TNF blockade in daily practice Bijl, A.E. van der

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(1)TNF blockade in daily practice Bijl, A.E. van der. Citation Bijl, A. E. van der. (2010, March 9). TNF blockade in daily practice. Retrieved from https://hdl.handle.net/1887/15056 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/15056. Note: To cite this publication please use the final published version (if applicable)..

(2) Chapter 1: introduction. Rheumatoid arthritis Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease especially involving the joints. The disease is characterised by chronic inflammation of the synovium resulting in damage of the articular structures e.g. cartilage and bone. Patients affected with RA suffer from pain, swelling and limited movement of the affected joints. Rheumatoid arthritis has a worldwide distribution and affects 0.8% of the population (prevalence)(1) from which ~70% is female. The annual incidence is 36/100 000 in women and 14/100 000 in men(1). For reasons unknown, the incidence, prevalence as well as mortality of RA appear to have fallen in women in the last 50 year(2). Besides involvement of the synovium, this systemic disease can lead to clinical symptoms outside the joints, the so-called extra-articular manifestation. Many patients have non-specific complaints including fatigue, anorexia, weight loss and increased body temperature. Another relative common clinical feature is nodulosis. This subcutaneous swelling is predominately located on the bony prominences and consists of inflammatory cells with central necrosis. Other, more severe extra-articular manifestations with considerable morbidity and mortality are mononeuritis (multiplex), serositis, vasculitis as well as eye-involvement such as panuveitis. These severe extra-articular manifestations, as well as distinct destruction of the joint, occur most often in longstanding and active RA. Patients suffering from RA have decreased life expectancy due to cardiovascular complications, infections, (lympho-proliferative) malignancy or gastroenterological disease(3). Besides the direct clinical symptoms, RA is a severe disease associated with substantial individual and societal costs. Health care, loss of productivity and benefit payments for work disability contribute to increased expenses(4;5). The diagnosis RA is based on the clinical findings in combination with specific laboratory and radiographic features. The American College of Rheumatology (ACR 1987) criteria(6) (see table) describe the classification criteria, including signs and symptoms that are associated with relatively advanced disease. At the first presentation, recognition of RA by the clinical symptoms may be difficult since the start of the disease can be diverse ranging from slowly progressive to acutely disabling(7). One third of patients who present with undifferentiated arthritis (UA) progress to the rheumatoid arthritis, yet, the clinical phenotypes of these patients can not be distinguished from those who do not progress to RA or who go into spontaneous remission (approximately 50%)(8;9). The clinical outcomes of the disease appear not to depend on the tempo in which the clinical symptoms develop(7). For this reason, prediction of the clinical course of the disease based on the initial clinical picture is difficult. The presence of the auto-antibodies, e.g. rheumatoid factor (RF) and anti-citrullinated protein/ peptide antibodies (ACPA), may help making an early diagnosis. These auto-antibodies occur much more frequent in UA patients who progress to RA(10) and appear to develop already years prior to the first symptoms of arthritis(11). Recently, ACPA results were integrated in a prediction model that was developed to estimate the chance of progression to RA in individual patients presenting with UA(12).. Chapter 1.

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(10) American College of Rheumatology classification criteria RA: the presence of 4 or more of the following criteria: morning stiffness morning stiffness in and around joints lasting for at least 1 hour before maximal improvement poly-arthritis soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician arthritis of the hand joints swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints symmetric arthritis rheumatoid nodules subcutaneous nodules over bony permanencies, extensor surfaces or in juxta-articular region rheumatoid factor radiographic erosions The criteria 1 through 4 must have been present for at least 6 weeks.. pathogenesis The cause of rheumatoid arthritis is still unknown. Both genetic and environmental factors play a role in the development of the disease. Genetic factors probably account for ~60% of disease susceptibility and expression. It has been suggested that the composition of the peptide-binding site by the shared epitope (SE) region on the HLA-DRB1 gene(13;14) resulted in presentation of arthritogenic peptides to T cells contributing to the pathogenesis of RA(15). In the resulting inflammation activated (T- and B-) lymphocytes, macrophages, cytokines (including TNF-Ơ) as well as synoviocytes play an important role. The presence of the shared epitope is a risk factor for the development of ACPA(16) and presence of ACPA is correlated with the severity of the disease(17). Previous observational studies indicated smoking as an important environmental risk factor contributing to the development of RA(18). Further investigations have shown that tobacco exposure is a risk factor for development of ACPA only in patients who carry HLA-DRB1 SE alleles(13;19). In patients with ACPA-negative rheumatoid arthritis HLA-DR3 was more frequent present indicating a different pathogenetic mechanisms underling ACPA-positive and ACPA-negative RA(20).. treatment Untreated or insufficiently treated RA will result in joint destruction and permanent disability and an at least 2-fold increase in mortality(3;21). Mortality appears to be increased due to specific causes such as infections, lympho-proliferative malignancies, gastro-enterological diseases and the inflammatory character of the disease itself(3). More recently it has been shown that patients with rheumatic arthritis have an increased risk of cardiovascular disease (CVD) which is not fully explained by the traditional. 8.

