Before we get to the list, let’s just talk a little bit about why I am such a proponent of sending postcards. The one thing to remember is that it doesn’t cost any more to send a great design than it does to send out a plain old boring, run of the mill crappy Realtor postcard. If they can’t find your house on the internet, there is a good chance they will never know it is for sale! Home for sale inventory is low and I have a buyer looking in your neighborhood…thinking of selling?
Tara’s “tell it like it is” personality combined with her 100 miles per hour presentations have earned her the title “The Queen of Marketing Ahhh’s” from her raving fans. Edit and print your own calendars for 2016 using our collection of 2016 Calendar Templates for Excel.
OpenOffice Users: The calendar templates below are Excel files that can also be opened using OpenOffice. 2016 Yearly Calendar Template - Create a calendar for 2016 or any year, using our Excel templates.
Every year, the CQC rates the Trusts' Mental Health Services, based on the National Patient Survey. Our Multi-Professional Care Philosophy is that we aspire to: Continue to improve the quality of our services with and for patients.
Making Every Contact Count (MECC) is about using every opportunity to talk to individuals about improving their health and well being. The Energise for Excellence vision is for at least 200,000 nurses, midwives and health visitors to sign up to Energise for Excellence, take action and tell others their quality and cost saving stories. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Small Molecule DMARD Therapy and Its Position in RA TreatmentHiroaki Matsuno1[1] Matsuno Clinic for Rheumatic Diseases, USA1.
Figure 3 illustrates the sales of 3 biological TNF antagonists per 100,000 populations in each country. Contemporary disease modifying antirheumatic drugs (DMARD) in patients with recent onset rheumatoid arthritis in a US private practice: methotrexate as the anchor drug in 90% and new DMARD in 30% of patients. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial.
A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
Disease activity, physical function, and radiographic progression after longterm therapy with adalimumab plus methotrexate: 5-year results of PREMIER. Direct medical costs and their predictors in patients with rheumatoid arthritis: a three-year study of 7,527 patients.
Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Radiological and clinical results of longterm treatment of rheumatoid arthritis with methotrexate and azathioprine.
The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis.
Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis.
I was an active Realtor in the state of Florida from 2007-2008 during probably the worst time in history to work that market.
This is because of two things… 1) people got them and put them in their drawer to remember who to call when they needed a Realtor and 2) because I often sent out beautiful cards that were suitable for framing or hanging on a bulletin board. I have to say that having spent the last couple of hours looking at sites offering realtor marketing for great designs, the pickings are pretty slim out there.
Check out her marketing courses and products at the Marketing Artfully Shop or visit her Etsy Store, Paperly People.
However, if you want a calendar designed specifically for OpenOffice.org, use the link to the right. You can also use these calendar images as clipart in brochures, documents, and printed calendars.
Albert Einstein Derbyshire Healthcare NHS Foundation Trust is delighted to announce a new Centre for Research and Development (R&D).
We value each person as an individual, respect their aspirations and commitments in life, and seek to understand their priorities, needs, abilities and limits. It sets out rights to which patients, public and staff are entitled, and pledges which the NHS is committed to achieve, together with responsibilities which the public, patients and staff owe to one another to ensure that the NHS operates fairly and effectively. Innovation, Health and Wealth: Accelerating Adoption and Diffusion in the NHS, published in December 2011, said that Innovation must become core business for the NHS Innovation is the only way we can meet the challenges we face.
This guidance is about enabling patients to make informed choices by involving and supporting them in decisions about prescribed medicines.
Under the Energise for Excellence umbrella we have gathered an array of tools, approaches and measures that will help you respond to the call to action and decide which priorites you want to focus on so that you can be confident that your patients receive the best possible care. Cumulative continuation rate of triple DMARDs combination therapy in JaSTAR Stady, Cumulative continuation rate of TNF inhibitors in DANBIO study was superimposed. IntroductionSmall molecule disease-modifying antirheumatic drugs (DMARDs) played a central role in drug therapy for rheumatoid arthritis (RA) before biological preparations (biologics) came into extensive use for the treatment of this disease. American College of Rheumatology ‘08 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis.
Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Here are 50 of the best kinds of postcards that you can send out to your clients, prospects and past clients to generate leads and make more sales.
