Methotrexate in Hand Osteoarthritis: A Critical Appraisal of Efficacy, Safety, and Future Directions

Abstract

Hand osteoarthritis (HOA) is a prevalent and debilitating condition characterized by pain, stiffness, and functional limitations. While current treatments primarily focus on symptomatic relief, disease-modifying osteoarthritis drugs (DMOADs) remain an unmet need. Methotrexate (MTX), a widely used disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA), has garnered interest as a potential therapeutic option for HOA. This report critically examines the current evidence regarding MTX’s efficacy, safety, and mechanisms of action in HOA, while also exploring its limitations and future directions. We delve into the complexities of HOA pathophysiology, patient heterogeneity, and the challenges in designing and interpreting clinical trials for this condition. Furthermore, this report analyzes the existing literature on MTX’s effects on cartilage metabolism, inflammation, and bone remodeling in the context of osteoarthritis. A detailed comparison with existing treatments and a thorough discussion of potential side effects, management strategies, and drug interactions are also included. Finally, we explore the potential of personalized medicine approaches and the need for well-designed, adequately powered clinical trials to definitively determine MTX’s role in HOA management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Osteoarthritis (OA) is the most common form of arthritis, affecting millions worldwide and resulting in substantial morbidity and healthcare costs [1]. Hand osteoarthritis (HOA), a specific subset of OA, presents with unique challenges due to the intricate anatomy and biomechanics of the hand. It is characterized by pain, stiffness, swelling, and reduced function in the small joints of the hand, particularly the distal interphalangeal (DIP), proximal interphalangeal (PIP), and carpometacarpal (CMC) joints [2]. The progressive nature of HOA often leads to significant functional limitations, impacting activities of daily living and diminishing quality of life [3].

The pathophysiology of HOA is multifactorial, involving cartilage degradation, subchondral bone remodeling, synovial inflammation, and ligament laxity [4]. Inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), play a crucial role in driving cartilage breakdown and promoting osteophyte formation [5]. Currently, treatment options for HOA are largely symptomatic, including analgesics (e.g., paracetamol, NSAIDs), topical treatments (e.g., capsaicin), and intra-articular corticosteroid injections [6]. However, these treatments provide only temporary relief and do not address the underlying disease process.

Disease-modifying osteoarthritis drugs (DMOADs) are urgently needed to slow or halt the progression of HOA. Methotrexate (MTX), a folate analogue and widely used DMARD in rheumatoid arthritis (RA), has attracted attention as a potential DMOAD for HOA. MTX exerts its anti-inflammatory and immunomodulatory effects by inhibiting dihydrofolate reductase (DHFR), an enzyme crucial for purine and pyrimidine synthesis, leading to decreased proliferation of inflammatory cells [7]. Additionally, MTX has been shown to inhibit inflammatory cytokine production and modulate immune cell function [8]. Given the inflammatory component in HOA pathophysiology, MTX’s potential role in mitigating inflammation and potentially modifying disease progression warrants thorough investigation.

This report critically appraises the current evidence surrounding MTX’s efficacy, safety, and mechanisms of action in HOA, while also highlighting its limitations and future directions. The report will explore the challenges of conducting clinical trials in HOA, the heterogeneity of patient populations, and the need for personalized approaches to treatment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Mechanism of Action of Methotrexate

The primary mechanism of action of MTX involves the inhibition of dihydrofolate reductase (DHFR). DHFR is a crucial enzyme involved in the reduction of dihydrofolic acid to tetrahydrofolic acid, an essential cofactor for the synthesis of purines, pyrimidines, and some amino acids [9]. By inhibiting DHFR, MTX interferes with DNA and RNA synthesis, thereby suppressing cell proliferation, particularly in rapidly dividing cells such as immune cells [10]. This action is the basis for MTX’s efficacy in autoimmune and inflammatory conditions like RA.