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(18) risk factors of CVD(22). Active inflammation and secondary disability are two of the major risk factors for CVD in patients with active RA(23). Recent data indicate that suppression of inflammation reduces the risk of CVD morbidity and mortality in patients with severe RA(22). Nowadays, the goal of treatment is to relieve symptoms, to prevent joint damage and to decrease the excess of mortality. Treatment of RA has changed considerably over the last decades. Before the 1980s patients were treated according to a “pyramid schedule” starting with non-steroid anti-inflammatory drugs (NSAIDs) for all patients and the introduction of disease modifying anti-rheumatic drugs (DMARDs) was reserved for ‘severe cases’ expressing rapid joint destruction. Subsequently, it became obvious that (early) introduction of DMARDs was important to delay the progression of joint damage(24;25). Nevertheless, it proved to be very difficult to stop or alter the course of the disease with the available drugs. In the next years, newer DMARDs and especially DMARD-combination therapy were initiated. Therapy strategies starting with, or moving quickly on to, a combination of drugs resulted in more and earlier effective suppression of the inflammation and the clinical symptoms as well as of radiological damage progression(26-30).. monitoring of disease activity In order to register disease activity in RA patients a Disease Activity Score (DAS) has been designed. The DAS can be calculated by a formula using the following parameters: number of tender and swollen joints, erythrocyte sedimentation rate (ESR) and a global health assessment. The score was first designed for clinical research(31), however, the DAS has become an important measurement for clinicians in order to adjust therapy(32). Currently, the most commonly used disease scores are the original DAS based on evaluation of 44 joints, and the DAS28, describing disease activity in 28 joints (see figure).. Chapter 1.

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(26) DAS-guided therapy Besides the application of intensive therapy in patients with (early) RA, DAS-guided therapy can further improve the clinical outcome of a patient with RA. Recently, a survey of clinical trials using tight control demonstrated a higher rate of remission compared to earlier trials and/or control groups(33). The TICORA trial demonstrated that compared to ‘routine care’, DAS-guided outpatient management is superior in improving the symptoms of RA and in preventing radiographic damage progression(30). Also in the CAMERA trial, intensive and frequent surveillance of patients aimed at achieving a set goal of low disease activity(27). The remarkable results of the DAS guided BeSt study(34) -more than 80% of patients in all 4 treatment arms achieve the goal of low disease activity, more than 40% achieved remission- demonstrate that rheumatologists have to target themselves and their patients higher goals in terms of aiming low disease activity or even remission, and use the available drugs until that goal is achieved. Once low disease is achieved the probability of maintaining a low DAS without further treatment adjustments is high as again demonstrated in the BeSt(35).. window of opportunity In recent years the treatment of RA has become more focused on optimal intervention in the early phase of the disease(36). It has been demonstrated that patients treated in this period have higher response rates to therapy than those receiving delayed treatment(25) and experienced less radiographic damage over time(24). A meta-analysis confirmed the perspective that early treatment was associated with sustained benefit in terms of less radiographic progression for up to even 5 years(37). It is hypothesized that intensive treatment in the early phase of the disease, the so-called “window of opportunity”, may not only result in a rapid and effective induction of low disease activity but may also effectively change the clinical course of the disease(38). The terms ‘remission’ and ‘remission induction’, both previously unknown in the vocabulary of rheumatologist and patients, have recently been introduced as possible treatment goals. Several studies gave support to the “window of opportunity” hypothesis. The BeSt demonstrated the superiority of initial intensive combination therapy -either with prednisone or infliximab- resulting in earlier achievement of low disease activity and remission and less progression of radiographic damage(26). This trial was also the first that allowed patients with permanent low disease activity to discontinue all medication after a prolonged period of drug tapering. Depending on the therapy, drug free disease remission (defined as DAS<1.6) was achieved in up to 18% of the patients(34). Both clinical remission and radiographic non-progression were achieved in 80% of patients with early severe rheumatoid arthritis after 1 year of combined treatment with etanercept plus MTX (COMET)(39). In another approach, the PROMPT trial showed that, in ACPA positive patients with UA, the clinical diagnosis of RA could be postponed by treating them with MTX(40). Unfortunately, most patients still developed RA after MTX was discontinued, indicating that MTX in these patients is not the right drug to induce remission during the “window of opportunity”.. 10.

