed by THA. In the bio group, postoperative superficial and deep infection developed in one and two joints, re‐ spectively. In the non-bio group, superficial infection developed in one joint, and deep infec‐ tion was not observed. The incidence of SSIs did not differ significantly between the two groups (Mann-Whitney *U*-test, *P*=0.31251). Delayed wound healing occurred in 15 joints (5.4%) in the bio group (all the patients were treated with ETN), and 12 joints (4.3%) in the non-bio group, but the difference was not statistically significant (Mann-Whitney *U*-test, *P*=0.522). They concluded that the use of biologics may not affect the incidence of postopera‐ tive adverse events related to SSI and wound healing.

Hayata et al. [31] performed a retrospective study to investigate the complications of ortho‐ peadic surgery for RA patients treated with IFX (52 patients). Commonest surgery was ar‐ throscopic synovectomy (n=30), followed by TJA (n=16). The mean timing of surgery after infusion of IFX was 4 weeks. There were two cases (3.8%) of superficial wound infection (one case was foot arthroplasty and the other was spine surgery), but there was no deep wound infection. Furthermore, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, rheumatoid arthritis particle-ag‐ glutination (RAPA) and the period until surgery after IFX infusion. They concluded that IFX did not increase the risk of either infection or surgical complications occurring in patients with RA within 1 year of orthopeadic surgery.

Thirdly, we take up 3 studies which compare the patients with postoperative infection and those without, to identify the association between anti-TNF therapy and the risk of infection.

Gilson et al. [32] carried out a retrospective case-control study using French RATIO registry to analyze the risk factors for TJA infections in patients receiving TNF blockers. 20 patients (18 with RA) treated with TNF blockers (IFX; 7, ETN; 5, ADA; 8) and presented with TJA infections were compared to controls (40 patients) without TJA infections on TNF blockers. TJA infections concerned principally the knee (n=12, 60%) and the hip (n=5, 25%). 8 cases (40%) versus 5 controls (13%) had undergone primary or revision TJA for the joint subse‐ quently infected during the previous year (*P*=0.03). Of these procedures, TNF blockers were continued in 5 cases compared to 1 in the control group (*P*=0.08). Multivariate analysis dem‐ onstrated that the predictors of infection were primary TJA or TJA revision for the joint sub‐ sequently infected within the last year (OR 88.3, 95% CI 1.1-7071.6, *P*=0.04) and increased daily steroid intake (OR 5.0 per 5 mg/day increase, 95% CI 1.1-21.6, *P*=0.03). They concluded that TJA infection was rare but potentially severe in patients receiving TNF blockers. Impor‐ tant risk factors were primary TJA or TJA revision for the joint subsequently infected within the last year, particularly when TNF blockers were not interrupted before surgery, and the daily steroid intake.

tive discontinuation of TNF blockers causes the reduction of effects of the agents at the operation date, thus the results of these studies may not show the accurate influences of TNF blockers on the risk of SSI. However, in the other four studies [25, 26, 30, 31], appropri‐ ate preoperative discontinuation of TNF blockers did not increase the risk of SSI compared with group on nbDMARDs. The risk factors for SSI, which most of RA patients undergoing TJA are considered to have, reported in 17 studies were the use of TNF blockers (OR 21.80 [27], OR 5.69 [28], and OR 4.4 [33]), prednisone dosage (OR 1.433) [27], increased daily ste‐ roid intake (OR 5.0 per 5mg/day increase) [32], longer disease duration (OR 1.169 [27] and OR 1.09 [28]), history of prior SSI or skin infection (OR 13.8) [24], primary or revision TJA for the joint subsequently infected within the last year (OR 88.3) [32], and "clean" surgical pro‐ cedure such as TJA (OR 2.12) [29]. Thus, it may be preferable to perform TJA, if needed, be‐ fore the induction of TNF blockers [32]. In cases of prosthetic surgery after induction of TNF blockers, their withdrawal during the perioperative period is highly recommended and ste‐

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Further larger prospective studies are clearly needed to make clear the association between perioperative use of TNF blockers and SSI, and in clinical practice until these studies are done, we should discontinue TNF blockers and take a sufficient antibiotic prophylaxis with

**5. Risk of wound healing complications in RA patients treated with anti-**

Patients with RA are already predisposed to impaired wound healing as a result of reduc‐ tion in skin thickness [2, 35]. Thus, many orthopaedic surgeons consider the risk of wound healing complication to be high in RA patients, especially treated with TNF blockers [36]. Wound healing is a complex process and TNF-α is required for normal wound healing. An "acute" wound healing process generally includes haemostasis/inflammation, proliferation and tissue remodeling stages [37]. On the other hand, in a "chronic" wound, wound healing is impaired and is characterized by excessive inflammation, enhanced proteolysis, and re‐ duced matrix deposition. Tarnuzzer et al. [38] demonstrated that the levels of TNF-α in fluid from "chronic" wounds were approximately 100-fold higher than those in fluid from an "acute" wound (mastectomy incision). However, the experimental data on the role of TNF-α in wound healing is still controversial. Mooney et al. [2] reported that local application of TNF-α increased wound disruption strength and eventually promoted wound healing, whereas Rapala et al. [39] and Salomon et al. [40] reported that local application of TNF-α down-regulated the synthesis of collagen and was detrimental to wound healing. Some studies analyzed the effect of blockade of TNF-α on wound healing. Mori et al. [41] reported that in TNF receptor p55-deficient mice, angiogenesis, collagen accumulation, and reepithe‐ lialization were up-regulated, and wound healing was accelerated eventually. Iglesias et al. [42] analyzed wound healing in SWISS-OF1 mice and reported that surgical wounds showed a higher degree of collagenization in ETN-treated versus untreated mice, with no difference in the time course of wound healing. They concluded that anti-TNF therapy did

roid intake should be reduced as low as possible before surgery [32].

a careful follow-up.

