Methotrexate and Oral Antirheumatic Drugs

Health Topics for Tokyoites Juntendo Medical Journal 2020. 66(1), 27-33 Methotrexate and Oral Antirheumatic Drugs

KWANGSEOK YANG＊1),MASAKAZU MATSUSHITA＊2),NAOTO TAMURA＊2)

＊1)Department ofGeneral Medicine, Juntendo University Faculty ofMedicine, Tokyo, Japan, ＊2)Department ofInternal Medicine and Rheumatology, Juntendo University Faculty ofMedicine, Tokyo, Japan

Methotrexate (MTX) and biological agents have revolutionized the rheumatoid arthritis (RA) treatment by shifting the focus from alleviating pain to preventing joint degeneration, improving the quality of life and remission ofthe disease. Many guidelines list MTX as a firstline and an anchor drug and recommend use ofbiologic agents or Janus kinase (JAK) inhibitors when responses to MTX treatment are not adequate. However, in clinical practice we encounter patients for whom this strategy is not feasible for various reasons, and others in whom good outcomes can be achieved with conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than MTX; thus, csDMARDs continue to be used for RA today. Thorough understanding of the characteristics ofother csDMARDs and their appropriate usage are important in RA care, rather than exclusive reliance on MTX and biologic agents. Key words: rheumatoid arthritis (RA), methotrexate (MTX), conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs)

Introduction followed by the approval of biological agents in 2003 that could specifically target tumor necrosis factor Rheumatoid arthritis (RA) is one ofthe most α (TNFα). Subsequently, other agents that could common connective tissue disorders and is primar- target interleukin-6 (IL-6) and a fusion protein of ily caused by immune dysfunction. It involves cytotoxic T-lymphocyte associated antigen 4 chronic inflammation of the synovial tissues lining (CTLA-4) and Fc portion ofimmunoglobulin G the joints, and is accompanied by pain, swelling, and were also approved as therapies for RA. Further- deformities. Prolonged inflammation can cause more, low molecular weight compound inhibitors bone, cartilage, and ligament destruction as well as against janus kinase (JAK) have also been ankylosis and tendon ruptures, resulting in signifi- approved 1). These agents are highly effective in RA cant decline in joint function. The medical treat- treatment and have made it possible to shift the ments for RA were once dominated by nonsteroidal goal ofRA treatment to structural and functional anti-inflammatory drugs (NSAIDs) and conven- remission instead ofjust clinical remission, as was tional synthetic disease modifying antirheumatic the case before. The 2016 Update of the European drugs (csDMARDs), such as gold sodium isothio- league against rheumatism (EULAR) recommen- malate (GST), auranofin, bucillamine (BUC), and dations for the management of rheumatoid arthritis sulfasalazine (SSZ); however, they were limited in with synthetic and biological disease modifying their therapeutic effects. Moreover, in Japan, antirheumatic drugs also recommends use ofMTX methotrexate (MTX) was approved in 1999, as a first-line drug, unless it is contraindicated, then,

Corresponding author: Kwangseok Yang Department ofGeneral Medicine, Juntendo University Faculty ofMedicine 3-3-20 Shinsuna, Koto-ku, Tokyo 136-0075, Japan TEL: +81-3-5632-3111 E-mail: [email protected] 43rd Health Topics for Tokyoites: Latest Rheumatoid Arthritis Medical Care and Its Important Points〔Held on Jan. 19, 2019〕〔Received Apr. 23, 2019〕〔Accepted Dec. 25, 2019〕

Copyright © 2020 The Juntendo Medical Society. This is an open access article distributed under the terms ofCreative Commons Attribution Li- cense (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited. doi: 10.14789/jmj.2020.66.JMJ19-R05

