Therapeutics
Methotrexate reduced pain and improved function in symptomatic knee osteoarthritis
Abou-Raya A, Abou-Raya S, Khadrawe T. Methotrexate in the treatment of symptomatic knee osteoarthritis: randomised placebocontrolled trial. Ann Rheum Dis. 2014 Mar 27. [Epub ahead of print]
Clinical impact ratings: F ★★★★★★✩ R ★★★★★★✩ Question
Patient follow-up: 90% (intention-to-treat analysis).
In adults with symptomatic knee osteoarthritis (OA), what is the efficacy of methotrexate (MTX)?
Main results
Methods
MTX reduced pain and need for assistance with ADL and improved global functioning compared with placebo (Table).
Design: Randomized placebo-controlled trial. ClinicalTrials.gov NCT01927484.
Conclusion
Allocation: Unclear allocation concealment.*
In adults with symptomatic knee osteoarthritis, weekly oral methotrexate reduced pain and improved function at 28 weeks.
Blinding: Blinded* (patients, clinicians, and outcome assessors). Follow-up period: 28 weeks.
*See Glossary.
Setting: Rheumatology and orthopedic clinics at a university hospital in Egypt.
Source of funding: Not stated.
Patients: 144 patients (mean age 66 y, 88% women) who had symptomatic knee OA (knee pain while standing, walking, or during motion for ≥ 25 of the previous 30 d), persistent knee pain (> 40 mm on a 100-mm visual analogue scale [VAS]), clinical signs of synovitis (warmth, joint margin tenderness, swelling, or effusion), and moderate to severe disease severity (Kellgren– Lawrence radiographic system). Exclusion criteria included systemic inflammatory arthritis; treatment with joint-specific oral supplements (e.g., glucosamine) or immunomodulatory drugs, including steroids in the past 90 days; steroid or hyaluronan knee injections in the past 6 months; previous joint surgery; creatinine clearance < 75 mL/min (1.25 mL/s); aspartate and alanine aminotransferase levels > 2 times the upper limit of normal; or serious cardiac or respiratory diseases. Intervention: Oral MTX, 10 mg/wk for 3 weeks and 25 mg/wk thereafter (n = 72), or placebo (n = 72). Both groups received folic acid, 5 mg 3 times/wk, and were able to continue usual pain treatments. Outcomes: Primary outcome was change in pain (VAS 0 to 100 mm) during the previous 48 hours. Secondary outcomes included physical function (Western Ontario and McMaster Universities Osteoarthritis Index subscore for pain and patient global assessment [VAS 0 to 100 mm]) and activities of daily living (ADL) (modified Katz ADL scale summed across 12 items, range 0 to 12 [higher score = worse function]). Methotrexate vs placebo for adults with symptomatic knee osteoarthritis† Outcomes
Mean change from baseline
Methotroxate Pain§
−26
WOMAC pain score||
−3.3
Global assessment§
−19
Activities of daily living¶
−2.5
Mean difference in change from baseline (95% CI) at 28 wk
Placebo −15 −1.4 −11 −1.3
11 (2.8 to 20) 1.9 (0.7 to 3.1) 8.4 (5.3 to 12) 1.2 (0.1 to 2.3)
†WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; other abbreviations defined in Glossary. For all scales, higher score = worse outcome.
For correspondence: Dr. Anna Abou-Raya, University of Alexandria, Alexandria, Egypt. E-mail [email protected]. ■
Commentary Although categorized as a degenerative joint disease, OA also seems to include synovial inflammation as a key component of pathogenesis (1). This finding provides a reasonable premise for including nonsteroidal antiinflammatory drugs and periodic intraarticular corticosteroid injections as interventions to manage the condition. What is vexing, however, is not only the frequency of treatment failures, but also the dearth of newer approaches that might suppress exacerbations or alter disease outcome in this very common, and often disabling, type of arthritis. The trial by Abou-Raya and colleagues is timely and relevant. The authors showed, in a robustly designed and efficiently executed clinical trial, that MTX, presumably through its antiinflammatory effects, can reduce pain, reverse features of active synovitis, and improve physical function in patients with knee OA. The trial provides an impetus for further research exploring antisynovitis therapies in OA and can complement ongoing initiatives to develop disease-modifying OA drugs (2). The trial builds on the results of an earlier open-label study of patients with knee OA (3). To more clearly define the role of MTX in OA treatment, larger studies of longer duration are needed. Trials should focus on determining the optimal time to introduce the drug; identifying whether certain subgroups or particular joints are more responsive and, if so, why; and providing guidance for optimizing dosage and ensuring safety within the context of a usually multimodal approach to OA management. Lawrence E. Hart, MB BCh, MSc, FRCPC McMaster University Hamilton, Ontario, Canada References 1. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 2001;44:1237-47. 2. Hunter DJ. Pharmacologic therapy for osteoarthritis—the era of disease modification. Nat Rev Rheumatol. 2011;7:13-22. 3. Wenham CY, Grainger AJ, Hensor EM, et al. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology (Oxford). 2013;52:888-92.
§Visual analogue scale 0 to 100 mm. ||Score range 0 to 20. ¶Score range 0 to 12.