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(34) The timing and duration of the “window of opportunity” is not known and the optimal therapy in order to induce disease remission is still under debate(41). Ideally, optimal timing and therapy would collaborate in a cure for early RA. It appears however, that the symptoms of joint inflammation may be a relative late manifestation of a disease process that may have started with auto-antibody formation(11) prior to the clinical picture defined as RA. Also the high rate of early erosions -up to 80%- in trials especially focused on early RA like BeSt and COBRA(26;28), suggests already longstanding inflammation of the joint prior to establishing the diagnosis. Identification of risk factors for the development of clinical diagnosis RA remains a challenge and it is currently unknown if intervention at the stage of asymptomatic RA would be superior to safe, effective and affordable treatment of early symptomatic RA.. anti-rheumatic drugs Several “conventional” DMARDs are currently available for the treatment of RA, such as methotrexate (MTX), sulphasalazine (SASP), leflunomide, gold salts, hydroxychloroquine (HCQ), azathioprine and cyclosporine. These drugs are moderately to well tolerated(42) and to some extent effective in suppressing the rheumatoid process(43), but this last claim depends on the definition of ‘effective’, which over time has become more stringent(44). Several comparative drug studies have shown that, in the majority of patients, anti-TNF therapy results in earlier and lower disease activity as well as better improvement of functional ability than treatment with MTX, either after previous failure on DMARDs or in untreated early RA(26;39;45-48). Furthermore, with the “conventional” DMARDs, prevention of joint damage progression seems inferior to that achieved with anti-TNF. Unfortunately, some patients do not benefit (enough) from treatment with these agents. Only between 46% and 67% of patients with advanced RA show a 50% improvement in clinical outcomes, and between 20% and 30% of patients show no significant improvement at all(49-51). In a systematic review the efficacy of the different TNF blocking agents was not different(52). In case of (secondary) inefficacy and/or a (allergic) side effect, in many countries patients may switch to a second TNF-blocking agent or other biologicals such as anti-B cell therapy or anti-activated T-cell therapy. However, study results on switching biological therapies are difficult to interpret because the definitions of the reasons for switching are often as vague as the definition of ‘success’ or ‘failure’ on the second drug. The efficacy of DMARDs can be increased by adding corticosteroids. In literature, most reports describe combination therapy with oral prednisolone, however, from a practical point of view, in daily practice parenteral administration of corticosteroids, intra-muscular or intra-articular, is used frequently. Initially corticosteroids were welcomed as a wonder drug in the late 1940s-1950s. Cortisone proved very effective in suppressing the inflammation of rheumatoid arthritis(53,54), however, later reports on side effects of long term and relatively high dose corticosteroids led to increasing reservations against using these drugs, both in physicians and in patients(55). These reservations remain to this day, although physicians and patients appear to be concerned about different side effects(56-58). Despite these limitations, it is adequately. Chapter 1.

