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A 2018 Approach to Combating Methotrexate Toxicity: Folic Acid and Beyond.

First introduced in 1955 as a chemotherapeutic agent for the treatment of leukemia, the role and utilization of methotrexate (MTX) has greatly evolved in the recent past. (1,2) In 1986, it became FDA approved for the treatment of adults with severe rheumatoid arthritis (RA) and in children with active polyarticular juvenile RA. (1,2) It is now known as the first line treatment for these diseases and remains arguably the anchor drug in the armamentarium of the rheumatologist treating RA. Among the rapidly changing landscape in rheumatology therapies, MTX continues to be the gold-standard drug against which all other biologics and disease-modifying anti-rheumatic drugs (DMARDs) are compared. However, it is not without its complications, which can often be a deterrent for patients either in treatment initiation or adherence. The main MTX side effects include gastrointestinal (GI) toxicity (malabsorption, diarrhea, nausea, and vomiting), stomatitis, alopecia, elevated liver transaminases, and CNS toxicity. (1-3) Effective adherence to MTX treatment is largely based on toxicity prevention and management.

Several studies have been published in the recent past with suggested modalities for combating MTX toxicity. Classically, folic acid and folinic acid, as well as a change from oral to subcutaneous (SC) MTX are well known regimens. Alternative treatments such as vitamin A supplementation and dextromethorphan may be less well-known but still effective strategies for the rheumatology community. Herein, we will provide a review of the literature pertaining to MTX toxicity treatment for 2018 (Table 1). With suggestion that MTX may be underutilized in diseases such as RA, and in an era of increased payer scrutiny over treatment decisions, we hope you will find this a relevant review. (3)

Folic Acid and Folinic Acid: Combating GI Toxicity, Hepatic Transaminase Elevations, and Hair Loss

While pharmacologically it is classified as a folate depleting antimetabolite, MTX works by modulating adenosine in rheumatic diseases. (2,4) The human body needs folate to perform many functions, including cell division, growth and hematopoiesis. Hence, due to lack of folate, many patients treated with MTX experience GI, hepatic, and hematologic toxicity. Supplementation with either folic acid or folinic acid during treatment with MTX has been shown to ameliorate many of these side effects. (5-11) Folinic acid (also known as its brand name Leucovorin) is the reduced and active form of folic acid. Folinic acid is chemically different from folic acid and is naturally found in a number of different foods. In contrast, folic acid is a synthetic form of folate.

Multiple reports have shown that folate supplementation with either folic and folinic acid have resulted in statistically significant reductions in GI side effects, such as malabsorption, nausea, vomiting, diarrhea, and abdominal pain, as well as hepatic dysfunction by lowering elevated serum transaminase levels. (5-11) Folate supplementation can also help protect against MTX induced stomatitis, although these changes were not reported as statistically significant (below we will discuss another strategy to combat stomatitis). (6,9,10) A study by van Ede et al. (8) posits that folate supplementation may have the additional benefit of cardiovascular protection due to its ability to prevent MTX-induced hyperhomocysteinemia. Finally, expert opinion has also demonstrated the utility of folinic acid in combating hair loss. (1)

With regard to dosing and timing of initiation, the guidelines to date remain ambiguous. While some reports suggest that folic acid only be added to MTX in certain situations, the 2013 European League Against Rheumatism (EULAR) Guidelines recommend that folate supplementation be used as soon as MTX is initiated regardless of whether the patient is experiencing side effects. (12) Furthermore, according to the FOLVARI study, a double blinded randomized controlled trial published in 2015 comparing "low dose" folic acid of 10 mg per week versus "high dose" folic acid of 30 mg per week, folic acid dosed to 10 mg per week is sufficient for the treatment of MTX induced side effects, and the higher folic acid dose does not offer any additional benefit (or harm)--of special note, this study included a number of patients with higher doses of MTX of approximately 22 mg per week. (11) The traditionally employed 5 to 10 mg per week folic acid dosing can come either in the form of daily dosing (which is currently the gold standard in the US) or weekly dosing. In the US, expert opinion demonstrated utility in daily folate supplementation with 1 mg per day equating to 7 mg per week, including the day of MTX administration. (13) In a recent study published by RHEUMNOW surveying US versus non-US rheumatologists, approximately 11% of physicians elect to hold the folic acid dose on the day of MTX dosing, the majority of which are non-US rheumatologists. (13) This practice, however, is not supported by expert opinion, nor is a weekly 5 mg dose, which is also favored among non-US rheumatologists. Given the heterogeneity in usage and the discrepancies between the research and clinical practice, further investigation with evidence-based studies is needed.