27 Yang K, et al: Methotrexate and oral antirheumatic drugs

Table-1 Antirheumatic drugs approved in Japan and their characteristics Year of Route of Precautions and examples of Generic name Maximum dosage approval administration severe adverse reactions Immunomodulators Intramuscular Rash, proteinuria, interstitial pneumonia, gold sodium thiomalate 1970 100 mg/week injection anaplastic anemia Rash, liver disorder, proteinuria, myelo- d-penicillamine 1970 Per os 600 mg/week suppression, dysgeusia, induction of autoimmune disease 240 mg/day, increase Acute renal failure, gastrointestinal dis- lobenzarit 1986 Per os dosage as needed order, rash auranofin 1986 Per os 6 mg/day Diarrhea, soft stool, rash Rash, proteinuria, interstitial pneumonia, bucillamine 1987 Per os 300 mg/day dysgeusia actarit 1994 Per os 300 mg/day Rash, gastrointestinal disorder Rash, gastrointestinal disorder, abnormal sulfasalazine 1995 Per os 1,000 mg/day liver function, myelosuppression Abnormal liver function, gastrointestinal iguratimod 2012 Per os 50 mg/day disorder Immunosuppressants 150 mg/day, increase mizoribine 1994 Per os Abnormal liver function, hyperuricemia dosage as needed Stomatitis, abnormal liver function, inter- methotorexate 1995 Per os 16 mg/week stitial pneumonia, myelosuppression, gastrointestinal disorder 100 mg/day x 3 days, Abnormal liver function, interstitial leflunomide 2003 Per os then 20 mg/day pneumonia, myelosuppression tacrolimus 2004 Per os 3 mg/day enal disorder, impaired glucose tolerance

the early administration ofbiological agents and matic drugs available in Japan are shown in JAK inhibitors is indicated should the response to Table-1. MTX be poor 2) 3). However, biological agents and JAK inhibitors may be contraindicated or usually 1. Methotrexate (MTX) avoided in patients with complications, such as lung diseases, serious infection, active tuberculosis, MTX is one ofthe strongest inhibitors ofdisease refractory nontuberculous mycobacterial infections, activity and osteoclast function among the and malignancies, such as lymphoproliferative csDMARDs. Early intervention with MTX is disorders and severe allergies. And these medica- recommended after RA diagnosis as per the tions are unaffordable in some patients. MTX or treatment guidelines ofmany countries and regions other csDMARDs or their combinations are particu- including the EULAR guidelines, which should be larly important for these patients. MTX is the first followed in the absence of contraindications 2) 3). line csDMARDs in the treatment algorithm ofthe MTX has a long history ofuse; it was synthesized Japan College ofRheumatology (JCR) guideline for in the 1940s as an antifolate, and its efficacy for RA the use ofMTX in patients with rheumatoid was reported subsequently in the 1980s 5). Today, it arthritis; however, alternatives such as BUC, SSZ, is considered an effective“anchor”drug for RA leflunomide (LFM), tacrolimus (TAC), and igurati- treatment and has contributed to breakthroughs in mod (IGU) are recommended when the use of RA therapy. It is important to note that among the MTX is not feasible 4). This article outlines the DMARDs, it has an extremely low rate ofescape mechanism ofaction, usage, adverse events, and phenomenon. After oral administration, MTX is cautions with the use ofMTX and other immediately incorporated into blood cells via the csDMARDs in clinical practice. The list ofantirheu- reduced folate carrier. A glutamate in MTX is then