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(42) proven that combination therapy with DMARDs and prednisolone is very effective as treatment for rheumatoid arthritis(59,60) and that during the use of low dose and short term the clinically significant side effects appear to be absent or manageable. When in the BeSt study, initial combination therapy with methotrexate, sulphasalazine and tapered high dose of prednisone was head to head compared to initial combination therapy with methotrexate and infliximab, a TNF-blocker, patients in both arms showed equal improvement and suppression of radiological damage over the first 2 years of follow up(61), although patients treated with infliximab showed greater improvement in quality of life(van der Hout ACR 2009), and appeared to be happier with the treatment received than patients treated with prednisone(62). Three TNF-blocking agents are currently registered in the Netherlands for the treatment of RA. Two monoclonal antibodies are used: infliximab (Remicade®; chimeric mouse-human antibody) and adalimumab (Humira®; humanised antibody). The third anti-TNF is a fusion-protein: etanercept (Enbrel®). TNF-blocking agents are administrated via intravenous infusion (infliximab) or subcutaneous injection (etanercept/ adalimumab). Infliximab and adalimumab are both monoclonal antibodies targeting free as well as bound TNF. In contrast, etanercept is a TNF-receptor only binding to free TNF. To date, in the Netherlands patients are reimbursed for treatment with a TNF-blocker only if at least 2 conventional DMARDs, including MTX, are unsuccessfully tried. Since TNF is produced locally in the synovium, intra-articular injections of infliximab and etanercept have been tried with varying results(63). For a long time, the optimal timing for the introduction of a TNF-blocking agent in RA had not been defined. The BeSt study evaluated the use of infliximab in four different treatment strategies (see below for details of the study design) and showed that initial treatment with a combination of drugs, including infliximab or prednisone, was more effective than initial treatment with monotherapy(26). Furthermore, initial treatment with infliximab was better than delayed treatment with anti-TNF after failure on conventional DMARDs(64). The higher costs of initial infliximab can probably be compensated by less indirect societal costs as patients treated with initial infliximab have less sick leave and work more paid hours(65). A French study suggests that even a period of three months methotrexate monotherapy, before treatment with anti-TNF, resulted in a delay of clinical improvement in the majority of patients but not in significant less usage of anti-TNF(66).. working mechanism of anti-TNF The 17 kDa polypeptide cytokine Tumor Necrosis Factor (TNF) is an important mediator of inflammation. The name stems from the fact that TNF, when administered locally in high dose, induces tumor necrosis. However, produced chronically it may in fact act as a tumor promoter(67;68). Induction of TNF by pathogenic stimuli induces a cascade of other inflammatory proteins such as cytokines and chemokines resulting in recruitment and activating of a range of cells at the site of the infection or tissue damage(69). A negative feedback mechanism controls this process. In auto-immune diseases, such as RA, there appears to be an imbalance between pro- and anti-inflam-. 12.