But I thrived because I did direct mail campaigns right into the neighborhoods I was trying to target AND sent postcards to my sphere. Instead of paying good money for sending some kind of crap design, make sure you take a little time and figure out a really cute card to send that might actually get noticed! We also have some yearly 2016 calendar images that you can use in documents or on your website (with attribution). These images are copyrighted, but you may use them if you include a reference link back to this page, like the example below. This new centre was opened on 17 April 2013, by Jane Cummings, Chief Nursing Officer for England. Our ambition is for Derbyshire Healthcare NHS Foundation Trust to be defined by its commitment to innovation. QIPP - The NHS Quality, Innovation, Productivity and Prevention Challenge: an introduction for clinicians. Unlike non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, which primarily alleviate the symptoms of RA such as pain and inflammation, DMARDs are known to suppress the progression of RA through their action against immunological abnormalities. In these countries, patients are usually required to pay no money or only very small amounts (less than 1,000 yen) as out-of-pocket payment during each visit to a medical facility [10,51]. We want your ideas as Innovation moves within Derbyshire from being a minority sport to become a core activity; the way we do our business. The consumption tax rate is high (about 20 to 30%) in these countries, and a large portion of the consumption tax collected is spent for social welfare, including medical expense.
The White paper Liberating the NHS expressly refers to the NHS Constitution and how it will be upheld. It may be that combining them will give you even better outcomes and a strong platfrom from which to begin your quality and cost reduction journey.
During the 1990s through the 2000s, the strategy and goals of RA therapy have undergone marked changes following the introduction of methotrexate (MTX) as another treatment option, the expansion of MTX as an anchor drug [2,3,4], endorsement of the usefulness of combined drug therapy involving DMARDs [5], the introduction of biologics into RA treatment [6,7,8], and other advances. By supporting and encouraging staff to own the research and development centre, staff will be supported not only in research but also with the implementation of their work. Together they build a picture of life in the county and help to identify where improvements are needed. In 2002, the American College of Rheumatology (ACR) released its Guidelines on RA Management, clearly indicating DMARDs as first-line drugs for the treatment of RA.
Excluding Medicare and Medicaid for elderly people, physically handicapped citizens and low-income families, healthcare in the United States depends on private sector insurance not mandatory for individual citizens. As a result, NSAIDs and steroids came to be positioned as auxiliary means of treating RA [9].The small molecule DMARDs that have been used frequently in Western countries are MTX, sulphasalazine (SASP), hydroxychloroquine (HCQ), leflunomide (LFN), and minocycline (MIN). The premium for private health insurance is high, and a high percentage of uninsured people is often highlighted as a social problem in this country.


In Japan, where the repertoire of drugs clinically available differs from that in Western countries, HCQ and MIN are not indicated for RA under the national health policy, and bucillamine (BUC) has been a more popular small molecule DMARD than these 2 drugs.The use of biologics such as TNF inhibitors began to spread around the world within several years of their clinical introduction as drugs that exert rapid action and are expected to improve long-term prognosis and to allow patients with RA to maintain physical function [10]. For individuals covered by health insurance, the out-of pocket payment is not very large, although it varies depending on the insurance plan selected by individuals. During the 2000s, revisions of the guidelines on RA treatment and criteria for diagnosis of RA were accelerated in various countries, with the goal of treatment shifting from symptom control (anti-inflammatory analgesia) and delayed disease progression to achievement of disease remission and suppression of disease progression. Furthermore, unique campaigns by pharmaceutical companies are available in the United States, promoting the treatment with biologics. The NHS provides a comprehensive service, available to all irrespective of gender, race, disability, age, sexual orientation, religion or belief. As an accumulation of clinical trial data became available revealing from a long-term perspective the advantageous effects of biologics not found in small molecule DMARDs, including suppression of progression of bone destruction and physical dysfunction [11,12], biologics began to replace small molecule DMARDs, primarily in patients anticipated to have a poor prognosis and those with rapidly advancing disease.
Under such campaigns, a majority of individual patient drug cost will be borne by the manufacturer to take over if the patients agree to treatment with specific drugs for a certain period of time and are registered with the treatment programs (RemiStart, Enbrel Support, My Humira, etc).In Japan, however, annual out-of-pocket payment amounting to about 400,000 to 500,000 yen (about 5000 to 6500 dollars) is needed for many patients receiving treatment with biologics, excluding some patients covered by social welfare programs for reduction of out-of-pocket payment of healthcare expenses (specific physically handicapped individuals, individuals covered by poverty program, and so on). It has a duty to each and every individual that it serves and must respect their human rights.