**TNF-α agents**

Giles et al. [33] performed a retrospective study to investigate the association between anti-TNF therapy and the development of serious postoperative infection in RA patients under‐ going orthopaedic surgery. 91 patients were identified as having at least one orthopedic procedure, and 10 of the 91 patients (11%) developed serious postoperative infection. The demographic features and RA therapies between infection group (n=10) and no infection group (n=81) were comparable. But infection group (7/10 patients; 70%) were significantly more likely treated with TNF-α blocker at the time of surgery compared with no infection group (28/81 patients; 35%) (*P*=0.041). Univariate analysis revealed that anti-TNF was signif‐ icantly associated with the development of postoperative infections (OR 4.4, 95% CI 1.10-18.41). This association remained statistically significant after adjustment for age, sex, and disease duration (OR 4.6, 95% CI 1.1-20.0); prednisone use, diabetes, and serum rheu‐ matoid factor status (OR 5.0, 95% CI 1.1-21.9); and all these 6 variables simultaneously (OR 5.3, 95% CI 1.1-24.9). They concluded that treatment with TNF blockers associated with in‐ creased risk of early infectious complications following orthopaedic surgery in patients with RA. They suggest that TNF blockers should be withheld prior to orthopaedic surgery.

Ruyssen-Witrand et al. [34] performed a systematic retrospective study to assess the complica‐ tion rates after surgery in rheumatic patients treated with TNF blockers. 127 surgical proce‐ dures (107 orthopaedic procedures, 84.3%) performed in 92 rheumatic patients (71 RA patients, 77.2%) receiving TNF blockers. Orthopaedic procedures had a postoperative complication rate of 12% (n=13) with 5.6% (n=6) of infections, whereas 'clean' orthopedic procedures such as joint replacement or vertebral surgery had a complication rate of around 10% (n=4) with 7% (n=3) in‐ fections. Among the procedures where TNF blockers were discontinued more than 5 half-lives before surgery (36 procedures), there were 19.4% (7/36) complications compared to 18.4% (12/65) for procedures where anti-TNF therapy was interrupted less than 5 half-lives before or was not interrupted at all (*P*=0.48). If therapy was discontinued for more than 2 half-lives the complication rate was 17.6%, versus 30.0% if therapy was discontinued less than 2 half-lives be‐ fore or was not discontinued (*P*=0.24). Thus, interrupting TNF blockers did not decrease the postoperative complications. No risk factors, either demographic or for severity, were statisti‐ cally significant in predicting post-surgical complications. Analysis of treatments showed more complications with ADA (28.6%) than ETN (11.5%), but this was not statistically significant (*P*=0.18). The cumulative corticosteroid dose was higher in the group with postoperative com‐ plications, but this was not also statistically significant. The authors concluded that the postop‐ erative complication rate is high in patients treated with TNF blockers, thus discontinuing TNF therapy before surgery should be considered.

In summary of this section, it is difficult to make definite conclusion on the association be‐ tween anti-TNF therapy and SSI in RA patients undergoing orthopedic surgery due to the retrospective nature and small sample size of most of reported studies. In 4 studies [13, 22-24], perioperative continuation of anti-TNF therapy did not increase the risk of SSI, whereas in 3 studies [27-29], the risk of SSI was increased in anti-TNF therapy group, re‐ gardless of discontinuation of the therapy perioperatively. Another point of view, preopera‐ tive discontinuation of TNF blockers causes the reduction of effects of the agents at the operation date, thus the results of these studies may not show the accurate influences of TNF blockers on the risk of SSI. However, in the other four studies [25, 26, 30, 31], appropri‐ ate preoperative discontinuation of TNF blockers did not increase the risk of SSI compared with group on nbDMARDs. The risk factors for SSI, which most of RA patients undergoing TJA are considered to have, reported in 17 studies were the use of TNF blockers (OR 21.80 [27], OR 5.69 [28], and OR 4.4 [33]), prednisone dosage (OR 1.433) [27], increased daily ste‐ roid intake (OR 5.0 per 5mg/day increase) [32], longer disease duration (OR 1.169 [27] and OR 1.09 [28]), history of prior SSI or skin infection (OR 13.8) [24], primary or revision TJA for the joint subsequently infected within the last year (OR 88.3) [32], and "clean" surgical pro‐ cedure such as TJA (OR 2.12) [29]. Thus, it may be preferable to perform TJA, if needed, be‐ fore the induction of TNF blockers [32]. In cases of prosthetic surgery after induction of TNF blockers, their withdrawal during the perioperative period is highly recommended and ste‐ roid intake should be reduced as low as possible before surgery [32].

the last year, particularly when TNF blockers were not interrupted before surgery, and the

Giles et al. [33] performed a retrospective study to investigate the association between anti-TNF therapy and the development of serious postoperative infection in RA patients under‐ going orthopaedic surgery. 91 patients were identified as having at least one orthopedic procedure, and 10 of the 91 patients (11%) developed serious postoperative infection. The demographic features and RA therapies between infection group (n=10) and no infection group (n=81) were comparable. But infection group (7/10 patients; 70%) were significantly more likely treated with TNF-α blocker at the time of surgery compared with no infection group (28/81 patients; 35%) (*P*=0.041). Univariate analysis revealed that anti-TNF was signif‐ icantly associated with the development of postoperative infections (OR 4.4, 95% CI 1.10-18.41). This association remained statistically significant after adjustment for age, sex, and disease duration (OR 4.6, 95% CI 1.1-20.0); prednisone use, diabetes, and serum rheu‐ matoid factor status (OR 5.0, 95% CI 1.1-21.9); and all these 6 variables simultaneously (OR 5.3, 95% CI 1.1-24.9). They concluded that treatment with TNF blockers associated with in‐ creased risk of early infectious complications following orthopaedic surgery in patients with RA. They suggest that TNF blockers should be withheld prior to orthopaedic surgery.