When comparing folic acid versus folinic acid, a 2013 Cochrane review found no statistically significant difference in efficacy between the two agents. Folinic acid was also shown to be significantly more expensive than folic acid. (9,10) With regard to dosing of folinic acid, despite lack of clear evidence for superiority over folic acid in the literature, it has been utilized as a second line supplement by many rheumatologists when folic acid has failed (including the authors of this review). Contrasting from dosing in oncologic use in cases of MTX overdose (wherein the dosing is recommended at 15 mg taken every 6 hours for up to 8 doses (11)), folinic acid when employed by rheumatologists is typically given as 5 mg for 2 to 3 doses 12 hours apart and starting 12 hours after the MTX dose. (14-17)

A few studies have been published cautioning providers that folic and folinic acid supplementation may in turn decrease MTX efficacy. These post hoc analyses suggest that dietary folate supplementation plus folic and folinic acid supplementation may ultimately increase MTX dosage requirements. (18) These analyses, however, represent minority viewpoints in the literature. (18) In fact, folic acid should not directly affect MTX efficacy as it does not compete for the same reduced folate carrier (RFC) that takes up MTX. Conversely, folinic acid is taken up by the same RFC as MTX and may have a more direct effect on MTX efficacy compared to folic acid (Fig. I). (18) At low doses and whenfolinic acid is given 10 to 12 hours after MTX administration, no changes in MTX efficacy are appreciated. However at higher oncologic doses, as mentioned previously, it is this direct competition of folinic acid against methotrexate transport that allows it to be useful in the setting of MTX overdose. (18)

As important as folate supplementation is to combating individual side effects of MTX, perhaps most importantly, folate supplementation with MTX has also been shown to significantly increase patient adherence to therapy. The 2013 Cochrane review demonstrated a statistically significant decrease in MTX withdrawal numbers between patients taking MTX in conjunction with folate supplementation and patients taking MTX alone. As a result, a higher persistence to MTX and less medication switching may ultimately reduce health care utilization and excess medication costs. (9,10)

Vitamin A: Combating Gl Toxicity and Stomatitis

Some MTX experts recommend the use of vitamin A to combat recalcitrant GI toxicity and stomatitis. Much of what is known about vitamin A comes from expert opinion and common practice, and there remains a paucity of peer-reviewed studies validating its utility. Regarding GI toxicity, there is only one human study (published in the pediatric oncologic literature) and several basic science rat studies investigating the potential protective effect of vitamin A in alleviating nausea and small intestine malabsorption. (19-23) With regard to combating stomatitis, expert opinion and common practice have demonstrated that vitamin A appears to decrease the intensity of oral ulcers more than folic acid. (1)

However, vitamin A dosing from a rheumatologic standpoint remains ambiguous. In the oncologic literature. 180,000 IU of vitamin A was used to combat MTX side effects without causing secondary vitamin A toxicity side effects (such as skin or vision changes). (19) From a rheumatology standpoint 8,000 to 10,000 IU has been used with success to combat GI toxicity and stomatitis. (1) Additional higher level of evidence investigations are needed to clarify vitamin As mechanism of action, its utility in ameliorating MTX-induced toxicity, and optimal dosing modalities.

Dextromethorphan: Combating Central Nervous System (CNS) Toxicity

Methotrexate-induced CNS toxicity is a frequent complication of MTX therapy. In fact up to one third of patients experience CNS symptoms ranging from mild, such as mood disturbances, malaise, and somnolence, to severe, such as focal neurologic symptoms. (24-29) The pathogenesis of MTX-induced CNS toxicity is multifactorial and not completely understood. Several hypotheses have been proposed, such as altered folate homeostasis and N-methyl d-aspartate (NMDA) receptor activation by homocysteine. (24) With regard to the latter hypothesis, dextromethorphan, a cough suppressant and weak non-competitive NMDA antagonist, has been proposed as a potential therapy for MTX neurotoxicity.

In the recent past, several studies from the oncologic literature have investigated the utility of dextromethorphan in successfully treating MTX-induced CNS toxicity in patients with malignancy. (25-27) However, there is a paucity of data investigating the appropriate use and dosing of dextromethorphan for MTX toxicity in the rheumatologic setting. An abstract published by Bettachi et al. (28) remains one of the few studies detailing the utility of dextromethorphan in RA patients. Based on this pilot study as well as expert opinion, 20 to 50 mg of dextromethorphan administered weekly, first at the time of MTX administration and then again 8 to 12 hours later, is recommended to combat CNS toxicity. (28) One strategy in the neurology literature for increasing systemic dextromethorphan concentration is by the co-administration of quinidine, although we are unaware of any specific study of this in the rheumatologic setting. (29) Future studies are needed to better understand the pathogenesis of MTX induced CNS toxicity, the underlying mechanism of how dextromethorphan works to ameliorate CNS side effects, as well as proper dosing.