At the same time, it has a wider social duty to promote equality through the services it provides and to pay particular attention to groups or sections of society where improvements in health and life expectancy are not keeping pace with the rest of the population. These issues represent obstacles to the establishment of biologics as a predominant means of treatment for RA. In recent years, several reports have been published in the United States and Europe providing data intended to serve as evidence for the view that treatment with a combination of 3 small molecule DMARDs is expected to improve long-term prognosis of RA to an extent comparable with biologics.
Current standard of care for RA It has been shown that intervention with biologics at early stages of RA is expected to control the disease activity and suppress subsequent joint destruction, thus facilitating remission of RA, biologics free and cure [52].
However, according to the Best study [53], the long-term outcome of treatment differs little among different treatment strategies.
It has thus been suggested to be more important to practice tight control through adjusting treatment flexibly depending on the disease activity in individual cases, instead of selecting biologics from the beginning (Figure 4).In 2012, the ACR published the "2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis," and recommended separate methods of treatment for patients at early stages of RA (less than 6 months after onset) and patients with established RA (6 months or more after onset) [18]. According to the revised guidelines, intervention with biologics is recommended for cases of established RA if the RA cannot be adequately controlled with recommended DMARD therapies (Figure 5).
Popular small molecule DMARDsDMARDs is the collective term for a set of drugs known to suppress the progression of RA via action against immunological abnormalities. The procedure for treatment under this system is more concrete than the ACR recommendations, and permits moving to therapy with biologics (anti-TNF preparations) or tocilizumab in cases that are poorly controlled despite attempts of treatment with DMARD combination therapy including MTX, even at the highest possible dose levels (Figure 6).
We put patients first in everything we do, by reaching out to staff, patients, carers, families, communities, and professionals outside the NHS.
DMARDs are generally slow in action, taking 1 to 3 months until manifestation of their effects. However, permission for the use of these biologics under the British system requires that the manufactures bear any individual drug costs exceeding ?9296 per year.16. The response to these drugs varies greatly among individuals, and a number of patients fail to respond to treatment with DMARDs.
Comparison between small molecule DMARDs combination therapy and biologics plus MTX combination therapyRegarding drug therapy at early stages of RA, the two-year data were recently reported on multicenter comparative clinical studies of three small molecule DMARDs combination therapy (MTX + SASP + HCQ) and biologics plus MTX combination therapy in the United States (TEAR study) [55] and Sweden (Swefot trial) [56]. Furthermore, patients whose disease activity is initially controlled by DMARDs sometimes cease to respond to the drugs (relapse) during prolonged use. In the TEAR study, the outcome as to DAS28-ESR did not differ between the oral triple therapy and the etanercept plus MTX combination therapy (first endpoint), and ACR20 and 50 was observed no difference between the two groups.
Another characteristic of DMARDs is a high incidence of adverse reactions, with the incidence of adverse events with each DMARD being between 20% and 50%. If adverse reactions are mild, treatment with DAMARDs can be often continued by means of dose reduction or symptomatic treatment, but the risk that patients will develop life-threatening serious adverse reactions, including hematological disorders, renal disorder, and interstitial pneumonia, is common.Some DMARDs are immune suppressors that are also used for control of host rejection of grafts and treatment of cancer, including MTX, LFN, tacrolimus (TAC), cyclosporine, azathioprine, and cyclophosphamide.
The NHS works across organisational boundaries and in partnership with other organisations in the interest of patients, local communities and the wider population.
The class also includes immune modulating agents, such as SASP, BUC, d-penicillamine, gold compound, and others, as well as HCQ, an anti-malaria agent, and MIN, an antibiotic (Table1).Here, the popular DMARDs used clinically are described.