Ruyssen-Witrand et al. [34] performed a systematic retrospective study to assess the complica‐ tion rates after surgery in rheumatic patients treated with TNF blockers. 127 surgical proce‐ dures (107 orthopaedic procedures, 84.3%) performed in 92 rheumatic patients (71 RA patients, 77.2%) receiving TNF blockers. Orthopaedic procedures had a postoperative complication rate of 12% (n=13) with 5.6% (n=6) of infections, whereas 'clean' orthopedic procedures such as joint replacement or vertebral surgery had a complication rate of around 10% (n=4) with 7% (n=3) in‐ fections. Among the procedures where TNF blockers were discontinued more than 5 half-lives before surgery (36 procedures), there were 19.4% (7/36) complications compared to 18.4% (12/65) for procedures where anti-TNF therapy was interrupted less than 5 half-lives before or was not interrupted at all (*P*=0.48). If therapy was discontinued for more than 2 half-lives the complication rate was 17.6%, versus 30.0% if therapy was discontinued less than 2 half-lives be‐ fore or was not discontinued (*P*=0.24). Thus, interrupting TNF blockers did not decrease the postoperative complications. No risk factors, either demographic or for severity, were statisti‐ cally significant in predicting post-surgical complications. Analysis of treatments showed more complications with ADA (28.6%) than ETN (11.5%), but this was not statistically significant (*P*=0.18). The cumulative corticosteroid dose was higher in the group with postoperative com‐ plications, but this was not also statistically significant. The authors concluded that the postop‐ erative complication rate is high in patients treated with TNF blockers, thus discontinuing TNF

In summary of this section, it is difficult to make definite conclusion on the association be‐ tween anti-TNF therapy and SSI in RA patients undergoing orthopedic surgery due to the retrospective nature and small sample size of most of reported studies. In 4 studies [13, 22-24], perioperative continuation of anti-TNF therapy did not increase the risk of SSI, whereas in 3 studies [27-29], the risk of SSI was increased in anti-TNF therapy group, re‐ gardless of discontinuation of the therapy perioperatively. Another point of view, preopera‐

daily steroid intake.

118 Innovative Rheumatology

therapy before surgery should be considered.

Further larger prospective studies are clearly needed to make clear the association between perioperative use of TNF blockers and SSI, and in clinical practice until these studies are done, we should discontinue TNF blockers and take a sufficient antibiotic prophylaxis with a careful follow-up.

## **5. Risk of wound healing complications in RA patients treated with anti-TNF-α agents**

Patients with RA are already predisposed to impaired wound healing as a result of reduc‐ tion in skin thickness [2, 35]. Thus, many orthopaedic surgeons consider the risk of wound healing complication to be high in RA patients, especially treated with TNF blockers [36]. Wound healing is a complex process and TNF-α is required for normal wound healing. An "acute" wound healing process generally includes haemostasis/inflammation, proliferation and tissue remodeling stages [37]. On the other hand, in a "chronic" wound, wound healing is impaired and is characterized by excessive inflammation, enhanced proteolysis, and re‐ duced matrix deposition. Tarnuzzer et al. [38] demonstrated that the levels of TNF-α in fluid from "chronic" wounds were approximately 100-fold higher than those in fluid from an "acute" wound (mastectomy incision). However, the experimental data on the role of TNF-α in wound healing is still controversial. Mooney et al. [2] reported that local application of TNF-α increased wound disruption strength and eventually promoted wound healing, whereas Rapala et al. [39] and Salomon et al. [40] reported that local application of TNF-α down-regulated the synthesis of collagen and was detrimental to wound healing. Some studies analyzed the effect of blockade of TNF-α on wound healing. Mori et al. [41] reported that in TNF receptor p55-deficient mice, angiogenesis, collagen accumulation, and reepithe‐ lialization were up-regulated, and wound healing was accelerated eventually. Iglesias et al. [42] analyzed wound healing in SWISS-OF1 mice and reported that surgical wounds showed a higher degree of collagenization in ETN-treated versus untreated mice, with no difference in the time course of wound healing. They concluded that anti-TNF therapy did not affect wound healing. Streit et al. [37] reported a case series of patients with "chronic", therapy-resistant leg ulcers responded well to topical application of IFX. Ashcroft et al. [43] also reported that inhibiting TNF-α is a critical event in reversing the severely impaired wound healing.

tion before surgery (5 interruptions/6 cases of flare vs. 13 interruption/44 cases without flare; Fisher's exact value=0.02). Kawakami et al. [27] reported that RA flares during the perioper‐ ative periods were found in 17.2% (11/64) of anti-TNF group. These flares were significantly increased in ETN group (31.0%, 9/29) compared with the IFX group (5.7%, 2/35) (*P*=0.009). The reason for increased risk of postoperative RA flare in ETN compared with IFX is un‐ clear, but considered as follows. The half-life of IFX is longer than that of ETN, and in the IFX group, the surgery was usually performed in the middle of the 8-week treatment of peri‐ od, and there was actually no withholding of anti-TNF therapy. Moreover, the function of IFX is based on an antigen-antibody reaction, whereas the function of ETN is a reversible

