Guideline for the management of knee and hip osteoarthritis

Recommendations

Investigational disease-modifying OA drugs (DMOADs)

Guideline for the management of knee and hip osteoarthritis
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Pharmacological interventions

Investigational disease-modifying OA drugs (DMOADs)


 

Interleukin-1   knee (IL-1) inhibitors –  Knee and/or hip

Recommendation

We do not recommend offering IL-1 inhibitors for people with knee

Strength of recommendation

Strong against recommendation

Quality of evidence

Low

What is it?

This is a group of agents that block the activity of a pro-inflammatory cytokine, IL-1, which is believed to play a role in inducing cartilage matrix degradation through the up-regulation of proteolytic enzymes.108 The most common IL-1 inhibitors are:

  1. IL-1 receptor antagonist – anakinra
  2. soluble decoy receptor – rilonacept
  3. neutralising monoclonal anti-IL-1β antibody – canakinumab.

In addition, a monoclonal antibody directed against the IL-1 receptor, AMG-108 and a neutralising anti-IL-1α or IL-1β antibody, ABT-981 are currently in clinical trials.

Rationale

Results from a three-arm trial of a single intra-articular injection of anakinra at a dose of 50 mg (n = 34) and 150 mg (n = 67) were available. The mean improvement from baseline at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was not statistically different between the anakinra and placebo groups (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document).

A placebo-controlled randomised controlled trial (RCT) of AMG-108, (which is not included in Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document) found non-statistically significant improvement on WOMAC pain after subcutaneous administration of AMG-108.109
As IL-1 inhibitors require an authority prescription, which cannot be prescribed by general practitioners (GPs), GPs need to work with specialists to get access to these agents. The working group discussed the limitations in current efficacy, safety, access and costs, and considered that IL-1 inhibitors are not a feasible nor cost-effective treatment.
There are currently no trials that have investigated the benefits and safety of IL-1 inhibitors in people with hip OA. Using knee OA data to extrapolate to hip or other OA requires additional caution.

Harms

The percentage of participants reporting adverse events was similar between the placebo and anakinra groups (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The most common adverse event was arthralgia (10%), with similar rates between anakinra 150 mg and placebo groups, but a lower rate for the anakinra 50 mg group (3%). Headache (10% versus 1%), upper respiratory tract infection (8% versus 1%), back pain (8% versus 3%) and extremity pain (6% versus 0%) occurred more often in the anakinra 150 mg group than in the placebo group. Infections were reported in 10% of participants, more frequently for the anakinra 150 mg group, compared with the anakinra 50 mg or the placebo group.

Anti-nerve growth factor (NGF) – Knee and/or hip

Recommendation

We suggest not offering NGF for people with knee  and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Moderate

What is it?

NGF is a secretory soluble protein that binds to two different cell surface receptors – 75 kDa neurotrophin receptor (p75NTR) and high-affinity NGF-specific tyrosine kinase receptor (TrkA). It is critical for normal development of sympathetic and sensory neurons that are responsible for nociception and temperature sensation.110
A humanised monoclonal antibody, tanezumab, was developed specifically to inhibit NGF from binding to its receptors on pain-signalling neurons. Fulranumab is a fully humanised recombinant immunoglobulin G2 (IgG2) monoclonal antibody that specifically neutralises the biological actions of human NGF.

Rationale

Results from five trials of tanezumab and one of fasimumab found a statistically significant lower WOMAC pain and  function score, compared with placebos with a pooled standardised mean differences (SMDs) of 0.6 and 0.64 respectively (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The dosage of tanezumab differed between phase II and phase III studies included in the systematic review. There were two phase II studies of tanezumab (References 3 and 5 in PICO, 2.8.3 – Knee in Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document) which demonstrated SMD ranging from –0.31 to 0.94 with five different dose groups (10 μg/kg, 25 μg/kg, 50 µg/kg, 100 μg/kg, 200 μg/kg). 109 The other phase III studies evaluated a narrower dose range (2.5 mg, 5 mg, 10 mg), and reported a correspondingly narrower range of SMD from 0.26 to 0.61, all of which are statistically significantly from placebo. In the study of fasinumab, all three doses of fasinumab were associated with significant improvements, compared with placebo in walking knee pain and WOMAC total and subscale scores.
In the included hip studies, statistically significant but less clinically relevant effects were found on WOMAC pain and function scores, with pooled SMDs of 0.33 and 0.4 respectively (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The study (Reference 3 in PICO, 2.8.3 – Hip in Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document) evaluated fulranumab with two different dosing frequencies (1 and 3 mg every four weeks; 3, 6 and 10 mg every eight weeks), showing a numerical difference from the active control (oxycodone), although no differentiation was seen between either fulranumab dose and placebo in the same study. The working group discussed that anti-NGF requires off-label prescribing and is expensive, which limited its accessibility and affordability.