The TEAR study revealed no difference between the oral triple therapy group and the biologics plus MTX combination therapy group from the 12th month on after the start of treatment, while the Swefot trial disclosed higher efficacy of biologics plus MTX combination therapy during the first 6-12 months of treatment, followed by gradual disappearance of the inter-group difference during the two-year follow-up period. The NHS is an integrated system of organisations and services bound together by the principles and values now reflected in the Constitution. BUC is approved as a DMARD for treatment of RA only in Japan and Korea, and currently, the use of BUC is almost exclusively confined to Japan, where this drug is still used in quantities as large as SASP, second to MTX among the approved DMARDs. 3. The NHS is committed to working jointly with local authorities and a wide range of other private, public and third sector organisations at national and local level to provide and deliver improvements in health and well-being. The drug has been reported to exert immunosuppressive activity through its action (suppression of proliferation) on immune competent cells by means of DNA synthesis inhibition, and to exert anti-inflammatory activity by inducing pooling of adenosine [19]. Details are unknown about the mechanism of its antirheumatic activity, but the drug has shown excellent efficacy and long duration, and it is the most frequently used small molecule DMARD in the world as an anchor drug for RA treatment [3,4]. The most recent guidelines recommend early initiation of treatment with MTX as a first-line drug in patients with factors associated with poor prognosis such as positive ACPA, bone erosion, extra-articular symptoms, or restricted physical function [18]. In Japan, HCQ has not been approved for use in the treatment of RA because of adverse reactions. Among the antirheumatic drugs, MTX tends to exert its effects relatively early (within 1 to 2 months) and these effects include suppression of joint destruction [20,21].Table 1summary of small molecule DMARDsAdverse reactions to MTX include infection, stomatitis, glossitis, nausea, hepatic dysfunction [22], and others. The three drug combined therapy (MRX + SASP + HCQ) is therefore not practically possible in Japan.
It is known that these adverse reactions are more likely to appear in patients with compromised renal function and in elderly patients, and that they can be reduced by concomitant use of folic acid or leucovorin [23,24,25].
The NHS is a national service funded through national taxation, and it is the Government which sets the framework for the NHS and which is accountable to Parliament for its operation. To date, case registration has been completed, achieving the targeting number (160 cases), and each patient enrolled to the study is now under follow-up. However, most decisions in the NHS, especially those about the treatment of individuals and the detailed organisation of services, are rightly taken by the local NHS and by patients with their clinicians. Interim analysis of the data during the first 6 months revealed a similar DAS28 remission rate between the three DMARDs combination therapy group and the biological TNF antagonists plus MTX combination therapy group (Figure 8). The system of responsibility and accountability for taking decisions in the NHS should be transparent and clear to the public, patients and staff. The treatment continuation rate among the 33 cases where one-year data have been analyzed was superior over the anti-TNF therapy continuation rate previously reported from the DANBIO registry [68] (Figure 9).
The Government will ensure that there is always a clear and up-to-date statement of NHS accountability for this purpose. Introduction of new small molecule DMARDs for RA treatmentIt is known that among the drugs currently used for treatment of RA, those targeted at cytokines, all of which fall under the category of biologics, have yielded particularly favorable outcomes. However, unless the open issues mentioned above are resolved, it is unlikely that biologics will play a central role in the treatment of RA. It is known that the effects of MTX are strengthened by concomitant use of biologics [27].4. One of them, tofacitinib, has been developed with attention focused on the role of cytokines in RA.
Sulphasalazine (SASP)This drug exerts action relatively rapidly (in 1 to 2 months) among the DMARDs. If tofacitinib is shown in clinical practice to be a means of RA treatment possessing both the advantages of biologics and the advantages of small molecule DMARDs, it is expected that another paradigm shift will occur in RA management.
The antirheumatic activity of SASP has not been sufficiently clarified, but because it suppresses joint destruction [20], it is considered as an option for treatment of RA with MTX.
As compared to other DMARDs, SASP can be characterized by low nephrotoxicity, and the risk for teratogenicity in pregnant women is also considered to be lower with SASP than with other DMARDs. It is shown to be an inhibitor of Janus kinase 3 (JAK3), an enzyme reported to be involved in cytokine receptor signal transduction. Adverse reactions to SASP include liver disorder, drug eruption, bone marrow disorders, and others. To date, tofacitinib has been experimentally shown to suppress all JAKs (1 through 3), rather than manifesting selective action against any particular JAK. Because the incidence of gastrointestinal disorders as an adverse reaction is high with the bulk form of SASP, it is usually administered in the form of an enteric-coated tablet for the treatment of RA. In May 2012, the US FDA issued an approval recommendation for the use of this drug in adults with moderate or severe RA. Leflunomide (LFN)LFN is a metabolic antagonist capable of suppressing the proliferation of T lymphocytes through pyrimidine synthesis inhibition [20]. According to the results of clinical trials, treatment with tofacitinib for 3 months achieved a semi-favorable (about 50%) ACR20 in patients who were responding poorly to TNF inhibitor treatment, with a placebo group achieving about 25%.
Clinical trials have also been conducted for tofacitinib as a first-line drug, and in patients responding poorly to MTX, each yielding favorable outcomes.