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(50) matory stimuli. TNF plays an important role(70). TNF is produced by macrophage cells as response to cytokines produced by activated CD4+ T-cells. Besides TNF, the macrophages produce other pro-inflammatory cytokines such as IL-1 and interferon. TNF binding to the target cell results in increased number of adhesion molecules of the endothelium (resulting in an increase of inflammatory cells), release of metalloproteïnasen (resulting in destruction of extracellular matrix) and production of proinflammatory cytokines. In RA the net effect is pro-inflammatory excess resulting in persistent inflammation with all its clinical characteristics. In humans the TNF-blocking agent infliximab demonstrated for the first time a reduction in disease activity and erosive damage(71). Infliximab binds to TNFƠ which in turn prevents the binding of TNFƠ to its receptors on the cell surface, prohibiting the start of the intracellular signal cascade that leads to more pro-inflammatory activity. In vitro, infliximab was found to bind to TNFƠ already bound to the cell receptors, which resulted in cell death(72;73). Whether this also happens in the living organism is unknown. Due to its mode of action, the anti-inflammatory effect of treatment with infliximab may therefore in theory be associated with an increased susceptibility to infections.. adverse events during treatment with anti-TNF: infectious Already in the 90’s, clinical observations demonstrated an increased risk for infection during the use of “conventional” DMARDs(74;75). Based on the theoretic risk, it cannot be ruled out that some of the reports on an increased number of serious infections in relation to anti-inflammatory drugs are subject to expectation bias. It is likely that physicians, and also patients after instruction, are more aware of possible signs and symptoms of infections, will investigate these more thoroughly, and are more prone to treat with intravenous antibiotics. On the other hand, such awareness might lead to an underestimation of the infectious risk because patients are instructed to come in earlier and may be treated with oral antibiotics, or other beneficiary treatment, in the earliest stages of what otherwise might have become a serious infection. In any case, increased numbers of (opportunistic) infections have been reported(76-79), and on the other hand, large database studies appear to demonstrate no significant increase of infections compared to MTX(80) or only an increase of non-serious infections of the skin and soft tissues(81). Annalists of the British Society for Rheumatology Biologics Register found that the adjusted incidence rate ratio for a serious infection in patients receiving anti-TNF compared to patients receiving “conventional” DMARDs was not increased(81). Interestingly, limiting the follow up to 90 days revealed a 4.6 times higher incidence ratio. The increased incidence ratio may be explained by the interruption of anti-TNF after a serious side effect, such as infection or allergic reaction. In RA patients the overall risk for infections -resulting in hospitalisation- seemed raised due to various associated risk factors such as leucopenia, extra-articular manifestation, increased age, co-morbidity and steroid-usage(83;84). Other factors influencing the number of infections may be differences in presence or virulence of specific pathogens in the general population. An example is the high background presence of latent tuberculosis in many countries in Europe, compared to the US (see below).. Chapter 1.

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(58) tuberculosis After the introduction of TNF-blocking agents their was an increase in the incidence of granulomatous infectious diseases, especially mycobacterium tuberculosis, in patients treated with these agents, and the clinical presentation also seemed more severe than in patients without anti-TNF(85-89). The rise in tuberculosis infections seemed mainly the result of reactivation of latent tuberculosis, which is present in a considerable part of the population in certain parts of Europe(89;90). After an infection with mycobacterium the micro-organisms that survive are sequestered in granuloma(91). TNF is required for the development and persistence of this granuloma. During anti-TNF therapy this defence mechanism is obstructed resulting in an active infection. Following these observations, screening for (latent) tuberculosis has been recommended by medical society committees such as the Dutch Society for Rheumatology(87;89;92;93). Prior to the start of a TNF blocking agent the patient should be screened by medical history, clinical examination, chest X-ray and a PPD (purified protein derivative) skin test. In patients over age 65 years an initially negative test should be repeated (twostep PPD). In case of positive findings for latent tuberculosis the patient should receive prophylactic therapy prior to the start of anti TNF. Patients with active tuberculosis are excluded from use of TNF blocking agents. influenza Influenza is a common viral infection with a high disease burden, causing significant morbidity and mortality in both immunocompetent and immunodeficient hosts(94). Although data on an increased morbidity and mortality due to influenza in patients treated with anti-TNF are lacking, guidelines recommend that patients at risk for complications of influenza, including those treated with anti-TNF, should be annually vaccinated against influenza(95;96). The use of immunosuppressive therapy can reduce the response upon vaccination. Data on the immunologic response to influenza vaccination during anti-TNF therapy are scarce and conflicting(97-100) and data on the clinical relevance of this vaccination in these patients are altogether lacking.. adverse events during treatment with anti-TNF: neurological A pivotal role for TNF in the pathogenesis of inflammatory demyelinating disease of the central nervous system has been suggested in several studies of MS in humans and in experimental autoimmune encephalomyelitis(101). TNF is overproduced in the serum and cerebrospinal fluid of MS patients and by resident and infiltrating cells at sites of CNS injury. There were high expectations that the use of anti-TNF-alpha in MS patients could suppress progression, but a randomized trial was adjourned prematurely because of an increase in exacerbations(102). On the other hand, new-onset neurologic signs and symptoms with signs of demyelination in the central nervous system have been reported in patients using TNF-blocking agents(103). Also case reports were published of patients with optic neuritis which developed during treatment with anti-TNF(104). How demyelination would be a result to use of anti-TNF is unknown, although several explanations have been proposed(105). Large database research, however, did not show an increase in neurological symptoms in patients treated with. 14.