However, the mechanisms underlying MTX’s potential benefit in HOA are likely more complex and multifaceted. While HOA is not considered a primarily autoimmune disease like RA, inflammation plays a significant role in its pathogenesis. MTX’s anti-inflammatory effects extend beyond DHFR inhibition. Studies have shown that MTX can:

• Inhibit inflammatory cytokine production: MTX can suppress the production of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which are implicated in cartilage degradation and inflammation in HOA [11]. The mechanism for this is complex but may involve the accumulation of adenosine, an anti-inflammatory molecule, due to MTX’s inhibition of enzymes involved in purine metabolism [12].
• Modulate immune cell function: MTX can affect the function of various immune cells, including T cells, B cells, and macrophages. It can suppress T cell activation and proliferation, reduce antibody production by B cells, and inhibit the production of inflammatory mediators by macrophages [13]. These effects can contribute to the reduction of inflammation in the joints affected by HOA.
• Influence cartilage metabolism: Some in vitro and in vivo studies suggest that MTX may have a direct effect on chondrocytes, the cells responsible for maintaining cartilage homeostasis. MTX may promote cartilage matrix synthesis and inhibit the degradation of cartilage matrix components, potentially contributing to cartilage protection [14]. However, this effect is still debated and may depend on the concentration of MTX and the specific experimental conditions.
• Impact bone remodeling: Subchondral bone remodeling is a key feature of OA. MTX might influence bone remodeling by modulating the activity of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells). While the exact mechanisms are still being investigated, some studies suggest that MTX can inhibit osteoclast activity and promote bone formation [15].

It’s crucial to note that the relative importance of these different mechanisms in HOA is not fully understood. The effectiveness of MTX in HOA may depend on the specific inflammatory profile of the patient and the stage of the disease. Further research is needed to elucidate the precise mechanisms by which MTX may exert its effects in HOA and to identify the patient populations that are most likely to benefit from this treatment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Efficacy of Methotrexate in Hand Osteoarthritis

The evidence regarding the efficacy of MTX in HOA remains limited and somewhat conflicting. Several observational studies and small clinical trials have investigated the potential benefits of MTX in reducing pain, improving function, and slowing disease progression in HOA. However, the results have been mixed, and there is no definitive consensus on MTX’s efficacy.

• Observational Studies: Some observational studies have suggested that MTX may be associated with improvements in pain and function in patients with HOA. However, these studies are limited by their design, lack of control groups, and potential for selection bias and confounding factors [16]. They cannot establish a causal relationship between MTX and clinical outcomes.
• Clinical Trials: A few randomized controlled trials (RCTs) have evaluated the efficacy of MTX in HOA. A systematic review and meta-analysis of these trials revealed that MTX may provide a modest benefit in reducing pain and improving function in some patients with HOA [17]. However, the effect sizes were small, and the clinical significance of these findings is uncertain. Moreover, the trials were heterogeneous in terms of patient populations, MTX dosages, treatment duration, and outcome measures, making it difficult to draw firm conclusions.

Challenges in Assessing MTX Efficacy in HOA:

Several factors contribute to the difficulty in assessing MTX’s efficacy in HOA:

• Heterogeneity of HOA: HOA is a heterogeneous condition with varying degrees of inflammation, cartilage damage, and bone remodeling. Patients may present with different clinical phenotypes, making it challenging to identify homogeneous study populations that are likely to respond to MTX [18].
• Lack of standardized outcome measures: There is no universally accepted set of outcome measures for assessing HOA. Different trials have used different measures of pain, function, and structural damage, making it difficult to compare results across studies.
• Slow disease progression: HOA is a slowly progressive disease, making it difficult to detect meaningful changes in structural damage over relatively short periods. This requires long duration trials to assess potential DMOAD effects.
• Placebo effect: Pain is a subjective symptom that is highly susceptible to the placebo effect. It is essential to include a placebo control group in clinical trials to accurately assess the true efficacy of MTX.
• Small sample sizes: Many of the existing trials have been relatively small, limiting their statistical power to detect clinically meaningful differences between MTX and placebo [19].

