Editing Rheumatoid arthritis (section)

===Disease-modifying agents===
[[Disease-modifying antirheumatic drugs]] (DMARDs) are the primary treatment for RA.<ref name=ACR2015/> They are a diverse collection of drugs, grouped by use and convention. They have been found to improve symptoms, decrease joint damage, and improve overall functional abilities.<ref name=ACR2015/> DMARDs should be started early in the disease as they result in disease remission in approximately half of people and improved outcomes overall.<ref name=ACR2015/>

The following drugs are considered DMARDs: [[methotrexate]], [[sulfasalazine]], [[leflunomide]], [[hydroxychloroquine]], [[TNF inhibitor]]s ([[Certolizumab pegol|certolizumab]], [[adalimumab]], [[infliximab]] and [[etanercept]]), [[abatacept]], [[anakinra]], and [[auranofin]]. Additionally, [[rituximab]] and [[tocilizumab]] are monoclonal antibodies and are also DMARDs.<ref name=ACR2015/> Use of tocilizumab is associated with a risk of increased cholesterol levels.<ref>{{cite book | vauthors = Isaacs D | editor-first1 = Jasvinder A. | editor-last1 = Singh | title = Cochrane Database of Systematic Reviews | chapter = Tocilizumab for rheumatoid arthritis | series = Advances in Experimental Medicine and Biology | volume = 764 | pages = 151–158 | date = 2010-07-07 | publisher = John Wiley & Sons | pmid = 23654064 | doi = 10.1002/14651858.cd008331.pub2 }}</ref>

The most commonly used agent is methotrexate with other frequently used agents including sulfasalazine and leflunomide.<ref name=ACR2015/> Leflunomide is effective when used from 6–12 months, with similar effectiveness to methotrexate when used for 2 years.<ref>{{cite journal | vauthors = Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P, Wells G | title = Leflunomide for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD002047 | date = 2003 | volume = 2002 | pmid = 12535423 | doi = 10.1002/14651858.CD002047 | pmc = 8437750 }}</ref> Sulfasalazine also appears to be most effective in the short-term treatment of rheumatoid arthritis.<ref>{{cite journal | vauthors = Suarez-Almazor ME, Belseck E, Shea B, Wells G, Tugwell P | title = Sulfasalazine for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD000958 | date = 1998-04-27 | volume = 1998 | pmid = 10796400 | doi = 10.1002/14651858.cd000958 | pmc = 7047550 }}</ref>

[[Hydroxychloroquine]], in addition to its low toxicity profile, is considered effective for treatment of moderate RA symptoms.<ref>{{cite journal | vauthors = Suarez-Almazor ME, Belseck E, Shea B, Homik J, Wells G, Tugwell P | title = Antimalarials for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD000959 | date = 2000 | volume = 2010 | pmid = 11034691 | doi = 10.1002/14651858.CD000959 | pmc = 8407035 }}</ref> Pharmacokinetic characteristics of Hydroxychloroquine are complex due to the large volume of distribution, significant tissue binding, and long terminal elimination half-life.
Historically, terminal elimination half-lives were considered very long, 40–50 days for Hydroxychloroquine as compare to up to 60 days
for Chloroquine. More recent studies suggest a shorter half-life of about 5 days. A long Hydroxychloroquine half-life is attributed to extensive tissue uptake rather than to an intrinsic inability to clear the drug. The expected delay in the attainment of steady-state concentrations (3–4 months) may be in part responsible for the slow therapeutic response observed with Hydroxychloroquine.<ref>Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis. 2022 Feb 14;14:1759720X211073001. doi: 10.1177/1759720X211073001. PMID: 35186126; PMCID: PMC8848057.</ref>

Agents may be used in combination, however, people may experience greater side effects.<ref name=ACR2015/><ref>{{cite journal | vauthors = Katchamart W, Trudeau J, Phumethum V, Bombardier C | title = Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD008495 | date = April 2010 | volume = 2015 | pmid = 20393970 | doi = 10.1002/14651858.cd008495 | pmc = 8946299 }}</ref> Methotrexate is the most important and useful DMARD and is usually the first treatment.<ref name=ACR2015/><ref name=NICE2015/><ref name="chapter94">{{cite book | vauthors = DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM | date = 2008 | title = Pharmacotherapy: a Pathophysiologic Approach | edition = 7th | location = New York | publisher = McGraw-Hill | isbn = 978-0-07-147899-1 }}</ref> A combined approach with methotrexate and biologics improves ACR50, HAQ scores and RA remission rates.<ref>{{cite journal | vauthors = Singh JA, Hossain A, Mudano AS, Tanjong Ghogomu E, Suarez-Almazor ME, Buchbinder R, Maxwell LJ, Tugwell P, Wells GA | title = Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD012657 | date = May 2017 | issue = 5 | pmid = 28481462 | pmc = 6481641 | doi = 10.1002/14651858.cd012657 }}</ref><ref name=":16" /> This benefit from the combination of methotrexate with biologics occurs both when this combination is the initial treatment and when drugs are prescribed in a sequential or step-up manner.<ref name=":16" /> Triple therapy consisting of methotrexate, sulfasalazine and hydroxychloroquine may also effectively control disease activity.<ref>{{cite journal | vauthors = Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJ, Bombardier C | title = Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD010227 | date = August 2016 | volume = 2016 | pmid = 27571502 | doi = 10.1002/14651858.cd010227.pub2 | pmc = 7087436 }}</ref> Adverse effects should be monitored regularly with toxicity including gastrointestinal, hematologic, pulmonary, and hepatic.<ref name="chapter94" /> Side effects such as nausea, vomiting or abdominal pain can be reduced by taking folic acid.<ref>{{cite journal | vauthors = Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P | title = Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 5 | issue = 5 | pages = CD000951 | date = May 2013 | pmid = 23728635 | doi = 10.1002/14651858.CD000951.pub2 | pmc = 7046011 }}</ref>