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(66) TNF-blockers compared to the general population, which puts a direct link between the use of TNF-alpha blockade and demyelination under debate(103;106;107). Still many agree that it seems prudent to avoid the use of anti-TNF in patients with a history of demyelination. In contrast to possible negative side effects of TNF blocking agents, from clinical experience it certainly appears that many patients experience an improvement in quality of life and wellbeing that rises above the degree of clinical improvement in the signs and symptoms of RA. On the other hand it has been suggested that inflammatory responses, including an increased TNF, may have an important role in the pathophysiology of depression(108;109). Also, an association of a TNF-308G/A promoter polymorphism with schizophrenia and bipolar affective disorder in a Polish population has been identified(110). This has resulted in speculation on a possible role of TNF and TNF blockade in mental processes.. discontinuation of anti-TNF in treatment of RA: Serious adverse events would of course be a reason to discontinue anti-TNF, as would be lack of response (see below). Discontinuation because of a good response was rarely tried in daily practice, since it was demonstrated that discontinuation led to exacerbation of the inflammatory process(111). Quinn et al were the first to demonstrate that in patients with early RA, initial treatment with anti-TNF could be discontinued without loss of efficacy(112). This was again shown on a larger scale in the BeSt study(26). The BeSt study is a randomized trial comparing the clinical and radiographic outcomes of 4 different treatment strategies: sequential monotherapy (group 1; start with MTX, subsequent steps for patients with an insufficient response were: SASP monotherapy, leflunomide monotherapy, MTX with infliximab, further steps), stepup combination therapy (group 2; start MTX, subsequent steps for patients with an insufficient response were: SASP added, followed by the addition of HCQ and then by prednisone, MTX with infliximab, further steps), initial combination therapy with MTX and tapered high-dose prednisone (group 3, subsequent steps for patients with an insufficient response were combination of MTX with ciclosporin and prednisone, MTX with infliximab, further steps), and initial combination therapy with MTX and infliximab (group 4, subsequent steps for patients with an insufficient response were SASP, leflunomide, further steps). The common goal in all strategies was to reduce disease activity rapidly and persistently by tight monitoring and immediate adjustment of therapy in the case of an insufficient response. Treatment adjustments were based on the DAS that was measured every 3 months and 1 to 2 weeks prior to each infliximab infusion by a research nurse who remained blinded for the allocated treatment strategy. Good clinical response to therapy was defined as a DAS ≤2.4, indicating low disease activity. If this was not achieved, the next step in the protocol was accomplished. According to the protocol, in case of persistently low disease activity (DAS ≤2.4 for at least 6 consecutive months) treatment intensity was reduced. In case of combinations of drugs, the drugs were discontinued one by one as long as a DAS ≤2.4 was maintained. The results of the BeSt study showed that more patients had earlier and. Chapter 1.