Subcutaneous MTX: Combating GI Toxicity

Switching from oral MTX to subcutaneous (SC) MTX in order to mitigate the effects of MTX toxicity continues to be a confusing and controversial topic. In general, SC MTX has a higher bioavailability than oral forms, which ultimately increases the body's absorption of the drug. (26-29) Methotrexate toxicity is positively correlated to its absorption. Thus, SC MTX is usually associated with increased toxicity side effects due to increased absorption and availability. However, several experts have demonstrated that switching to SC MTX can actually help decrease GI specific side effects including: nausea, vomiting, diarrhea, and dyspepsia. (30-33) Given the increased bioavailability of SC MTX, switching to a low dose SC MTX may be beneficial in patients requiring higher doses of oral MTX in order to maintain higher absorption with decreased GI toxicity. (29,33)

Patient Risk Education: Increasing MTX Adherence

Patient awareness of potential toxicity associated with MTX as well as risk education play an important role in overall reducing toxicity effects. (1) Generally, it is observed that when patients have a clear idea of the potential side effects, coupled with known treatment modalities for side effect management, they will be more likely to continue taking the MTX instead of self-discontinuing it. (1) Risk communication and developing a toxicity treatment plan prior to MTX initiation will help tremendously with treatment adherence.

Conclusion

Methotrexate continues to be the standard of care for the treatment of RA against which many of the new biologic agents are measured. However, it is associated with several debilitating toxicity side effects, which in turn decreases patient medication tolerability and adherence. Today there are only a handful of treatment modalities in the armamentarium of the rheumatologist to combat MTX induced toxicity. While there is ample literature on the classically used agents, folic acid and folinic acid, much of what is known about vitamin A and dextromethorphan come from basic science investigations and expert opinion. Gastrointestinal toxicity, which is the most common side effect described by patients, can also be alleviated by switching to subcutaneous MTX. Finally, patient risk education and a toxicity treatment plan should be discussed prior to MTX initiation in order to improve patient medication adherence.

Disclosure Statement

None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

References

(1.) DSB: Managing Methotrexate Toxicity. Rheum Now. http://rheumnow.com/content/dsb-managing-methotrexate-toxicity. Accessed: Wednesday, 10 Jan 2018.

(2.) Goodman SM, Cronstein BN, Bykerk VP. Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. Clin Exp Rheumatol. 2015 Mar-Apr;33(2):272-8.

(3.) Rohr MK, Mikuls TR, Cohen SB, et al. Underuse of Methotrexate in the Treatment of Rheumatoid Arthritis: A National Analysis of Prescribing Practices in the US. Arthritis Care Res (Hoboken). 2017 Jun;69(6):794-800.

(4.) Cronstein BN, Sitkovsky M. Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol. 2017 Jan;13(l):41-51.

(5.) Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford). 2004 Mar;43(3):267-71.

(6.) Ortiz Z, Shea B, Suarez Almazor M, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2000;(2):CD000951.

(7.) van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001 Jul;44(7):1515-24.

(8.) van Ede AE, Laan RF, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002 Jun;41(6):658-65.

(9.) Shea B, Swinden MV, Tanjong Ghogomu E, et al. Folic Acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013 May 31;(5):CD000951.

(10.) Singh JA. Folic Acid supplementation for rheumatoid arthritis patients on methotrexate: the good gets better. Cochrane Database Syst Rev. 2013 Jul 22;(7):ED000063.

(11.) Dhir V, Sandhu A, Kaur J, et al. Comparison of two different folic acid doses with methotrexate--a randomized controlled trial (FOLVARI Study). Arthritis Res Ther. 2015 Jun 11;17:156.

(12.) Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014 Mar;73(3):492-509.

(13.) Kremer J. Methotrexate and folate use by rheumatologists--survey results. Rheum Now. February 2017. Available at: http://rheumnow.com/content/methotrexate-and-folate-use-rheumatologists-survey-results.

(14.) Shiroky JB, Neville C, Esdaile JM, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1993 Jun;36(6):795-803.

(15.) Weinblatt ME, Maier AL, Coblyn JS. Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial. J Rheumatol. 1993 Jun;20(6):950-2.

(16.) Joyce DA, Will RK, Hoffman DM, Laing B, Blackbourn SJ. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis. 1991 Dec;50(12):913-4.

(17.) Hanrahan PS, Russell AS. Concurrent use of folinic acid and methotrexate in rheumatoid arthritis. J Rheumatol. 1988 Jul;15(7): 1078-80.