This drug is therefore reported to be promising not only as an additional option during biologic therapy but also as a first-line drug. Adverse reactions to LFN include infection, diarrhea, bone marrow disorders, hypertension, liver disorder, nausea, alopecia, and others.


Adverse reactions that require caution are elevations in blood cholesterol levels and neutrophilia.20.
Interstitial pneumonia is an adverse reaction that requires utmost caution and is potentially fatal. IguratimodIguratimod was formulated as a COX2 inhibitor and was later found to have immune modulating activity. For a couple planning pregnancy, it is necessary for both partners to take cholestyramine to eliminate the active metabolites of LFN completely. Iguratimod has been shown to be useful in combination with other drugs in patients failing to respond well to MTX.
Hydroxychloroquine (HCQ)HCQ was used as an anti-malaria agent before it was used as an antirheumatic drug [32]. The anti-malaria activity of HCQ is considered to have no relationship to its antirheumatic activity.
While it is also known that treatment with biologics is useful in cases of high activity RA, even in these cases, there may be patients for whom combination therapy using existing DMARDs should be considered before introduction of biologics. HCQ is believed to suppress antigen presentation by elevating the pH of the cytoplasmic compartment of antigen-presenting macrophages [33]. More recently, it was reported that HCQ acts on the toll-like receptor to manifest effects on the immune system [34]. Although the tolerability is high, adverse reactions such as nausea and dizziness occasionally appear.
Furthermore, the drug has a high affinity for the retina and thus exerts high ocular toxicity. Although retinal disorders induced by HCQ are irreversible and if severe can lead to blindness, recovery from retinal disorders is sometimes possible if they are detected early.
Minocycline (MIN)The US Food and Drug Administration (FDA) has not approved MIN for treatment of RA. However, a slow efficacy of this drug against RA has been shown in some double-blind trials [36,37,38,39]. Although the usefulness of this drug as a means of treatment for RA is low, it has evidenced effects at early stages of RA. Compounds of the tetracycline family are known to suppress matrix metalloproteinase [40], and this action is believed to suppress narrowing of the joint space in patients with RA. The activity of MIN as an antibiotic is considered to have no relationship to its antirheumatic activity.8. Its antirheumatic activity is slightly stronger, that is comparable to or higher than, that of SASP [41,42]. The pharmacologic actions that have been reported as likely to be involved in the drug's antirheumatic effects include suppression of cytokine production in the synoviocytes [43], suppression of antibody production from B-lymphocytes [44,45], and suppression of osteoclast differentiation [46]. According to a recent report, the effect of this drug in inhibiting Akt signals is involved in the suppression of antibody production from B-lymphocytes and the suppression of cytokine production by the synoviocytes [47,48]. Numerous adverse reactions including renal disorders and skin disorders are known, with serious adverse reactions including interstitial pneumonia and hematological disorders, and therefore patients must be watched closely.
The known effects of TAC include inhibition of the proliferation and differentiation of T lymphocytes involved in persistence of RA-associated inflammation and suppression of inflammatory cytokine production. It shows excellent efficacy when used as an additional drug in combination therapy for patients who have insufficient response to MTX alone [49]. In Western countries, this drug is not used frequently because the results of clinical trials of mono-therapy have been unsatisfactory, and the ACR has not advocated the use of TAC as a means of treating RA because of its insufficient efficacy [18].
Adverse reactions to TAC include headache, renal disorders, hyperglycemia, hyperuricemia, hypertension, and others. Since TAC is less likely to affect the respiratory system, it is occasionally used in patients who have respiratory complications. Gold CompoundTwo formulations of gold compound (injection and oral-dose preparations) are available. The response rate is relatively high, but effects are usually not evident until after 3 to 6 months. The frequency of discontinuation of treatment due to adverse reactions is high, with skin and mucosal disorders being the most frequent causes for discontinuation. Adequate monitoring for proteinuria and renal dysfunction is necessary, and care is also needed regarding hematological disorders, since leukopenia, thrombocytopenia, and hypoplastic anemia can develop following treatment with this drug.
The efficacy of the oral-dose preparation is less than that of the injection and takes up to 9 months to appear.