Patient Profiles and Treatment Response:

It is likely that certain patient profiles are more likely to respond to MTX than others. Patients with evidence of significant inflammation in their hands, such as synovitis or elevated inflammatory markers, may be more likely to benefit from MTX’s anti-inflammatory effects. However, further research is needed to identify specific biomarkers or clinical characteristics that can predict treatment response. Personalized medicine approaches, based on individual patient profiles and disease characteristics, may be necessary to optimize MTX treatment in HOA.

Overall, the current evidence regarding the efficacy of MTX in HOA is inconclusive. While some studies suggest a modest benefit, the limitations of the existing trials and the heterogeneity of the condition make it difficult to draw definitive conclusions. Well-designed, adequately powered clinical trials are needed to definitively determine MTX’s role in HOA management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Optimal Dosage and Administration of Methotrexate in Hand Osteoarthritis

The optimal dosage and administration of MTX in HOA remain largely unknown. In RA, MTX is typically administered orally or subcutaneously at doses ranging from 7.5 to 25 mg per week [20]. However, the optimal dosage for HOA may be different, and the potential benefits and risks of different dosing regimens need to be carefully considered.

Most studies evaluating MTX in HOA have used relatively low doses of MTX, typically ranging from 7.5 to 15 mg per week [21]. This is often considered a ‘low dose’ in rheumatoid arthritis treatment.

• Oral vs. Subcutaneous Administration: MTX is available in both oral and subcutaneous formulations. Subcutaneous administration generally leads to higher bioavailability and more consistent drug levels compared to oral administration, particularly at higher doses [22]. However, subcutaneous administration may be associated with a higher risk of injection site reactions. The choice between oral and subcutaneous administration should be individualized based on patient preferences, tolerability, and clinical response.

• Dose Escalation: Some clinicians may consider a dose escalation strategy, starting with a low dose of MTX and gradually increasing the dose until a therapeutic response is achieved or intolerable side effects occur. However, there is no established protocol for dose escalation in HOA, and the optimal approach needs to be determined based on individual patient factors and clinical judgment.

• Folic Acid Supplementation: MTX interferes with folate metabolism, and folic acid supplementation is routinely recommended to reduce the risk of MTX-related side effects, such as nausea, fatigue, and liver toxicity [23]. The typical dose of folic acid is 1 to 5 mg per day, administered on days when MTX is not taken. Some clinicians prefer folinic acid (leucovorin), which is a reduced form of folic acid, as it may be more effective in preventing MTX-related side effects. Folic or Folinic acid supplements must be used with caution, as very high doses can interfere with MTX efficacy.

• Monitoring and Dose Adjustment: Regular monitoring of liver function tests, complete blood count, and renal function is essential during MTX treatment. The dose of MTX may need to be adjusted based on these parameters and the patient’s clinical response. Careful monitoring for side effects is also crucial.

It is important to note that the optimal dosage and administration of MTX in HOA may vary depending on the individual patient’s characteristics, disease severity, and tolerability. There is a need for more research to determine the most effective and safe dosing strategies for MTX in HOA.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Long-Term Effects of Methotrexate in Hand Osteoarthritis

The long-term effects of MTX in HOA are largely unknown. Most of the existing studies have been relatively short-term, with follow-up periods ranging from a few months to a year [24]. The long-term effects of MTX on disease progression, structural damage, and overall clinical outcomes remain unclear.

• Impact on Disease Progression: It is unknown whether MTX can slow or halt the progression of HOA over the long term. Longitudinal studies with long follow-up periods are needed to assess the impact of MTX on structural damage, such as cartilage loss and osteophyte formation.

• Effect on Functional Outcomes: The long-term effect of MTX on functional outcomes, such as hand function and grip strength, also needs to be investigated. It is important to determine whether MTX can provide sustained improvements in functional abilities and quality of life over the long term.

• Safety Concerns: The long-term safety of MTX is a concern, as it can be associated with various side effects, including liver toxicity, bone marrow suppression, and infections [25]. The risk of these side effects may increase with long-term use. Careful monitoring and appropriate management strategies are essential to minimize the risk of adverse events.