JC6
© 2014 American College of Physicians
19 August 2014 | ACP Journal Club | Volume 161 • Number 4
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Weill Medical College User on 07/16/2017
Methotrexate reduced pain and improved function in symptomatic knee osteoarthritis
Abou-Raya A, Abou-Raya S, Khadrawe T. Methotrexate in the treatment of symptomatic knee osteoarthritis: randomised placebocontrolled trial. Ann Rheum Dis. 2014 Mar 27. [Epub ahead of print]
Clinical impact ratings: F ★★★★★★✩ R ★★★★★★✩ Question
Patient follow-up: 90% (intention-to-treat analysis).
In adults with symptomatic knee osteoarthritis (OA), what is the efficacy of methotrexate (MTX)?
Main results
Methods
MTX reduced pain and need for assistance with ADL and improved global functioning compared with placebo (Table).
Design: Randomized placebo-controlled trial. ClinicalTrials.gov NCT01927484.
Conclusion
Allocation: Unclear allocation concealment.*
In adults with symptomatic knee osteoarthritis, weekly oral methotrexate reduced pain and improved function at 28 weeks.
Blinding: Blinded* (patients, clinicians, and outcome assessors). Follow-up period: 28 weeks.
*See Glossary.
Setting: Rheumatology and orthopedic clinics at a university hospital in Egypt.
Source of funding: Not stated.
Patients: 144 patients (mean age 66 y, 88% women) who had symptomatic knee OA (knee pain while standing, walking, or during motion for ≥ 25 of the previous 30 d), persistent knee pain (> 40 mm on a 100-mm visual analogue scale [VAS]), clinical signs of synovitis (warmth, joint margin tenderness, swelling, or effusion), and moderate to severe disease severity (Kellgren– Lawrence radiographic system). Exclusion criteria included systemic inflammatory arthritis; treatment with joint-specific oral supplements (e.g., glucosamine) or immunomodulatory drugs, including steroids in the past 90 days; steroid or hyaluronan knee injections in the past 6 months; previous joint surgery; creatinine clearance < 75 mL/min (1.25 mL/s); aspartate and alanine aminotransferase levels > 2 times the upper limit of normal; or serious cardiac or respiratory diseases. Intervention: Oral MTX, 10 mg/wk for 3 weeks and 25 mg/wk thereafter (n = 72), or placebo (n = 72). Both groups received folic acid, 5 mg 3 times/wk, and were able to continue usual pain treatments. Outcomes: Primary outcome was change in pain (VAS 0 to 100 mm) during the previous 48 hours. Secondary outcomes included physical function (Western Ontario and McMaster Universities Osteoarthritis Index subscore for pain and patient global assessment [VAS 0 to 100 mm]) and activities of daily living (ADL) (modified Katz ADL scale summed across 12 items, range 0 to 12 [higher score = worse function]). Methotrexate vs placebo for adults with symptomatic knee osteoarthritis† Outcomes
Mean change from baseline
Methotroxate Pain§
−26
WOMAC pain score||
−3.3
Global assessment§
−19
Activities of daily living¶
−2.5
Mean difference in change from baseline (95% CI) at 28 wk
Placebo −15 −1.4 −11 −1.3
11 (2.8 to 20) 1.9 (0.7 to 3.1) 8.4 (5.3 to 12) 1.2 (0.1 to 2.3)
†WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; other abbreviations defined in Glossary. For all scales, higher score = worse outcome.
For correspondence: Dr. Anna Abou-Raya, University of Alexandria, Alexandria, Egypt. E-mail [email protected]. ■
Commentary Although categorized as a degenerative joint disease, OA also seems to include synovial inflammation as a key component of pathogenesis (1). This finding provides a reasonable premise for including nonsteroidal antiinflammatory drugs and periodic intraarticular corticosteroid injections as interventions to manage the condition. What is vexing, however, is not only the frequency of treatment failures, but also the dearth of newer approaches that might suppress exacerbations or alter disease outcome in this very common, and often disabling, type of arthritis. The trial by Abou-Raya and colleagues is timely and relevant. The authors showed, in a robustly designed and efficiently executed clinical trial, that MTX, presumably through its antiinflammatory effects, can reduce pain, reverse features of active synovitis, and improve physical function in patients with knee OA. The trial provides an impetus for further research exploring antisynovitis therapies in OA and can complement ongoing initiatives to develop disease-modifying OA drugs (2). The trial builds on the results of an earlier open-label study of patients with knee OA (3). To more clearly define the role of MTX in OA treatment, larger studies of longer duration are needed. Trials should focus on determining the optimal time to introduce the drug; identifying whether certain subgroups or particular joints are more responsive and, if so, why; and providing guidance for optimizing dosage and ensuring safety within the context of a usually multimodal approach to OA management. Lawrence E. Hart, MB BCh, MSc, FRCPC McMaster University Hamilton, Ontario, Canada References 1. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 2001;44:1237-47. 2. Hunter DJ. Pharmacologic therapy for osteoarthritis—the era of disease modification. Nat Rev Rheumatol. 2011;7:13-22. 3. Wenham CY, Grainger AJ, Hensor EM, et al. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology (Oxford). 2013;52:888-92.
§Visual analogue scale 0 to 100 mm. ||Score range 0 to 20. ¶Score range 0 to 12.
JC6
© 2014 American College of Physicians
19 August 2014 | ACP Journal Club | Volume 161 • Number 4
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Weill Medical College User on 07/16/2017