Rituximab combined with methotrexate appears to be more effective in improving symptoms compared to methotrexate alone.<ref name=":0" /> Rituximab works by decreasing levels of B-cells (immune cell that is involved in inflammation). People taking rituximab had improved pain, function, reduced disease activity and reduced joint damage based on x-ray images. After 6 months, 21% more people had improvement in their symptoms using rituximab and methotrexate.<ref name=":0">{{cite journal | vauthors = Lopez-Olivo MA, Amezaga Urruela M, McGahan L, Pollono EN, Suarez-Almazor ME | title = Rituximab for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD007356 | date = January 2015 | issue = 1 | pmid = 25603545 | doi = 10.1002/14651858.CD007356.pub2 | pmc = 11115378 }}</ref>

Biological agents should generally be used only if methotrexate and other conventional agents are not effective after a trial of three months.<ref name=ACR2015/> They are associated with a higher rate of serious infections as compared to other DMARDs.<ref>{{cite journal | vauthors = Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, Ghogomu ET, Coyle D, Clifford T, Tugwell P, Wells GA | title = Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis | journal = Lancet | volume = 386 | issue = 9990 | pages = 258–265 | date = July 2015 | pmid = 25975452 | pmc = 4580232 | doi = 10.1016/S0140-6736(14)61704-9 }}</ref> Biological DMARD agents used to treat rheumatoid arthritis include: [[tumor necrosis factor alpha]] inhibitors (TNF inhibitors) such as [[infliximab]]; [[interleukin 1]] blockers such as [[anakinra]], [[monoclonal antibody|monoclonal antibodies]] against [[B cell]]s such as [[rituximab]], [[interleukin 6]] blockers such as tocilizumab, and [[T cell]] co-stimulation blockers such as abatacept. They are often used in combination with either methotrexate or leflunomide.<ref name=ACR2015/><ref name=Lancet2016/> Biologic monotherapy or [[tofacitinib]] with methotrexate may improve ACR50, RA remission rates and function.<ref>{{cite journal | vauthors = Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA | title = Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA) | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | pages = CD012437 | date = November 2016 | issue = 11 | pmid = 27855242 | pmc = 6469573 | doi = 10.1002/14651858.cd012437 }}</ref><ref>{{cite journal | vauthors = Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Maxwell LJ, Buchbinder R, Lopez-Olivo MA, Suarez-Almazor ME, Tugwell P, Wells GA | title = Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD012591 | date = March 2017 | issue = 3 | pmid = 28282491 | pmc = 6472522 | doi = 10.1002/14651858.cd012591 }}</ref> Abatacept should not be used at the same time as other biologics.<ref>{{cite journal | vauthors = Maxwell L, Singh JA | title = Abatacept for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007277 | date = October 2009 | volume = 2009 | pmid = 19821401 | pmc = 6464777 | doi = 10.1002/14651858.CD007277.pub2 }}</ref> In those who are well controlled (low disease activity) on TNF inhibitors, decreasing the dose does not appear to affect overall function.<ref name=":11">{{cite journal | vauthors = Verhoef LM, van den Bemt BJ, van der Maas A, Vriezekolk JE, Hulscher ME, van den Hoogen FH, Jacobs WC, van Herwaarden N, den Broeder AA | title = Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity | journal = The Cochrane Database of Systematic Reviews | volume = 5 | pages = CD010455 | date = May 2019 | issue = 6 | pmid = 31125448 | pmc = 6534285 | doi = 10.1002/14651858.CD010455.pub3 }}</ref> Discontinuation of TNF inhibitors (as opposed to gradually lowering the dose) by people with low disease activity may lead to increased disease activity and may affect remission, damage that is visible on an x-ray, and a person's function.<ref name=":11" /> People should be screened for [[latent tuberculosis]] before starting any [[TNF inhibitor]] therapy to avoid reactivation of tuberculosis.<ref name="McGraw Hill"/>