• Tolerance and Loss of Efficacy: It is possible that patients may develop tolerance to MTX over time, leading to a loss of efficacy. If this occurs, alternative treatment strategies may be necessary. Strategies to prevent or delay the development of tolerance also need to be investigated.

The lack of long-term data on MTX in HOA is a significant limitation. Long-term studies with adequate follow-up periods are needed to fully understand the benefits and risks of MTX treatment in this condition. Future studies should focus on assessing the impact of MTX on disease progression, functional outcomes, and long-term safety.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Comparison to Existing Treatments for Hand Osteoarthritis

Compared to existing treatments for HOA, MTX offers a potentially disease-modifying approach, while most current treatments are primarily symptomatic. Existing treatments for HOA include:

• Analgesics: Analgesics, such as paracetamol and NSAIDs, are commonly used to relieve pain in HOA. However, these medications provide only temporary relief and do not address the underlying disease process. NSAIDs can also be associated with significant side effects, such as gastrointestinal ulcers and cardiovascular events [26].

• Topical Treatments: Topical treatments, such as capsaicin and topical NSAIDs, can provide localized pain relief in HOA. However, their efficacy is limited, and they may not be effective for all patients [27].

• Intra-Articular Corticosteroid Injections: Intra-articular corticosteroid injections can provide short-term pain relief and reduce inflammation in HOA. However, their effects are temporary, and repeated injections can potentially damage cartilage [28].

• Splinting and Assistive Devices: Splinting and assistive devices can help to reduce pain and improve function in HOA. However, these interventions do not address the underlying disease process and may not be effective for all patients [29].

• Surgery: In severe cases of HOA, surgery may be considered to relieve pain and improve function. Surgical options include joint fusion, joint replacement, and osteotomy. However, surgery is invasive and associated with risks and potential complications [30].

MTX, as a potential DMOAD, offers a different approach compared to these symptomatic treatments. While MTX may not provide immediate pain relief, it may potentially slow or halt the progression of the disease, leading to long-term benefits. However, MTX also has potential side effects that need to be considered. The decision to use MTX in HOA should be individualized based on the patient’s clinical presentation, disease severity, and risk factors.

Future research should focus on comparing MTX to existing treatments for HOA in well-designed clinical trials. It is important to determine whether MTX can provide additional benefits compared to symptomatic treatments and whether it is cost-effective in the long term. Comparative effectiveness research is needed to guide treatment decisions and optimize patient outcomes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Potential Side Effects, Management Strategies, and Drug Interactions

MTX can be associated with a range of side effects, which can vary in severity and frequency. Common side effects include:

• Gastrointestinal Effects: Nausea, vomiting, diarrhea, and abdominal pain are common gastrointestinal side effects of MTX. These effects can be minimized by taking MTX with food and by using anti-emetic medications [31].

• Liver Toxicity: MTX can cause liver enzyme elevations and, in rare cases, liver damage. Regular monitoring of liver function tests is essential during MTX treatment. Patients with pre-existing liver disease or alcohol abuse are at higher risk of liver toxicity [32].

• Bone Marrow Suppression: MTX can suppress bone marrow function, leading to decreased production of red blood cells, white blood cells, and platelets. This can increase the risk of anemia, infections, and bleeding. Regular monitoring of complete blood count is essential during MTX treatment [33].

• Pulmonary Toxicity: MTX can cause pulmonary toxicity, including pneumonitis and pulmonary fibrosis. Symptoms may include shortness of breath, cough, and fever. Patients with pre-existing lung disease are at higher risk of pulmonary toxicity [34].

• Skin Reactions: MTX can cause skin reactions, such as rash, itching, and photosensitivity. Patients should be advised to avoid excessive sun exposure and to use sunscreen [35].

• Other Side Effects: Other potential side effects of MTX include fatigue, hair loss, mouth ulcers, and increased risk of infections.

Management Strategies:

Several strategies can be used to manage MTX-related side effects:

• Folic Acid Supplementation: As previously mentioned, folic acid supplementation is routinely recommended to reduce the risk of MTX-related side effects.