(18.) Khanna D, Park GS, Paulus HE, et al. Reduction of the efficacy of methotrexate by the use of folic acid. Posthoc analysis from two randomized controlled studies. Arthritis Rheum. 2005 Oct;52(10):3030-8.

(19.) Dagdemir A, Yildirim H, Aliyazicioglu Y, et al. Does vitamin A prevent high-dose-metotrexate-induced D-xylose malabsorption in children with cancer? Support Care Cancer. 2004 Apr;12(4):263-7.

(20.) Madhyastha S, Prabhu LV, Saralaya V, Rai R. A comparison of Vitamin A and Leucovorin for the prevention of methotrexate-induced micronuclei production in rat bone marrow. Clinics (Sao Paulo). 2008 Dec:63(6):821-6.

(21.) Ewees MG, Abdelghany TM, Abdel-Aziz AA. All-trans retinoic acid mitigates methotrexate-induced liver injury in rats; relevance of retinoic acid signaling pathway. Naunyn Schmiedebergs Arch Pharmacol. 2015 Sep;388(9):931-8.

(22.) Nagai Y, Horie T, Awazu S. Vitamin A, a useful biochemical modulator capable of preventing intestinal damage during methotrexate treatment. Pharmacol Toxicol. 1993 Aug;73(2):69-74.

(23.) Warden RA, Noltorp RS, Francis JL, et al. Vitamin A deficiency exacerbates methotrexate-induced jejunal injury in rats. JNutr. 1997 May;127(5):770-6.

(24.) Vijayanathan V, Gulinello M, AliN, Cole PD. Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav Brain Res. 2011 Dec l;225(2):491-7.

(25.) Coker SA, Pastel DA, Davis MC, et al. Methotrexate encephalopathy: Two cases in adult cancer patients, who recovered with pathophysiologically based therapy. SAGE Open Med Case Rep. 2017 May 4;5:2050313X17706875.

(26.) Drachtman RA, Cole PD, Golden CB, et al. Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol. 2002 Jul-Aug;19(5):319-27

(27.) Afshar M, Birnbaum D, Golden C. Review of dextromethorphan administration in 18 patients with subacute methotrexate central nervous system toxicity. Pediatr Neurol. 2014 Jun;50(6):625-9.

(28.) Bettachi CJ, Kamen BA, Cush JJ. Post-methotrexate (MTX) CNS toxicity: symptom reduction with dextromethorphan. Arthritis Rheum. 1999;42:S236.

(29.) Werling LL, Lauterbach EC, Calef U. Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. Neurologist. 2007 Sep;13(5):272-93.

(30.) Bakker MF, Jacobs JW, Welsing PM, et al. Are switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotrexate useful steps in a tight control treatment strategy for rheumatoid arthritis? A post hoc analysis of the CAMERA study. Ann Rheum Dis. 2010 Oct;69:1849-52.

(31.) Yadlapati S, Efthimiou P. Inadequate response or intolerability to oral methotrexate: Is it optimal to switch to subcutaneous methotrexate prior to considering therapy with biologies? Rheumatol Int. 2016 May;36(5):627-33.

(32.) Li D, Yang Z, Kang P, Xie X. Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate: A systemic review and meta-analysis. Semin Arthritis Rheum. 2016 Jun;45(6):656-62.

(33.) Kromann CB, Lage-Hansen PR, Koefoed M, Jemec GB. Does switiching from oral to subcutaneous administration of methotrexate influence on patient reported gastro-intestinal adverse effects? J Dermatolog Treat. 2015 Apr;26(2):188-90.

(34.) Morgan SL, Baggot JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo controlled trial. Ann Intern Med.l994 Dec 1;121(11):833-41.

Jessica G. Labadie, MD, Rasiya Hashim, MD, Shafay Raheel, MD, Leen Awad, MD, and Manish Jain, MD

Jessica G. Labadie, MD, Rasiya Hashim, MD, Shafay Raheel, MD, and Leen Awad, MD, Department of Internal Medicine, Presence St. Joseph Hospital, Chicago, Illinois, USA. Manish Jain, MD, Department of Internal Medicine, Presence St. Joseph Hospital, and Program Director for the Transitional Year Residency, Presence St. Joseph Hospital, Chicago, Illinois, USA.

Correspondence: Manish Jain, MD, 2900 North Lake Shore Drive, Chicago, Illinois 60657, USA; manishjain.rheum@gmail.com.