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On the other hand, intensive treatment with TNF blockers and MTX leads to clinical remission in approximately 20-50% of RA patients. This excellent clinical result raised a new problem, whether the patients with RA on TNF therapy can discontinue their therapy after acquisition of low disease activity (LDA). In the BeST study [45], 67% of RA patients treated early with combi‐ nation of IFX and MTX were able to stop anti-TNF treatment. Brocq et al. [46] performed a small prospective cohort study to determine the time to relapse after cessation of TNF antagonist ther‐ apy. The mean disease duration was 11.3 years. Amongst the 20 patients, three quarter (75%) re‐ lapsed within the first 12 months with the mean time to relapse of 15 weeks. Saleem et al. [47] reported comparative data for patients treated early (n=27) versus late (n=20) with combination therapy of MTX and anti-TNF. All patients fulfilled the criteria of clinical remission for at least 6 months. Anti-TNF therapy was then discontinued, while remaining on MTX for 24 months. The primary outcome measure was a flare of the disease determined by an increase in Disease Activ‐ ity Score (DAS). At 24 months, there were significantly more patients in the initial treatment group that had sustained remission compared with the delayed treatment group (59% vs. 15%, *P*=0.003). Shorter disease duration was found for be a predictor of sustained remission follow‐ ing cessation of TNF blockers. Tanaka et al. [48] conducted a multicenter study (remission in‐ duction by Remicade in RA; RRR study) to determine whether IFX might be discontinued after achievement of LDA in patient with RA and to evaluate progression of articular destruction during the discontinuation. 114 RA patients with RA who had received IFX treatment, and dis‐ continued the drug after achieving DAS 28<3.2 (LDA) for >24 weeks, were studied. The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and modified total Sharp score (mTSS) 63.3. 12 patients withdrew from the study. Out of the 102 patients, 56 patients (55%) remained to have DAS 28<3.2 (RRR-achieved group) and 44 patients (43%) reached DAS 28<2.6 at 1 year after discontinuing IFX. On the other hand, 29 patients flared within 1 year (mean duration 6.4 months) after the discontinuation and in 17 patients DAS28 was >3.2 at 1 year. Thus, the remission induction by IFX was failed in 46 patients (45%) at 1 year after the dis‐ continuation (RRR-failed group). Yearly progression of mTSS (ΔTSS) remained <0.5 (structural remission) in 67% and 44% of the RRR-achieved and RRR-failed group, respectively. Patients for whom RRR was achieved were younger (49.5 vs. 56.1 years), their disease duration was shorter (4.8 vs. 7.8 years) and mTSS was lower (46.9 vs. 97.2) than for those whom RRR failed. DAS28 at RRR-study entry had the most marked correlation with the maintenance of LDA for 1 year after the discontinuation. They concluded that after attaining LDA by IFX, 55% of the pa‐ tients with RA able to discontinue IFX for >1 year without progression of radiological articular

connection response of ETN of TNF [27, 44].

Surgical wound in elective orthopaedic surgery is basically considered as "acute" wound. In the 9 of 17 studies taken up in section 4, the association between anti-TNF therapy and "acute" wound healing complications in RA patients were reported as follows. Den Broeder et al. [24] reported that wound dehiscence occurred more frequently in patients who contin‐ ued anti-TNF therapy (9/92 cases, 9.8%) compared to those temporarily discontinued anti-TNF therapy (1/104 cases, 0.9%) (OR 11.2, 95% CI 1.4-90). Wendling et al. [23] reported that three cases (6%) of delayed wound healing were recorded in patients on TNF blockers (50 surgical procedures). Ruyssen-Witrand et al. [34] reported that postoperative wound heal‐ ing complications occurred in 6 cases (4.7%) in patients treated with TNF blockers (127 sur‐ gical procedures). Kubota et al. [30] reported that delayed wound healing occurred in 15 joints (5.4%) in bio group and 12 joints (4.3%) in non-bio group, but the difference between two groups was not statistically significant. Hirano et al. [26] reported that adverse events of surgical wounds occurred after two operations (5.1%) in the TNF group (n=39) and five op‐ erations (6.8%) in the nbDMARDs group (n=74), but the difference between two groups was not statistically significant. Suzuki et al. [29] reported that delayed wound healing occurred in 14 cases (IFX; 2, ETN; 9, TCZ; 3) (0.4%) in biologics group (n=3,468). In the remaining 3 of 9 studies by Kawakami et al. [27], Momohara et al. [28], and Bibbo et al. [25], there was no delayed wound healing in patients with anti-TNF therapy.

In summary of this section, the role of TNF-α in wound healing is still controversial. Anti-TNF therapy seems to be preferable for improvement in healing of "chronic" wounds where the level of TNF-α is excessive compared with "acute" wounds. Thus, perioperative discon‐ tinuation of anti-TNF therapy is preferable to decrease the risk of wound healing complica‐ tions, but reported data are controversial and insufficient to make clear conclusion about this matter.

## **6. Perioperative discontinuation of anti-TNF-α agents and risk of RA flare**

For orthopaedic surgeons, one of the major concerns is whether perioperative discontinua‐ tion of TNF blockers results in flare up of the disease activity. Because RA flare may com‐ promise postoperative rehabilitation, which strongly affect the result of orthopaedic surgery. However, the information about perioperative RA flare after discontinuation of an‐ ti-TNF therapy in perioperative period is very limited. Only some comments about the flare were reported in 3 of 17 studies taken up section 4. Talwalker et al. [22] reported that one flare up occurred postoperatively in a patient receiving ETN, but the flare up was well con‐ trolled once the drug was restarted. Wendling et al. [23] reported that postoperative RA flares were observed in 6 cases (12%) and significantly associated with anti-TNF interrup‐ tion before surgery (5 interruptions/6 cases of flare vs. 13 interruption/44 cases without flare; Fisher's exact value=0.02). Kawakami et al. [27] reported that RA flares during the perioper‐ ative periods were found in 17.2% (11/64) of anti-TNF group. These flares were significantly increased in ETN group (31.0%, 9/29) compared with the IFX group (5.7%, 2/35) (*P*=0.009). The reason for increased risk of postoperative RA flare in ETN compared with IFX is un‐ clear, but considered as follows. The half-life of IFX is longer than that of ETN, and in the IFX group, the surgery was usually performed in the middle of the 8-week treatment of peri‐ od, and there was actually no withholding of anti-TNF therapy. Moreover, the function of IFX is based on an antigen-antibody reaction, whereas the function of ETN is a reversible connection response of ETN of TNF [27, 44].

not affect wound healing. Streit et al. [37] reported a case series of patients with "chronic", therapy-resistant leg ulcers responded well to topical application of IFX. Ashcroft et al. [43] also reported that inhibiting TNF-α is a critical event in reversing the severely impaired