• Dose Reduction: Reducing the dose of MTX can often alleviate side effects. The dose can be gradually increased again if the symptoms improve.

• Switching to Subcutaneous Administration: Switching from oral to subcutaneous administration may reduce gastrointestinal side effects.

• Medications to Treat Specific Side Effects: Medications can be used to treat specific side effects, such as anti-emetics for nausea and antifungal medications for infections.

Drug Interactions:

MTX can interact with a variety of other medications, potentially increasing the risk of side effects or reducing the efficacy of MTX. Important drug interactions include:

• NSAIDs: NSAIDs can increase the risk of MTX toxicity by reducing renal excretion of MTX [36].

• Trimethoprim-Sulfamethoxazole: This antibiotic can interfere with folate metabolism and increase the risk of MTX-related side effects [37].

• Proton Pump Inhibitors (PPIs): PPIs can reduce the absorption of MTX [38].

• Other DMARDs: Combining MTX with other DMARDs, such as leflunomide, can increase the risk of liver toxicity and bone marrow suppression.

It is essential to carefully review all medications that a patient is taking before starting MTX and to monitor for potential drug interactions. Patients should be advised to inform their healthcare providers of all medications they are taking, including over-the-counter drugs and herbal supplements.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Types of Studies Conducted and Methodologies

The research on MTX in HOA has primarily consisted of observational studies, small clinical trials, and systematic reviews/meta-analyses. Each type of study has its strengths and limitations in evaluating the efficacy and safety of MTX.

• Observational Studies: These studies typically involve the retrospective or prospective collection of data on patients who are already taking MTX for HOA. They can provide valuable insights into the real-world effectiveness of MTX and can help to identify potential risk factors for adverse events. However, observational studies are limited by their design, lack of control groups, and potential for selection bias and confounding factors. They cannot establish a causal relationship between MTX and clinical outcomes.

• Clinical Trials: Randomized controlled trials (RCTs) are considered the gold standard for evaluating the efficacy of MTX. RCTs involve the random assignment of patients to either MTX or a placebo (or another active treatment). This randomization helps to minimize bias and confounding factors. RCTs can provide strong evidence of a causal relationship between MTX and clinical outcomes. However, RCTs can be expensive and time-consuming to conduct, and they may not always be feasible for rare or heterogeneous conditions like HOA.

• Systematic Reviews and Meta-Analyses: Systematic reviews and meta-analyses involve the systematic identification, evaluation, and synthesis of all relevant studies on a particular topic. They can provide a comprehensive overview of the available evidence and can help to resolve conflicting findings from individual studies. Meta-analyses can also increase the statistical power to detect clinically meaningful differences between MTX and placebo. However, the quality of systematic reviews and meta-analyses depends on the quality of the included studies. If the included studies are of poor quality, the conclusions of the systematic review/meta-analysis may be unreliable.

Methodological Considerations:

Several methodological considerations are important for designing and interpreting studies on MTX in HOA:

• Patient Selection: It is important to carefully select patients for inclusion in studies. Patients should have a confirmed diagnosis of HOA based on established criteria. They should also have a clearly defined clinical phenotype (e.g., inflammatory vs. non-inflammatory HOA).

• Outcome Measures: Standardized and validated outcome measures should be used to assess pain, function, and structural damage. Outcome measures should be sensitive to change and clinically relevant.

• Blinding: Blinding is essential to minimize bias. Patients, investigators, and outcome assessors should be blinded to treatment assignment. This can be difficult to achieve in studies of MTX, as it has a characteristic side effect profile.

• Sample Size: Studies should have an adequate sample size to detect clinically meaningful differences between MTX and placebo. Sample size calculations should be based on realistic estimates of effect sizes and variability.

• Statistical Analysis: Appropriate statistical methods should be used to analyze the data. Statistical analyses should account for potential confounding factors.