Caption: Figure 1 Schematic detailing the mechanism of action of folinic acid as a non-competitive antagonist of MTX. Folinic acid is taken up by the same reduced folate carrier (RFC) as MTX. (This figure is an adaptation of "Methotrexate Mechanism" by Vtvu licensed under Creative Commons Attribution-Share Alike 3.0 Unpolled license and accessed at https://commons.wikimedia.org/wiki/File: Methotrexate_Mechanism.jpg.)
Table 1 List of MTX Toxicity Agents and Key Illustrative Studies

                                    Patient
                                    Population
Agent (Dose)                        Disease/Age
Toxicity Treated   Key Studies      Group        Study Details

Folic Acid         Van Ede et al.   Rheumatoid   Randomized
(1 mg PO daily or  2001 (7)         arthritis    Control
5 mg PO weekly)                     (RA)/adult   Trial (RCT),
&                                                double blind
Folinic Acid                                     (DB), placebo
(5mg PO for 2-3    Van Ede et al.   RA/adult     RCT, DB,
doses)             2002 (8)                      placebo
GI toxicity        Shea et al.      RA/adult     Meta-analysis
Hepatic            2013 (9)
transaminase
elevation          Dhir et al.      RA/adult     RCT, DB,
Homocysteine       2015 (11)                     placebo
Stomatitis
                   Shiroky et al.   RA/adult     RCT, DB,
                   1993 (14)                     placebo


                   Morgan et al.    RA/adult     RCT, DB,
                   1994 (34)                     placebo


Vitamin A          Dagdemir et      Leukemia     RCT, not
(8000 IU)          al. 2004 (19)    and          blinded
GI Toxicity                         Lymphoma
Stomatitis                          /pediatric
                   RheumNow (1)     RA/adult     Expert
                                                 opinion
Dextromethorphan   Bettachi et al.  RA/adult     Randomized
(20 to 50 mg PO    1999 (28)                     survey
weekly)            Afshar et al.    Oncologic    Retrospective
CNS Toxicity       2014 (27)        disease/     study
                                    pediatric

Subcutaneous       Li et al.        RA/adult     Meta-analysis
MTX                2016 (32)
GI toxicity



Agent (Dose)       Duration
Toxicity Treated   (weeks)

Folic Acid            48
(1 mg PO daily or
5 mg PO weekly)
&
Folinic Acid
(5mg PO for 2-3       48
doses)
GI toxicity          N/A
Hepatic
transaminase
elevation             24
Homocysteine
Stomatitis
                      52



                      52



Vitamin A            N/A
(8000 IU)
GI Toxicity
Stomatitis
                     N/A

Dextromethorphan     N/A
(20 to 50 mg PO
weekly)              N/A
CNS Toxicity


Subcutaneous         N/A
MTX
GI toxicity



Agent (Dose)
Toxicity Treated   Conclusions

Folic Acid         Both folic and folinic acid decrease liver enzyme
(1 mg PO daily or  levels.
5 mg PO weekly)
&
Folinic Acid
(5mg PO for 2-3    Both folic and folinic acid decrease homocysteine
doses)             levels--potentially decreasing cardiovascular risk.
GI toxicity        Both folic and folinic acid decrease GI and hepatic
Hepatic            side effects. There is a trend toward reduction in
transaminase       stomatitis.
elevation          No additional benefit (or harm) associated with
Homocysteine       higher dose folic acid (30 mg per week) versus
Stomatitis         lower dose (10 mg per week total).
                   Folinic acid 2.5 to 5 mg given 24 hours after
                   MTX demonstrated decrease in GI toxicity,
                   transaminase elevation and stomatitis without
                   decreasing MTX efficacy.
                   Folic acid 5 mg per week given as weekly dosing
                   lowers side effects (mainly GI toxicity, hepatic
                   transaminase elevation, stomatitis) while not
                   decreasing MTX efficacy.
Vitamin A          Vitamin A before high dose MTX may protect
(8000 IU)          against D-xylose malabsorption--a marker of
GI Toxicity        mucosal damage.
Stomatitis
                   Vitamin A decreases stomatitis and improves GI
                   toxicity.
Dextromethorphan   Pilot study showing CNS toxicity improvement
(20 to 50 mg PO    with dextromethorphan.
weekly)            Using dextromethorphan concomitantly with
CNS Toxicity       MTX has the potential to improve CNS toxicity.
                   Earlier administration of dextromethorphan results
                   in faster improvement of symptoms.
Subcutaneous       Subcutaneous administration of MTX at high
MTX                doses reduces GI upset.
GI toxicity


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Author:Labadie, Jessica G.; Hashim, Rasiya; Raheel, Shafay; Awad, Leen; Jain, Manish
Publication:Bulletin of the NYU Hospital for Joint Diseases
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Date:Jul 1, 2018
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