Surgical wound in elective orthopaedic surgery is basically considered as "acute" wound. In the 9 of 17 studies taken up in section 4, the association between anti-TNF therapy and "acute" wound healing complications in RA patients were reported as follows. Den Broeder et al. [24] reported that wound dehiscence occurred more frequently in patients who contin‐ ued anti-TNF therapy (9/92 cases, 9.8%) compared to those temporarily discontinued anti-TNF therapy (1/104 cases, 0.9%) (OR 11.2, 95% CI 1.4-90). Wendling et al. [23] reported that three cases (6%) of delayed wound healing were recorded in patients on TNF blockers (50 surgical procedures). Ruyssen-Witrand et al. [34] reported that postoperative wound heal‐ ing complications occurred in 6 cases (4.7%) in patients treated with TNF blockers (127 sur‐ gical procedures). Kubota et al. [30] reported that delayed wound healing occurred in 15 joints (5.4%) in bio group and 12 joints (4.3%) in non-bio group, but the difference between two groups was not statistically significant. Hirano et al. [26] reported that adverse events of surgical wounds occurred after two operations (5.1%) in the TNF group (n=39) and five op‐ erations (6.8%) in the nbDMARDs group (n=74), but the difference between two groups was not statistically significant. Suzuki et al. [29] reported that delayed wound healing occurred in 14 cases (IFX; 2, ETN; 9, TCZ; 3) (0.4%) in biologics group (n=3,468). In the remaining 3 of 9 studies by Kawakami et al. [27], Momohara et al. [28], and Bibbo et al. [25], there was no

In summary of this section, the role of TNF-α in wound healing is still controversial. Anti-TNF therapy seems to be preferable for improvement in healing of "chronic" wounds where the level of TNF-α is excessive compared with "acute" wounds. Thus, perioperative discon‐ tinuation of anti-TNF therapy is preferable to decrease the risk of wound healing complica‐ tions, but reported data are controversial and insufficient to make clear conclusion about

**6. Perioperative discontinuation of anti-TNF-α agents and risk of RA**

For orthopaedic surgeons, one of the major concerns is whether perioperative discontinua‐ tion of TNF blockers results in flare up of the disease activity. Because RA flare may com‐ promise postoperative rehabilitation, which strongly affect the result of orthopaedic surgery. However, the information about perioperative RA flare after discontinuation of an‐ ti-TNF therapy in perioperative period is very limited. Only some comments about the flare were reported in 3 of 17 studies taken up section 4. Talwalker et al. [22] reported that one flare up occurred postoperatively in a patient receiving ETN, but the flare up was well con‐ trolled once the drug was restarted. Wendling et al. [23] reported that postoperative RA flares were observed in 6 cases (12%) and significantly associated with anti-TNF interrup‐

delayed wound healing in patients with anti-TNF therapy.

wound healing.

120 Innovative Rheumatology

this matter.

**flare**

On the other hand, intensive treatment with TNF blockers and MTX leads to clinical remission in approximately 20-50% of RA patients. This excellent clinical result raised a new problem, whether the patients with RA on TNF therapy can discontinue their therapy after acquisition of low disease activity (LDA). In the BeST study [45], 67% of RA patients treated early with combi‐ nation of IFX and MTX were able to stop anti-TNF treatment. Brocq et al. [46] performed a small prospective cohort study to determine the time to relapse after cessation of TNF antagonist ther‐ apy. The mean disease duration was 11.3 years. Amongst the 20 patients, three quarter (75%) re‐ lapsed within the first 12 months with the mean time to relapse of 15 weeks. Saleem et al. [47] reported comparative data for patients treated early (n=27) versus late (n=20) with combination therapy of MTX and anti-TNF. All patients fulfilled the criteria of clinical remission for at least 6 months. Anti-TNF therapy was then discontinued, while remaining on MTX for 24 months. The primary outcome measure was a flare of the disease determined by an increase in Disease Activ‐ ity Score (DAS). At 24 months, there were significantly more patients in the initial treatment group that had sustained remission compared with the delayed treatment group (59% vs. 15%, *P*=0.003). Shorter disease duration was found for be a predictor of sustained remission follow‐ ing cessation of TNF blockers. Tanaka et al. [48] conducted a multicenter study (remission in‐ duction by Remicade in RA; RRR study) to determine whether IFX might be discontinued after achievement of LDA in patient with RA and to evaluate progression of articular destruction during the discontinuation. 114 RA patients with RA who had received IFX treatment, and dis‐ continued the drug after achieving DAS 28<3.2 (LDA) for >24 weeks, were studied. The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and modified total Sharp score (mTSS) 63.3. 12 patients withdrew from the study. Out of the 102 patients, 56 patients (55%) remained to have DAS 28<3.2 (RRR-achieved group) and 44 patients (43%) reached DAS 28<2.6 at 1 year after discontinuing IFX. On the other hand, 29 patients flared within 1 year (mean duration 6.4 months) after the discontinuation and in 17 patients DAS28 was >3.2 at 1 year. Thus, the remission induction by IFX was failed in 46 patients (45%) at 1 year after the dis‐ continuation (RRR-failed group). Yearly progression of mTSS (ΔTSS) remained <0.5 (structural remission) in 67% and 44% of the RRR-achieved and RRR-failed group, respectively. Patients for whom RRR was achieved were younger (49.5 vs. 56.1 years), their disease duration was shorter (4.8 vs. 7.8 years) and mTSS was lower (46.9 vs. 97.2) than for those whom RRR failed. DAS28 at RRR-study entry had the most marked correlation with the maintenance of LDA for 1 year after the discontinuation. They concluded that after attaining LDA by IFX, 55% of the pa‐ tients with RA able to discontinue IFX for >1 year without progression of radiological articular progression. Klarenbeek et al. [49] conducted a study using five-year data of the BeSt study to determine the relapse rate after discontinuing treatment in patients with RA in sustained clini‐ cal remission, to identify predictors of relapse and evaluate treatment response after restarting treatment. 508 patients with recent-onset RA were randomized into four dynamic treatment strategies, aiming at DAS≦2.4. When DAS was <1.6 for≧6months, the last DMARD was ta‐ pered and discontinued. If DAS increased ≧1.6, the last DMARD was immediately reintro‐ duced. 115/508 patients (23%) achieved drug-free remission during a five-year period. Of these 53/115 patients (46%) restarted treatment because the DAS≧1.6 after a median of 5 months, 59/115 patients (51%) remained drug-free remission for median duration of 23 months. To focus the group of initial combination with IFX (n=128), 36/128 patients (28%) achieved drug-free re‐ mission during a five-year period. Of these 15/36 patients (42%) restarted treatment, 21/36 pa‐ tients (58%) remained drug-free remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3-6 months after the restart without showing radiological progres‐ sion during the relapse.

ly. The national guidelines on each society recommend preoperative discontinuation of TNF blockers and show the preoperative off-period based on the half-life of each agents (Table 1).