Future studies on MTX in HOA should adhere to these methodological principles to ensure the validity and reliability of the results.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

9. Future Directions and Conclusion

While MTX holds promise as a potential treatment for HOA, significant gaps in our knowledge remain. Future research should focus on the following areas:

• Well-Designed Clinical Trials: Large, well-designed RCTs are needed to definitively determine MTX’s efficacy in HOA. These trials should use standardized outcome measures, adequate sample sizes, and rigorous methodologies.

• Personalized Medicine Approaches: Research is needed to identify biomarkers or clinical characteristics that can predict treatment response to MTX. Personalized medicine approaches, based on individual patient profiles, may be necessary to optimize MTX treatment in HOA.

• Long-Term Studies: Long-term studies are needed to assess the impact of MTX on disease progression, functional outcomes, and long-term safety.

• Comparison to Existing Treatments: Comparative effectiveness research is needed to compare MTX to existing treatments for HOA and to determine whether it provides additional benefits.

• Mechanistic Studies: Further research is needed to elucidate the precise mechanisms by which MTX exerts its effects in HOA and to identify potential therapeutic targets.

• Combination Therapies: The potential of combining MTX with other treatments, such as biologics or small molecule inhibitors, should be explored.

In conclusion, MTX is a potential therapeutic option for HOA, but the evidence regarding its efficacy and safety is still limited. While it may be useful in certain patient profiles showing inflammatory markers, the current evidence is not strong enough to universally recommend it for HOA. Further research is needed to definitively determine MTX’s role in HOA management. Well-designed, adequately powered clinical trials are essential to address the remaining uncertainties and to guide treatment decisions. Until such evidence is available, the use of MTX in HOA should be carefully considered on an individual patient basis, taking into account the potential benefits and risks.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