Adverse reactions to the oral-dose preparation are akin to those of the injection, although the incidence of renal and hematological disorders is slightly lower with the oral preparation.11. AzathioprineThis drug is a purine analog and is shown to exert immunosuppressive effects by antimitotic action induced by inhibiting the synthesis of DNA and proteins. Adverse reactions to azathioprine include gastrointestinal disorders, liver disease, leukopenia, and others.12. CyclosporineCyclosporine is an immune suppressor that is generally used as means of suppressing host rejection of grafts. This drug suppresses the production and physiological actions of interleukin-2 and lymphocyte growth factor, taking 6 to 12 weeks before manifestation of its efficacy against RA. Frequently observed adverse reactions to this drug include renal disorders, hypertension, gingival thickening, increased body hair, and others. Cyclosporine is recommended only for treatment of severe and advanced RA that has failed to respond to other drugs.13. CyclophosphamideCyclophosphamide is an alkylating agent with nonspecific cytotoxic activity. This dug has been positioned to play an important role in the treatment of SLE and vasculitis. Changes in the position of small molecule DMARDs in the treatment of RAAccording to the pyramid therapy [1] model that had been established by the beginning of the 1990s, RA treatment focused on alleviation of symptoms (pain, inflammation, etc.) with the use of NSAIDs and steroids at sufficiently high doses. Use of antirheumatic drugs was confined to cases with marked progression of bone erosion and other severe manifestations. It was noted that in cases requiring treatment by NSAIDs and steroids inflammation appeared to subside gradually by means of burnout over time. However, the RA itself remained unchanged and bone destruction continued to advance, accompanied by progression of joint dysfunction [50].
MTX had become clinically available for use in the treatment of RA in the 1980s to 1990s, and subsequently began to be used extensively as an anchor drug for the treatment of RA [2,3,4].
In the management of RA, MTX was positioned as a drug whose necessity would be determined on the basis of the severity of the disease, and which would become indispensable in cases where the disease severity exceeded a certain level.
After the mid-1990s, a series of data were published that provided new evidence of the efficacy of combined DMARD therapy (2 or 3 DMARDs) as compared to DMARD mono-therapy, stimulating active adoption of DMARD combination therapy.
During this time, MTX also came to be positioned as a key drug in combination therapy, and to date, the prominence MTX as an anchor drug has not changed [5]. From the late 1990s to the 2000s, biologics, primarily TNF inhibitors, began to be introduced clinically as drugs expected to improve long-term prognosis and to maintain physical function [6,7,8], and by the 2000s, these events had led to an acceleration in some countries to revise existing treatment guidelines and diagnostic criteria for RA, which was accompanied by a shift of the focus of treatment from anti-inflammatory analgesia and delay of disease progression to achievement of disease remission and prevention of progression. The RA management guidelines that were published by the ACR in 2002 positioned DMARDs as first-line drugs for RA treatment, which were to be started within 3 months after disease onset, while positioning NSAIDs and steroids as auxiliary drugs for symptoms such as pain and inflammation [9]. These guidelines additionally recommended switching patients to different DMARDs if the initially prescribed DMARDs failed to exert sufficient efficacy within 3 months of the initiation of treatment. This guideline clearly positioned MTX as an anchor drug, allowing clinicians to acknowledge that a current framework of RA treatment had been decided at that time. It was also recommended by this guideline that biologics should be used in cases that were failing to respond well to treatment with DMARDs, including MTX. We may infer that in their early days, the clinical use of biologics was confined to intractable cases because this class of drug had not yet been evaluated in a sufficient number of cases (Figure 1). During the period from the late 1990s to 2000s, as a series of new biologics were introduced and the clinical trial data on these drugs accumulated, it was suggested by some of these data that active use of biologics beginning soon after disease onset might be advantageous in some patients in terms of efficacy of long-term RA management, notably when focusing on the effects of biologics in suppressing progression of bone destruction and physical dysfunction, which were not seen with small molecule DMARDs [11,12].
In some patients, primarily those anticipated to have poor prognoses and those with rapidly progressive RA, biologics began to replace small molecule DMARDs. Campaigns promoting a better long-term prognosis by earlier start of treatment with biologics based on these developments and bolstered by financial programs that assisted patients with out-of-pocket payments for biologics created stiff competition over biologics among manufacturers, and has reportedly promoted an increase in the quantity of biologics used for RA treatment.
However, there are still many open issues surrounding biologics, including the high percentage of patients who fail to respond to biologics [14], the high price that causes large burdens on individuals and society [15], and the risk of serious adverse reactions such as infection [16,17]. The use of DMARDs, primarily in combination therapy, has also fallen under renewed scrutiny following publication of new studies.



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