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metabolized to polyglutamates (MTX-PGs) during toms, such as stomatitis and nausea, liver dysfunc- weeks, and the MTX-PGs levels has been reported tion, and cytopenia due to bone marrowsupression. to consistently correlate with its efficacy and Since MTX is primarily eliminated by renal toxicity. The mechanism ofaction ofMTX or MTX- excretion, its dosage must be closely monitored and PGs is still unclear, however, it is considered mainly adjusted in individuals with reduced renal function, due to the inhibition ofpyrimidine synthesis by elderly, and patients with low body weight 6). inhibiting dihydrofolate reductase and prevention Screening before and monitoring after adminis- oflymphocyte proliferationby inhibiting DNA tration ofMTX is extremely important. Blood tests synthesis. The in vivo antirheumatic effects of MTX and chest radiography are performed before are believed to involve anti-inflammatory effects administration to assess the liver and kidney through the inhibition ofproliferationofmonocytes, function and the presence of abnormal blood cells, macrophages, neutrophils, vascular endothelial pulmonary lesions, such as interstitial pneumonia cells, and synovial fibroblasts, and by reducing (IP), pulmonary or extrapulmonary tuberculosis, synovial inflammation 6). and hepatitis B virus. In particular, in patients who First approved in the Japanese market as a RA have not been vaccinated for hepatitis B, virus treatment in 1999, MTX has since been widely used reactivation can be seen in individuals who are HBs for the treatment of RA patients. Though it is used antibody (Ab) or HBcAb positive, even ifthey are as 15-20 mg weekly doses in Western countries, the HBs antigen negative; although this can rarely maximum dosage at the time ofapproval forRA in happen, it is important to examine this before MTX Japan was 8 mg/week. Due to lack ofprevious administration 7). Furthermore, laboratory data, experience with the use ofthis drug, it was not including blood cell counts and liver functions, accepted as a first-line drug in the beginning. should be regularly monitored by blood tests after However, given the dose-dependent efficacy of MTX administration to avoid missing the signs of MTX, and data from Western countries showing adverse events, such as myelosuppression, abnor- that MTX had greater potential to inhibit the mal liver function or infection. Particularly, the progression ofRA joint destruction at higher doses, complaints offeverand respiratory symptoms, such the public knowledge-based application was as cough and expectoration could be the early approved because of the continued efforts of the symptoms ofserious complications, such as IP and JCR in 2011 allowing the administration ofup to 16 pneumocystis pneumonia. Thus, chest radiography, mg/week doses in Japan. Subsequently, high CT scans, and sputum examination should be remission rates, inhibition ofjoint destruction, and performed appropriately. In recent years, MTX- good adherence rates were observed in patients associated lymphoproliferative disorder (MTX- who were started on MTX treatment during the LPD) is drawing attention in addition to the side early period after the onset. Thus, the revised effects mentioned above. MTX-LPD is a lympho- (JCR) guideline for the use of methotrexate in proliferative disorder commonly seen in patients patients with rheumatoid arthritis, published in who have been on MTX therapy for 2 or more September 2016, indicates that aggressive treat- years. The common histological classification is ment with MTX as first-line therapy should be diffuse large B-cell lymphoma, if not otherwise started in the early period after onset in RA specified (DLBCL, and latent infection of EB virus patients presenting poor prognosis factors, such as (EBV)), that occurs at a high frequency. The high levels ofrheumatoid factor(RF) and anti- lesions may not only be seen in the lymph nodes; cyclic citrullinated peptide (CCP) antibodies, or extranodular lesions are also often found in the oral with early joint destruction 4). In clinical practice, cavity, pharynx, skin liver, spleen, and lungs. Since MTX treatment is started at a 4-8 mg weekly dose, complete remission is known to occur by discontin- which can be increased up to 16 mg weekly doses if uing MTX treatment in certain number ofpatients the effects are insufficient. However, weekly doses with this lymphoproliferative disorder, it is essential over 8 mg are divided into 2-4 doses and 5-10 mg of to discontinue MTX treatment first if this disease is folic acid is added 24-48 h after the final dose to diagnosed. Links between MTX-LPD and TNFα prevent adverse events, including digestive symp- inhibitors and calcineurin inhibitors has also been