TNF inhibitors and methotrexate appear to have similar effectiveness when used alone and better results are obtained when used together.<ref>{{Cite report |url=https://doi.org/10.23970/AHRQEPCCER211 |title=Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update |last1=Donahue |first1=Katrina E. |last2=Gartlehner |first2=Gerald |date=2018-07-16 |publisher=Agency for Healthcare Research and Quality (AHRQ) |doi=10.23970/ahrqepccer211 |language=en |last3=Schulman |first3=Elizabeth R. |last4=Jonas |first4=Beth |last5=Coker-Schwimmer |first5=Emmanuel |last6=Patel |first6=Sheila V. |last7=Weber |first7=Rachel Palmieri |last8=Lohr |first8=Kathleen N. |last9=Bann |first9=Carla}}</ref> [[Golimumab]] is effective when used with methotraxate.<ref>{{cite journal | vauthors = Singh JA, Noorbaloochi S, Singh G | title = Golimumab for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD008341 | date = January 2010 | volume = 2010 | pmid = 20091667 | doi = 10.1002/14651858.CD008341 | pmc = 10732339 }}</ref> TNF inhibitors may have equivalent effectiveness with [[etanercept]] appearing to be the safest.<ref>{{cite journal | vauthors = Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordström DC, Blom M | title = Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e30275 | year = 2012 | pmid = 22272322 | pmc = 3260264 | doi = 10.1371/journal.pone.0030275 | veditors = Hernandez AV | bibcode = 2012PLoSO...730275A | doi-access = free }}</ref> Injecting etanercept, in addition to methotrexate twice a week may improve ACR50 and decrease radiographic progression for up to 3 years.<ref>{{cite journal | vauthors = Lethaby A, Lopez-Olivo MA, Maxwell L, Burls A, Tugwell P, Wells GA | title = Etanercept for the treatment of rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD004525 | date = May 2013 | volume = 2014 | pmid = 23728649 | doi = 10.1002/14651858.cd004525.pub2 | pmc = 10771320 }}</ref> Abatacept appears effective for RA with 20% more people improving with treatment than without but long term safety studies are yet unavailable.<ref>{{cite journal | vauthors = Maxwell L, Singh JA | title = Abatacept for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD007277 | date = October 2009 | volume = 2009 | pmid = 19821401 | doi = 10.1002/14651858.CD007277.pub2 | veditors = Maxwell L | pmc = 6464777 }}</ref> [[Adalimumab]] slows the time for the radiographic progression when used for 52 weeks.<ref>{{cite journal | vauthors = Navarro-Sarabia F, Ariza-Ariza R, Hernandez-Cruz B, Villanueva I | title = Adalimumab for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD005113 | date = July 2005 | pmid = 16034967 | doi = 10.1002/14651858.CD005113.pub2 }}</ref> However, there is a lack of evidence to distinguish between the biologics available for RA.<ref>{{cite journal | vauthors = Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Tanjong Ghogomu E, Tugwell P | title = Biologics for rheumatoid arthritis: an overview of Cochrane reviews | journal = The Cochrane Database of Systematic Reviews | volume = 128 | issue = 4 | pages = CD007848 | date = October 2009 | pmid = 19821440 | doi = 10.1002/14651858.CD007848.pub2 | type = Submitted manuscript | veditors = Singh JA | pmc = 10636593 }}</ref> Issues with the biologics include their high cost and association with infections including [[tuberculosis]].<ref name=Lancet2016/> Use of biological agents may reduce fatigue.<ref name=":2" /> The mechanism of how biologics reduce fatigue is unclear.<ref name=":2">{{cite journal | vauthors = Almeida C, Choy EH, Hewlett S, Kirwan JR, Cramp F, Chalder T, Pollock J, Christensen R | title = Biologic interventions for fatigue in rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD008334 | date = June 2016 | volume = 2016 | pmid = 27271314 | doi = 10.1002/14651858.cd008334.pub2 | pmc = 7175833 }}</ref>

====Gold and cyclosporin====
{{Anchor|Gold|Sodium aurothiomalate|Auranofin|Cyclosporin}}
[[Sodium aurothiomalate]], [[auranofin]], and [[cyclosporin]] are less commonly used due to more common adverse effects.<ref name=ACR2015/> However, cyclosporin was found to be effective in the progressive RA when used up to one year.<ref>{{cite journal | vauthors = Wells G, Haguenauer D, Shea B, Suarez-Almazor ME, Welch VA, Tugwell P | title = Cyclosporine for rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD001083 | date = 2000 | volume = 1998 | pmid = 10796412 | doi = 10.1002/14651858.CD001083 | pmc = 8406939 }}</ref>

====Hydrogen Therapy====
Patients with RA given H<sub>2</sub>-water [[hydrogen therapy]] for four weeks showed significant improvement of symptoms.<ref name="pmid24769081">{{cite journal | author = Ohta S | title = Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine | journal = [[Pharmacology & Therapeutics]] | volume = 144 | issue = 1 | pages = 1–11 | date = 2014 | doi = 10.1016/j.pharmthera.2014.04.006 | pmid = 24769081 | doi-access = free }}</ref>