Perioperative Surgical Site Infections and Complications in Elective Orthopedic Surgery in Patients with...

Infliximab (IFX) 8-10 16-20 24-30 40-50 Etanercept (ETN) 4.3 8.6 12.9 21.5 Adalimumab (ADA) 14 28 42 70 Golimumab (GOL) 12 24 36 60 Certolizumab (CTZ) 14 28 42 70

The current American Society of Rheumatology (ACR) guidelines (2008) state that anti-TNF should not be used during the preoperative period, for at least 1week prior to and 1 week after surgery. It was recommended this decision should be further tempered by the pharma‐ cokinetic properties of a given biologic agent (e.g., longer periods of time off therapy may be

The recently updated British Society of Rheumatology (BSR) guidelines (2010) propose as follows. In RA patients on anti-TNF, the potential benefit of preventing postoperative infec‐ tions by stopping treatment (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of a perioperative flare in RA activi‐ ty. If anti-TNF is to be stopped before surgery, consideration should be given TNF blockers three to five times the half-life of the relevant drug prior to surgery and should not be re‐ started after surgery until there is good wound healing and no evidence of infection [51]. The Club Rhumatismes et Inflammation (CRI) (French Society of Rheumatology) provides guidelines that based on drug half-lives and clinical settings. For minor surgery, in a sterile setting with minor risk infection, IFX, ADA and ETN should be withheld, respectively, at least 1 month, 3-4 weeks and 1-2 weeks. However, for surgery performed in a septic envi‐ ronment, the respective duration for interruption of IFX, ADA and ETN are 8, 4-6 and 2-3

Recently updated the Board of Japan College of Rheumatology (JCR) guidelines (2012) cau‐ tion that surgery should be delayed until a sufficient time had elapsed from the last admin‐ istration of TNF-α antagonists (recommend to keep 2-4 weeks for ETN or 4 weeks for IFX with long half-life), because it is not clear whether or not TNF-α blockade interferes with the healing of wounds and prevention of postoperative infection. Treatment with TNF-α antag‐ onists could be resumed after complete healing of the surgical wound and in the absence of

The Canadian Rheumatology Association (CRA) guidelines state that biologic DMARD should be held prior to surgical procedures. The timing for withholding biologic DMARD

appropriate when using agents with longer half-lives.), and the type of surgery [50].

**Table 1.** Mean half-lives of TNF blockers

weeks [52].

any postoperative infection [53].

**mean half-life 2 half-lives 3 half-lives 5 half-lives (days) (days) (days) (days)**

http://dx.doi.org/10.5772/54012

123

As mentioned above, after maintaining LDA by intensive treatment with TNF blockers, dis‐ continuation of TNF blockers without disease flare, joint damage progression, and function‐ al impairment is possible in some RA patients. Patients with shorter disease duration are more likely to remain in remission after discontinuing TNF blockers compared to their counterparts with established disease [45-48]. Furthermore, patients with longstanding dis‐ ease are more likely to have orthopaedic surgical intervention, especially prosthetic surgery, compared to those with early disease. However, the significance of discontinuation of anti-TNF therapy in perioperative periods is different from the cessation after achievement of LDA. Because perioperative discontinuation of anti-TNF therapy is basically temporary, and the therapy is restarted promptly after confirmation of good wound healing and no evi‐ dence of infection. Therefore, if TNF blockers are withheld prior to surgery, those with lon‐ ger disease duration need to be monitored carefully for features of relapse [36].

In summary of this section, perioperative discontinuation of anti-TNF therapy in elective or‐ thopaedic surgery likely caused postoperative RA flare. The risk of postoperative flare was increased in ETN which had a shorter half-life compared with IFX, and also increased in the patients with long disease duration. Shortening the period of withholding anti-TNF therapy is desirable to prevent the postoperative flare, but shortening the duration of discontinua‐ tion may cause an increase in SSI and wound healing complications. This is the clinical di‐ lemma for orthopaedic surgeons. Data on this matter also insufficient to make definite conclusion, thus further studies are clearly needed.

## **7. Recommended perioperative discontinuation period of anti-TNF-α agents in national guidelines**

Although the conclusions about the influences of continuation of anti-TNF therapy in perio‐ perative period on SSI, wound healing and RA flare are somewhat conflicting, but there are few studies which recommend the perioperative continuation of anti-TNF therapy positive‐


ly. The national guidelines on each society recommend preoperative discontinuation of TNF blockers and show the preoperative off-period based on the half-life of each agents (Table 1).

**Table 1.** Mean half-lives of TNF blockers

progression. Klarenbeek et al. [49] conducted a study using five-year data of the BeSt study to determine the relapse rate after discontinuing treatment in patients with RA in sustained clini‐ cal remission, to identify predictors of relapse and evaluate treatment response after restarting treatment. 508 patients with recent-onset RA were randomized into four dynamic treatment strategies, aiming at DAS≦2.4. When DAS was <1.6 for≧6months, the last DMARD was ta‐ pered and discontinued. If DAS increased ≧1.6, the last DMARD was immediately reintro‐ duced. 115/508 patients (23%) achieved drug-free remission during a five-year period. Of these 53/115 patients (46%) restarted treatment because the DAS≧1.6 after a median of 5 months, 59/115 patients (51%) remained drug-free remission for median duration of 23 months. To focus the group of initial combination with IFX (n=128), 36/128 patients (28%) achieved drug-free re‐ mission during a five-year period. Of these 15/36 patients (42%) restarted treatment, 21/36 pa‐ tients (58%) remained drug-free remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3-6 months after the restart without showing radiological progres‐