29 Yang K, et al: Methotrexate and oral antirheumatic drugs

suggested; thus, these drugs are also contraindi- some commonly encountered adverse reactions in cated after remission 8). TAC therapy. Since it is metabolized by CYP3A4 in the liver, it should be administered with caution in 2. Tacrolimus (TAC) patients taking other drugs that are also metabolized by CYP3A4; specifically, the contraindications Immunosuppressant TAC is a 23-membered include coadministration with cyclosporin, bosen- macrolide lactone, which was isolated as a metabo- tan, and potassium sparing diuretics. Several lite ofStreptomyces tsukubaensis, an actinomycete agents, such as macrolide antibiotics, azole antifun- discovered in a soil sample from Mt. Tsukuba in gals, calcium channel antagonists, and omeprazole 1985. TAC binds to FK-binding protein (FKBP) in can elevate blood TAC levels and should therefore the cytoplasm ofT cells to forma complex that can be used with caution. Grapefruit also has the same inhibit calcineurin, thereby inhibiting the nuclear effect. Conversely, antiepileptic drugs, such as translocation ofnuclear factorofactivated T cells carbamazepine and rifampicin lower the blood TAC (NFAT), which is a regulatory factor for various levels, and thus, also warrant caution 11) 12). cytokines including IL-2 that inhibits T cell activity 9). Kitahara et al demonstrated the expres- 3. Bucillamine (BUC) sion ofFKBP and calcineurin genes in the synoviocytes ofjoints ofRA patients, and that adding TAC BUC is the analog version ofD-penicillamine can inhibit the production ofinflammatorycyto- developed in Japan and was approved for RA in kines in these cells 10). Therefore, the anti-rheumatic 1987. Currently, it is approved for insurance only in effects of MTX involve action on not only T cells but Korea and Japan. BUC has two SH bases in contrast also on synoviocytes. TAC had mainly been used to to one in D-penicillamine. The antirheumatic treat graft versus host disease (GVHD) in bone properties ofBUC involve the followingmecha- marrow transplants or to reduce graft rejection in nisms: once taken into the body in its unaltered the liver or renal transplants, myasthenia gravis form, SA96 inhibits B cell antibody production. Its (MG), or externally for atopic eczema. Its efficacy metabolite SA981, which forms a ring structure for RA was also evaluated in 2005, after which it containing a disulfide bond (S-S bond) inhibits the was approved as an insurance-covered treatment production ofIL-6 and IL-8. Furthermore, it for RA. It is even indicated for RA not treatable by inhibits the differentiation of marrow-derived MTX or that does not respond adequately to MTX. fibroblast-like cells and the production of matrix In general, approximately 3 mg/day is the optimal metalloproteinases (MMP)-1 and vascular endo- dose with careful monitoring to avoid exceeding a thelial growth factor (VEGF) to inhibit osteoclast trough blood concentration of10 ng/d l. However, differentiation 15). given that it can be effective at low doses, low doses BUC are available in 50 mg and 100 mg tablets. In ofaround 1-1.5 mg are ideal, particularly forthe routine clinical practice, it is used within the daily elderly 11) 12). In a multicenter open-label study by dose range of100-300 mg. However, it can be Kremer et al on 80 MTX-resistant RA patients, adequately effective at lower doses; since adverse 53.3% ofpatients achieved the American College of reactions often increase in a dose-dependent Rheumatology definition of 20% improvement manner, it is ideal to start at a 50 mg or 100 mg daily (ACR20) with MTX and TAC combination ther- dose. Since this agent is not immediately effective, apy, while only 27.6% ofpatients who switched to several weeks to months are required to assess the TAC only therapy achieved ACR20, showing that efficacy. Several studies have assessed its safety the efficacy of TAC is increased in combination and efficacy: Sagawa et al found moderately with MTX 13). Furthermore, a Japanese study by improved disease activity score 28 (DAS28) in Morita et al also showed good efficacy of TAC and 87.5% ofthe 81 DMARDs-naïve RA patients after MTX combination therapy for RA without increas- 24 months ofBUC monotherapy. Another 24 ing the adverse reactions 14). The digestive disor- months later, 60.5% still adhered to BUC, ofwhich ders, such as nausea, renal disorder, impaired 59.2% underwent BUC monotherapy, demonstrat- glucose tolerance, and susceptibility to infection are ing high efficacy, safety, and adherence rate of BUC.