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(74) better clinical response, and less joint damage progression, after initial treatment with combination therapy, either including prednisone or infliximab, than after initial treatment with MTX monotherapy (and subsequent steps if necessary). More than 50% of patients who had started treatment with MTX and infliximab and achieved a DAS ≤2.4 could permanently discontinue infliximab without loosing the clinical response. These results demonstrated that “window of opportunity”, where the RA process can be effectively arrested or even reversed, probably exists and that infliximab can be effective as ‘remission induction therapy’, with the additional benefits of reduced exposure time, less risks for side effects and less costs in the long term. Another indication for the “window of opportunity” is the experience in the BeSt that using MTX plus infliximab as initial treatment for recent onset RA patients is more effective than reserving MTX plus infliximab for patients who failed on traditional DMARDs(64).. switching anti-TNF As pointed out before, in clinical trials up to 70% of RA patients showed at least some improvement after treatment with anti-TNF. Approximately 30% did not achieve clinical improvement. Predictors of non-response were smoking and high disease activity and no relation between the efficacy of TNF blocking agents and age, disease duration, rheumatoid factor or number of DMARD was demonstrated(113). In daily clinical practice, as registered in an open database of anti-TNF use by rheumatologists joined in the DREAM (Dutch Rheumatoid Arthritis Monitoring), the response rate appeared to be lower compared to previous randomised controlled trials(114). This was possibly due to the inclusion of patients with different disease characteristics at the onset of anti-TNF therapy compared to the ones included in randomised clinical trials. Although the net result for all TNF-blockers is the same, which is inhibition of TNF, the mechanisms of action are slightly different. This suggests that, in case of primary inefficacy -immediate insufficient clinical response to an anti-TNF-, switching to another TNF-blocker may be successful(115). However, the results of the ‘switch studies’ are sometimes difficult to interpret because the reasons for discontinuation of the first TNF-blocker were not always clear and the criteria for claiming ‘success’ were not always very strict. Secondary inefficacy -a loss of the original response to a TNF-blocker after some time- is thought to be associated with the development of antibodies against the TNF-blocking agent(116). Reports on switching to another TNF-blocker in these patients suggest that this could be as successful as in primary inefficacy. However, a recent study suggests that patients who produced antibodies against one TNF-blocker have a higher likelihood to produce antibodies to a second one(117). The development of these antibodies affects the clinical response to treatment. It is therefore sometimes suggested that after failure on a TNF-blocker, other targeted therapies may be superior to another TNF-blocker(118;119).. 16.

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(82) other targeted therapy In recent years, anti-B-cell treatment (rituximab), anti IL-6 (tocilizumab) and regulation of T-cell interaction (abatacept) have been introduced for the treatment of RA, and are generally marketed for patients who failed on anti-TNF. Initial trials have shown promising response rates(118;120;121), but in daily practice experience with these drugs is still limited. Other biological therapies are in advanced stages of development and testing: new TNF-blockers golimumab and certolizumab (pegolated anti-TNF), ofatumumab (anti-CD20) and oral JAK and Syk inhibitors(122-126). These drugs give hope for patients who have failed on anti-TNF but may also in due time find a place in the treatment of patients with early RA.. outline of the thesis The current thesis investigates some practical aspects of the use of anti-TNF in daily practice. In chapter 2 we describe the efficacy and safety of a second TNF-Ơ blocking agent, adalimumab, in patients who had an inadequate response or a side effect on infliximab causing them to stop that drug. During anti-TNF-alpha therapy, neurologic symptoms ascribed to demyelination have been reported. There are also links between pro-inflammatory cytokines, including TNF, and behavioural disorders, notably depression(109;127). In chapter 3 we describe the effect of anti-TNF-alpha on the brain parenchyma by using magnetic resonance (MR). National and international guidelines advise influenza as well as pneumococcal vaccination in immunocompromised patients, including patients using TNF-blocking agents. In chapters 4 and 5 we report on the efficacy of influenza and pneumococcal vaccination in patients using anti-TNF-Ơ therapy compared to that in healthy individuals and in patients using other (non-biological) immunosuppressive therapy. Chapter 6 is a report on the use of a combination of infliximab plus methotrexate as initial therapy in patients with recent onset RA. The impact of intensive therapy with infliximab in early RA provides new insights in the clinical course of the disease and could change the way the new biological drugs are positioned in the treatment of RA. We speculate on the possibility of remission induction treatment with infliximab. Currently the use of anti-TNF-Ơ is focused on systemic treatment of patients with a poly-arthritis such as in patients with RA. In cases of mono-arthritis, intra-articular treatment with corticosteroids is the advocated approach. However, recurrent inflammations are frequent, and a more effective therapy would be desirable. Theoretically, intra-articular therapy with anti-TNF-Ơ could be very effective. In chapter 7 we evaluated the effect of infliximab intra-articular in patients with a recurrent and/or chronic gonarthritis. Advanced, insufficiently controlled rheumatoid inflammation affects organs and body tissues outside the joints. This is a condition that is called rheumatic vasculitis. This condition has a high morbidity and mortality, and for the traditional therapy with high dose corticosteroids and immunosuppressants, the same is true. Anti-TNF is probably a safer therapy and has been tried, with various successes, as treatment in patients with rheumatoid vasculitis. In chapter 8 we report a case of a patient treated with infliximab.. Chapter 1.

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