As mentioned above, after maintaining LDA by intensive treatment with TNF blockers, dis‐ continuation of TNF blockers without disease flare, joint damage progression, and function‐ al impairment is possible in some RA patients. Patients with shorter disease duration are more likely to remain in remission after discontinuing TNF blockers compared to their counterparts with established disease [45-48]. Furthermore, patients with longstanding dis‐ ease are more likely to have orthopaedic surgical intervention, especially prosthetic surgery, compared to those with early disease. However, the significance of discontinuation of anti-TNF therapy in perioperative periods is different from the cessation after achievement of LDA. Because perioperative discontinuation of anti-TNF therapy is basically temporary, and the therapy is restarted promptly after confirmation of good wound healing and no evi‐ dence of infection. Therefore, if TNF blockers are withheld prior to surgery, those with lon‐

In summary of this section, perioperative discontinuation of anti-TNF therapy in elective or‐ thopaedic surgery likely caused postoperative RA flare. The risk of postoperative flare was increased in ETN which had a shorter half-life compared with IFX, and also increased in the patients with long disease duration. Shortening the period of withholding anti-TNF therapy is desirable to prevent the postoperative flare, but shortening the duration of discontinua‐ tion may cause an increase in SSI and wound healing complications. This is the clinical di‐ lemma for orthopaedic surgeons. Data on this matter also insufficient to make definite

**7. Recommended perioperative discontinuation period of anti-TNF-α**

Although the conclusions about the influences of continuation of anti-TNF therapy in perio‐ perative period on SSI, wound healing and RA flare are somewhat conflicting, but there are few studies which recommend the perioperative continuation of anti-TNF therapy positive‐

ger disease duration need to be monitored carefully for features of relapse [36].

conclusion, thus further studies are clearly needed.

**agents in national guidelines**

sion during the relapse.

122 Innovative Rheumatology

The current American Society of Rheumatology (ACR) guidelines (2008) state that anti-TNF should not be used during the preoperative period, for at least 1week prior to and 1 week after surgery. It was recommended this decision should be further tempered by the pharma‐ cokinetic properties of a given biologic agent (e.g., longer periods of time off therapy may be appropriate when using agents with longer half-lives.), and the type of surgery [50].

The recently updated British Society of Rheumatology (BSR) guidelines (2010) propose as follows. In RA patients on anti-TNF, the potential benefit of preventing postoperative infec‐ tions by stopping treatment (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of a perioperative flare in RA activi‐ ty. If anti-TNF is to be stopped before surgery, consideration should be given TNF blockers three to five times the half-life of the relevant drug prior to surgery and should not be re‐ started after surgery until there is good wound healing and no evidence of infection [51].

The Club Rhumatismes et Inflammation (CRI) (French Society of Rheumatology) provides guidelines that based on drug half-lives and clinical settings. For minor surgery, in a sterile setting with minor risk infection, IFX, ADA and ETN should be withheld, respectively, at least 1 month, 3-4 weeks and 1-2 weeks. However, for surgery performed in a septic envi‐ ronment, the respective duration for interruption of IFX, ADA and ETN are 8, 4-6 and 2-3 weeks [52].

Recently updated the Board of Japan College of Rheumatology (JCR) guidelines (2012) cau‐ tion that surgery should be delayed until a sufficient time had elapsed from the last admin‐ istration of TNF-α antagonists (recommend to keep 2-4 weeks for ETN or 4 weeks for IFX with long half-life), because it is not clear whether or not TNF-α blockade interferes with the healing of wounds and prevention of postoperative infection. Treatment with TNF-α antag‐ onists could be resumed after complete healing of the surgical wound and in the absence of any postoperative infection [53].

The Canadian Rheumatology Association (CRA) guidelines state that biologic DMARD should be held prior to surgical procedures. The timing for withholding biologic DMARD should be based on the individual patient, the nature of the surgery, and the pharmacoki‐ netic properties of the agent. Biologic DMARD may be restarted postoperatively if there is no evidence of infection and wound healing is satisfactory [54].

The risk factors for SSIs, which most of RA patients undergoing TJA are considered to have, are the use of TNF blockers, increased daily steroid intake, older age and longer disease duration, history of prior SSI or skin infection, and "clean" surgical procedure such as TJA, thus it may be preferable to perform TJA, if needed, before the induction of TNF blockers. When withholding the anti-TNF therapy, the potential benefit of prevent‐ ing SSI (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of RA flare, and we should also take pharmacokinetic properties of the agents into consideration. Shortening the period of withholding anti-TNF therapy is desirable to prevent the postoperative flare, but it may cause an increase in SSI and wound healing complications. This is the clinical dilemma for orthopaedic sur‐ geons. Further larger prospective studies are clearly needed to make definite conclusion of perioperative management of TNF blockers, and in clinical practice until these studies are done, we should follow each one's national guidelines and take a sufficient antibiotic

Perioperative Surgical Site Infections and Complications in Elective Orthopedic Surgery in Patients with...

http://dx.doi.org/10.5772/54012

125

Department of Orthopaedic Surgery, Fujita Health University Second Hospital, Aichi, Japan

[1] Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK. The importance of the disease process and disease-modifying antirheumatic drug treatment in the de‐ velopment of septic arthritis in patients with rheumatoid arthritis. Arthritis and

[2] Mooney DP, O'Reilly M, Gamelli RL. Tumor necrosis factor and wound healing. An‐

[3] Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative compli‐ cations in patients with rheumatoid arthritis undergoing elective orthopaedic sur‐

[4] Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based

[5] Weston VC, Jones AC, Bradbury N, Fawthrop F, Doherty M. Clinical features and outcome of septic arthritis in a single UK Health District 1982-1991. Annals of the

gery. Annals of the Rheumatic Diseases 2001; 60(3): 214-217.

study. Arthritis and Rheumatism 2002; 46(9): 2287-2293.

prophylaxis with a careful follow-up.

Koichiro Komiya and Nobuki Terada

\*Address all correspondence to: komiya@qb3.so-net.ne.jp

Rheumatism 2007; 57(7): 1151-1157.

nals of Surgery1990; 211(2): 124-129.

Rheumatic Diseases 1999; 58(4): 214-219.

**Author details**

**References**

In clinical practice, we should follow each one's national guidelines and medical circum‐ stance of each country. We summarized concisely the recommendations of main national guidelines in Table 2.