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Higher efficacy and adherence rates were also with active RA, and showed that the patients who found in early RA patients (within 2 years of onset) took SSZ and LEF achieved ACR20 and ACR50 at undergoing BUC and MTX combination therapy the rates of56% and 30%, and 55% and 33%, than those who underwent BUC therapy alone 16) 17). respectively. SSZ and LEF were both effective for The adverse reactions to BUC include skin RA with no significant differences observed symptoms, such as rash and yellow nail syndrome, between the two therapies; thus, SSZ is anticipated dysgeusia, myelophathy, proteinuria, and IP. Protei- to have efficacy comparable to LEF 21). The maxi- nuria is often caused by membranous nephropathy mum recommended daily dose in Western coun- and can be improved by discontinuing BUC therapy tries is 2,000 mg, whereas the data on efficacy and in its early stages. However, cases with high levels safety have indicated that 1,000 mg is the maximum or prolonged proteinuria may require adequate daily dose in Japan. The starting dose is 500 mg, and treatment, such as treatment with steroids. A it is recommended to increase the dose gradually if differential diagnosis with renal amyloidosis and there are no problems. SSZ is the first-line drug for other disorders may be required, but as ofthe mild to moderate early RA with no factors of poor present, the incidence has dropped dramatically prognosis, or RA in which adverse reactions or because the number ofpatients with poorly complications prevent the use ofMTX. Skin controlled RA has decreased 16). symptoms, such as rash and erythema, are typical adverse reactions and can become severe in some 4. Sulfasalazine (SSZ) patients. Gastrointestinal disorders, such as the abnormal liver function, nausea, diarrhea, head- SSZ is a DMARDs developed by Nanna Svartz et aches, and dizziness, and myelopathy including al in 1938 and is the oldest treatment that is still leukocytopenia are the other adverse reactions that frequently used for RA. Approved for ulcerative patients undergoing this treatment should be colitis in Japan in 1969, it also became approved for monitored for. Many adverse reactions appear RA after its efficacy for this disease was assessed in within 1-3 months ofintroducing the therapy, but 1995. SSZ is composed ofanti-inflammatorydrug some, including myelophathic reactions, may 5-aminosalicylic acid (5-ASA) that is linked to appear after a long duration of therapy, and antibiotic sulfapyridine (SP) by an azo bond. The therefore, constant monitoring for these symptoms speculated mechanisms ofaction ofSSZ forRA is required. SSZ is contraindicated in patients with a involve inhibition ofthe maturation ofdendritic history ofsensitivity to sulfadrugs and salicylic cells by inhibiting nuclear factor-kappa B (NF-κB), acids, warranting screening ofthese patients before inhibition ofT cell mediated inflammatorybowel administration ofSSZ 18) 20). disease through cytokine and antibody production, and inhibition of osteoclast differentiation by 5. Iguratimod (IGU) reducing the expression ofreceptor activator of NF-κB ligand (RANKL) and nuclear factor of Similar to BUC, IGU is a DMARDs that was activated T cells 1 (NFATc1), and the inhibition of developed in Japan, and was approved for RA cartilage cell destruction by inhibiting the produc- treatment in September 2012. Its structure consists tion ofcollagenases 18). oftwo types ofamide groups introduced into a There have been many assessments ofsafetyand chromone skeleton and is the newest ofthe efficacy of SSZ for RA. Capell et al reported the csDMARDs. Its mechanisms ofaction forRA safety and efficacy of MTX and SSZ combination involve inhibiting the production ofhuman macro- therapy in a controlled trial ofSSZ monotherapy phage-derived inflammatory cytokines TN Fα, versus SSZ and MTX combination therapy for 687 IL-1β，IL-6, IL-8, and monocyte chemotactic RA patients 19). Another study reported that the protein-1 (MCP-1) and inhibition ofthe production efficacy of SSZ was approximately similar to that of of immunoglobulins by directly affecting the B MTX 20). Smolen et al conducted a three-armed cells 22). The clinical non-inferiority to SSZ was controlled trial ofSSZ, LFM (described in detail proven in a controlled efficacy trial, and signifi- later), and a placebo for 24 weeks on 358 patients cantly better therapeutic outcomes ofIGU