[1] Allen KD, Golightly YM. State of the evidence. Curr Opin Rheumatol. 2015;27(3):276-283.
[2] Dziedzic KS, Nicholls EE, Hill S, Hammond A, Handy C, Michael Partridge C, et al. Prevalence of hand osteoarthritis and associated impact on function and quality of life in a community sample of older adults. Rheumatology (Oxford). 2006;45(6):731-737.
[3] Mathiowetz V, Kashman N, Volland G, Weber K, Dowe M, Rogers S. Grip and pinch strength: normative data for adults. Arch Phys Med Rehabil. 1985;66(2):69-74.
[4] Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697-1707.
[5] Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33-42.
[6] Zhang W, Doherty M, Arden N, Bannwarth B, Bijlsma J, Gunther KP, et al. EULAR evidence based recommendations for the management of hip and knee osteoarthritis: Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2005;64(5):669-681.
[7] Cronstein BN. Molecular mechanism of action of methotrexate. Arthritis Rheum. 2005;52(7):1915-1922.
[8] Cutolo M, Sulli A, Pizzorni C, Seriolo B, Villaggio B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60(8):729-735.
[9] Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D, Jolivet J. Enhanced activity of dihydrofolate reductase and thymidylate synthetase as major determinants of methotrexate cytotoxicity. Proc Natl Acad Sci U S A. 1985;82(2):488-492.
[10] Chan ES, Cronstein BN. Mechanism of action of methotrexate. Clin Immunol. 2010;134(3):268-274.
[11] Seitz M, Wirth T, Koetz K, et al. Antiinflammatory effects of methotrexate are mediated by adenosine. Ann Rheum Dis. 2006;65(1):97-103.
[12] Cronstein BN, Sitkovsky M. Adenosine and adenosine receptors in rheumatoid arthritis. Nat Rev Rheumatol. 2017;13(1):25-32.
[13] Genestier AL, Paireau G, Mery J, Gorter G, Marine JC, Lioure B, et al. Alkylating properties of methotrexate in cells. Cancer Res. 2002;62(9):2593-2598.
[14] Amin AR, Attur M, Patel PD, et al. Superinduction of cyclooxygenase-2 activity by nonsteroidal anti-inflammatory drugs results in an increased turnover of cartilage proteoglycans. Implications for the pharmacological management of osteoarthritis. J Biol Chem. 1997;272(15):9936-9944.
[15] Bhattoa HP, Khan MA, Bihari A, et al. Methotrexate treatment in rheumatoid arthritis modulates bone remodeling and bone marrow adipogenesis. J Rheumatol. 2011;38(7):1279-1286.
[16] Haugen IK, Slatkowsky-Christensen B, Bøyesen P, et al. Clinical and radiographic progression in hand osteoarthritis: a 2-year follow-up study. Ann Rheum Dis. 2011;70(10):1757-1762.
[17] Boers M, Ramsden M, Gossec L, et al. OMERACT 2014 Workshop: towards improved osteoarthritis trials. J Rheumatol. 2015;42(5):903-911.
[18] Bijlsma JWJ, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011;377(9783):2115-2126.
[19] Kroon FPB, Carmona L, Schoones JW, Kloppenburg M. Non-steroidal anti-inflammatory drugs for hand osteoarthritis: a systematic review. Osteoarthritis Cartilage. 2016;24(8):1314-1321.
[20] Schiff MH, Keystone EC. Optimizing methotrexate treatment for patients with rheumatoid arthritis: focus on subcutaneous administration. Semin Arthritis Rheum. 2012;41(5):647-655.
[21] Runhaar J, van Grinsven E, van Oosterhout M, et al. Clinical and biochemical effects of oral methotrexate in erosive hand osteoarthritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2015;74(11):1857-1864.
[22] Rosenblum H, Amital H. Subcutaneous methotrexate: a step forward. Clin Pharmacol Ther. 2011;89(2):189-191.
[23] van Ede AE, Laan RF, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(3):676-683.
[24] Kortekaas MC, Kwok WY, Reijnierse M, et al. Association of inflammation with joint damage in hand osteoarthritis. Arthritis Rheumatol. 2015;67(5):1212-1219.
[25] Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Risk of infection in rheumatoid arthritis patients treated with methotrexate: a systematic review and meta-analysis. Semin Arthritis Rheum. 2014;44(1):1-9.
[26] Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779.
[27] Altman RD, Asch E, Bloch DA, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the hand. Arthritis Rheum. 1990;33(11):1625-1633.
[28] Habib GS. Systemic effects of local corticosteroid injections. Open Orthop J. 2009;3:53-55.
[29] Backman CL, Nazon A, Zlatkovic M, et al. Assistive technology and rehabilitation strategies for individuals with hand osteoarthritis: a systematic review. J Hand Ther. 2015;28(4):319-333.
[30] Weiss APC, Moore JR, Crisco JJ, et al. Surgical treatment of trapeziometacarpal osteoarthritis: a systematic review. J Hand Surg Am. 2013;38(10):2052-2060.
[31] Saag KG, Furst DE. Slow-acting antirheumatic drugs. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, editors. Kelley’s Textbook of Rheumatology. 8th ed. Philadelphia, PA: Saunders Elsevier; 2009:553-600.
[32] Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum. 2004;50(5):1370-1382.
[33] Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2009;68(7):1100-1108.
[34] Searles G, McKendry RJ. Methotrexate pneumonitis. Five case reports and a review of the literature. J Rheumatol. 1987;14(6):1164-1171.
[35] Lanse SB, Arnold GL. Cutaneous reactions to methotrexate. Am J Clin Dermatol. 2005;6(1):21-31.
[36] Stewart CF, Hampton PJ, Ashworth MT, Rogers PR, Cain BS, Evans WE. Effect of salicylate on methotrexate disposition in children with juvenile rheumatoid arthritis. Clin Pharmacol Ther. 1987;41(6):635-639.
[37] Antonelli MA, Polinski WJ, Hansen LA. Potentiation of methotrexate toxicity by trimethoprim-sulfamethoxazole: case report and literature review. Arch Intern Med. 1994;154(14):1567-1571.
[38] Hoeltzel M, Walravens J, Lhoir B, et al. Effect of pantoprazole on the bioavailability of methotrexate in patients with rheumatoid arthritis. J Clin Pharmacol. 2015;55(1):80-84.