**Table 2.** Recommendations for perioperative management of TNF blockers in national guidelines

#### **8. Conclusions**

It is difficult to draw definite conclusion on the influence of perioperative use of TNF block‐ ers on the risk of SSI, wound healing and flare of disease activity in RA patients undergoing orthopaedic surgery, due to the retrospective nature and small sample size of most of past studies. Although we have a limitation in the review of the perioperative management of TNF blockers, it is seemed for us that perioperative discontinuation of anti-TNF therapy was preferable to decrease the risk of SSI and wound healing complication, whereas it likely caused the increased risk of RA flare. At present, the national guidelines on each society rec‐ ommend preoperative discontinuation of TNF blockers.

The risk factors for SSIs, which most of RA patients undergoing TJA are considered to have, are the use of TNF blockers, increased daily steroid intake, older age and longer disease duration, history of prior SSI or skin infection, and "clean" surgical procedure such as TJA, thus it may be preferable to perform TJA, if needed, before the induction of TNF blockers. When withholding the anti-TNF therapy, the potential benefit of prevent‐ ing SSI (different surgical procedures pose different risks of infection and wound healing) should be balanced against the risk of RA flare, and we should also take pharmacokinetic properties of the agents into consideration. Shortening the period of withholding anti-TNF therapy is desirable to prevent the postoperative flare, but it may cause an increase in SSI and wound healing complications. This is the clinical dilemma for orthopaedic sur‐ geons. Further larger prospective studies are clearly needed to make definite conclusion of perioperative management of TNF blockers, and in clinical practice until these studies are done, we should follow each one's national guidelines and take a sufficient antibiotic prophylaxis with a careful follow-up.

## **Author details**

should be based on the individual patient, the nature of the surgery, and the pharmacoki‐ netic properties of the agent. Biologic DMARD may be restarted postoperatively if there is

In clinical practice, we should follow each one's national guidelines and medical circum‐ stance of each country. We summarized concisely the recommendations of main national

(adalimumab) and 2-3 weeks(etanercept)

and wound healing is satisfactory

It is difficult to draw definite conclusion on the influence of perioperative use of TNF block‐ ers on the risk of SSI, wound healing and flare of disease activity in RA patients undergoing orthopaedic surgery, due to the retrospective nature and small sample size of most of past studies. Although we have a limitation in the review of the perioperative management of TNF blockers, it is seemed for us that perioperative discontinuation of anti-TNF therapy was preferable to decrease the risk of SSI and wound healing complication, whereas it likely caused the increased risk of RA flare. At present, the national guidelines on each society rec‐

**Table 2.** Recommendations for perioperative management of TNF blockers in national guidelines

ommend preoperative discontinuation of TNF blockers.

and in the absence of any postoperative infection

**Recommended perioperative management of TNF blockers**

perioperative RA flare (three to five times the half-life of the relevant drug prior to surgery) \*Should not be restarted after surgery until there is good wound healing and no evidence of infection

\*Minor surgery: discontinue for at least 1 month (infliximab), 3-4 weeks (adalimumab) and 1-2 weeks (etanercept) \*Surgery in a septic environment: discontinue for 8 weeks (infliximab), 4-6 weeks

\*Discontinue for 2-4 weeks (etanercept) or 4 weeks (infliximab) \*Could be resumed after complete healing of the surgical wound

\*Discontinuation should be based on the individual patient, the nature of the surgery, and the pharmacokinetic properties of the agent. \*Restarted postoperatively if there is no evidence of infection

\*Discontinue for at least 1week prior to and 1 week after surgery (this decision should be further tempered by the pharmacokinetic properties of a given biologic agent and the type of surgery)

\*Discontinuation should be balanced against the risk of a

no evidence of infection and wound healing is satisfactory [54].

guidelines in Table 2.

124 Innovative Rheumatology

American Society of Rheumatology (ACR)

British Society of Rheumatology (BSR)

Club Rhumatismes et Inflammation (CRI)

Japan College of Rheumatology (JCR)

Canadian Rheumatology Association (CRA)

**8. Conclusions**

Koichiro Komiya and Nobuki Terada

\*Address all correspondence to: komiya@qb3.so-net.ne.jp

Department of Orthopaedic Surgery, Fujita Health University Second Hospital, Aichi, Japan

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**Chapter 7**

**Extraskeletal Manifestations**

**in Rheumatoid Arthritis -**

Katarzyna Romanowska-Próchnicka,

Przemysław Rzodkiewicz, Marzena Olesińska, Dariusz Szukiewicz and Sławomir Maśliński

Additional information is available at the end of the chapter

Rheumatoid arthritis (RA) is a chronic, autoimmune disease, which attacks the joints but also may cause extra-articular complications. The disease can present itself in a variety of ways. It depends on many factors, including the presence of rheumatoid factor, pres‐ ence and rate of anti-CCP, number of swollen and painful joints (over 20 in the begin‐ ning of the disease), levels of inflammatory markers (ESR, CRP), patient's young age, occurrence of rheumatoid nodules. Patients who present the above criteria, especially with early, polyarticular onset of the disease, have usually aggressive, progressive and destructive course of the disease manifested by extra-articular manifestations. Proper pri‐ mary treatment in the early stage of RA may reduce the number of swollen joints and severity of inflammation, slow the progression of joint deformations and decrease the amount of erosions. However, it does not completely preserve the occurrence of extraarticular complications. A lot of these complications can be observed in patients with long lasting RA, with recurrent exacerbations, undertreated or non compliant. Many of RA symptoms can also be seen in other diseases. That is why the recognition of the dis‐

In this paper we provide overview of major extra-articular complications of RA, describing its incidence and clinical features. To illustrate the complexity, variety of course and most

and reproduction in any medium, provided the original work is properly cited.

© 2013 Romanowska-Próchnicka et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

common diagnostic problems, descriptions of four case studies are also included.

**Clinical Cases**

http://dx.doi.org/10.5772/53739

ease in many times is difficult.

properly cited.

**1. Introduction**


**Chapter 7**