31 Yang K, et al: Methotrexate and oral antirheumatic drugs

combination therapy were achieved in patients who involved 27). Due to the above reasons, use ofLFM in did not respond adequately to MTX. Furthermore, Japan is extremely limited. good tolerability to long-term administration for 52 weeks has also been confirmed 23). However, when 7. Other csDMARDs IGU was started at 50 mg daily, the levels of aspartate aminotransferase (AST) and alanine In addition to the drugs described above, aminotransferase (ALT) increased at higher rates mizoribine, another immunosuppressant developed than a 25 mg daily dose; thus, it is considered better in Japan and immunomodulators, such as actarit, to start at 25 mg daily for 4 weeks, then increase to GST, auranofin, d-penicillamine, and lobenzarit are 50 mg, as needed after confirming the absence of also DMARDs approved in Japan. However, for the adverse effects on the liver function. Furthermore, most part, these are only used when the response to IGU is contraindicated in patients with peptic ulcer, MTX is inadequate or when other csDMARDs and it must be avoided to administer with warfarin cannot be used, and it has become rare for some of because it possibly induces gastrointestinal bleed- them to be prescribedon new patients due to safety ing. IGU is indicated for RA when the standard or efficacy issues 3) 4). therapy with MTX is not possible because ofany reason, or when the responses to MTX are not Conclusions adequate 24). This article has summarized csDMARDs, which 6. Leflunomide (LFM) are the treatments for RA. Recent advances in molecular biology have contributed to better LFM is an isoxazole derivative DMARD with an understanding ofthe details ofRA pathology, and antirheumatic action that targets dihydroorotate the therapeutic strategies have also changed dehydrogenase (DHODH), which is involved in de dramatically. In particular, the approval ofMTX to novo pyrimidine nucleotide synthesis. The orally up to 16 mg maximum weekly dose and the administered LFM is absorbed in the digestive tract approval ofbiological agents targeting TNF α, IL-6, and is converted into teriflunomide (TER). TER and T cellshave improved the therapeutic goals of acts on de novo synthesis ofmitochondrial pyrimi- RA. However, there also remain many patients who dine by specifically inhibiting DHODH, thereby, cannot use these drugs despite needing them, due inhibiting the T and B cell proliferation and to adverse reactions or comorbidities. These drugs production ofinflammatorycytokines secreted by can also place a heavy financial burden on the the peripheral blood monocytes 25). LFM has been patients. There are ample reasons why csDMARDs used in western countries as a highly safe and should be indicated for such patients, some of whom effective RA treatment since 1998 and is considered may show a good response to them. Physicians an important csDMARDs, such as SSZ 26).Itwas treating RA should always keep in mind the option approved in Japan in April 2003 and has been used ofusing these alternatives to MTX and biologics in on many RA patients. However, fatal IP occurred in their practice. 61 patients, corresponding to 12% ofthe 5,054 patients, who used the drug since it became References commercially available. The majority ofthese fatalities were due to acute pulmonary failure that 1) Mian A, Ibrahim F, Scott DL: A systematic review of occurred within 20 weeks ofstarting LFM therapy. guidelines for managing rheumatoid arthritis. BMC Rheumatol, 2019; 3: 42. Other factors related to this were considered to be 2) Smolen JS, Aletaha D, Bijlsma JW, et al; T2T Expert that it was administered to many patients for whom Committee: Treating rheumatoid arthritis to target: MTX could not be administered due to existing recommendations ofan international task force.Ann Rheum Dis, 2010; 69: 631-637. pulmonary lesions or through administration ofa 3) Smolen JS, Landewé R, Bijlsma J, et al: EULAR loading dose of100 mg for3 days anticipating high recommendations for the management of rheumatoid blood concentrations in short period. Genetic factors arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis, particular to East Asians may have also been

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