Harms

Based on current evidence, the number of adverse events was not significantly different between treatment and placebo groups. Reported adverse events included arthralgia, headache, upper respiratory tract infection and abnormal peripheral sensation (eg paraesthesia, dysesthesia, hyperaesthesia, hypoesthesia). A meta-analysis of tanezumab safety suggested the use of tanezumab plus nonsteroidal anti-inflammatory drug (NSAID) treatment had a higher occurrence of serious adverse events than NSAID alone. 111 A recent adjudication of joint-related adverse events in the tanezumab clinical program reported that the drug was not associated with an increased risk of osteonecrosis, but was associated with an increased risk of rapidly progressive OA, especially in people on higher doses of tanezumab, tanezumab plus NSAIDs, or pre-existing subchondral insufficiency fractures.112

Fibroblast growth factor (FGF) – Knee and/or hip

Recommendation

We do not recommend offering FGF for people with knee and/or hip OA.

Strength of recommendation

Strong against recommendation

Quality of evidence

Very low

What is it?

Sprifermin is a recombinant and truncated version of human FGF-18 that binds to, and specifically activates, FGF receptor-3 in cartilage in order to promote chondrocyte proliferation and cartilage matrix production.

Rationale

There is one trial of 190 participants with knee OA evaluating the effects of intra-articular injection of sprifermin as a single treatment and multiple-dose regimen (three doses of either 10, 30 or 100 μg). Results found that all groups had improved WOMAC pain scores, with statistically significantly less improvement at 12 months in participants receiving the 100 μg dose of sprifermin, compared with participants receiving placebo. No statistically significant relationship between treatment group and reduction in central medial femorotibial compartment cartilage thickness was observed. However, sprifermin was associated with statistically significant, dose-dependent reductions in the loss of total and lateral femorotibial cartilage thickness and volume, and in joint space widening in the lateral femorotibial compartment (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The reasons for the seemingly preferential effect on the lateral knee compartment in the present and previous studies are not clear. In OA, the status of cartilage differs between the medial and lateral femorotibial compartments, with the medial compartment more commonly severely affected. An anabolic agent acting on cartilage may be less effective in tissue that is severely damaged.
Currently, sprifermin is expensive and mainly available in phase II trials.
No trial has investigated the benefits and safety of sprifermin in people with hip OA. Using knee OA data to extrapolate to hip or other OA requires additional caution.

Harms

According to the findings in two recent trials, the overall proportion of participants experiencing at least one treatmentemergent adverse event (TEAE) was not increased in the sprifermin group, compared with the placebo group (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). Incidence, severity and nature of reported TEAEs raised no local or systemic safety concerns for doses up to 300 μg.113

Colchicine – Knee and/or hip

Recommendation

We suggest not offering colchicine for people with knee and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Very low

What is it?

Colchicine is a medication most commonly used to treat gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus colchicum. The hypothesis of action of colchicine is that it can block inflammasomemediated inflammatory and biochemical joint degradation. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever to OA, pericarditis and atherosclerosis.114

Rationale

There is currently a lack of high-quality evidence supporting the use of colchicine for symptomatic relief for people with knee OA. While two small trials (one comparing colchicine to placebo; one comparing the combination of colchicine and an anti-inflammatory medication to the anti-inflammatory medication alone) indicate colchicine may provide symptomatic relief (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document), its efficacy and safety remains unproven. In the trials, participants who received colchicine reported more gastrointestinal adverse effects, and the benefit to risk profile needs to be investigated in larger studies. One randomised placebo-controlled trial for people with knee OA that commenced enrolment of 120 participants in June 2014 in Singapore is reported to have been completed (Identifier: NCT02176460; ClinicalTrials.gov), but the results have not been published. One additional trial was identified in a search of the World Health Organization’s (WHO’s) International Clinical Trials Registry Platform (ICTRP). This trial is reported to have recruited 81 participants between March and September 2012 in Iran, and was retrospectively registered in September 2015 (IRCT2015071623240N1). These results have also not been published.
There are currently no trials investigating the benefits and safety of colchicine in people with OA of the hip.
Colchicine currently does not have an indication via the Therapeutic Goods Administration (TGA) for OA, and should be considered as an investigational medication only.

Harms

There was no significant adverse event in the included trials of colchicine. The most commonly reported adverse events encountered with colchicine were gastrointestinal adverse events (eg loose bowel movements, pain in the abdomen), which were usually mild.

Methotrexate – Knee and/or hip

Recommendation

We suggest not offering methotrexate for people with knee  and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Low

What is it?

Methotrexate is a chemotherapy agent and immune system suppressant, which is commonly used to treat cancer and autoimmune diseases (eg rheumatoid arthritis, psoriasis). For treating inflammatory arthritis, multiple mechanisms appear to be involved, including the inhibition of:

  1. enzymes involved in purine metabolism, leading to accumulation of adenosine
  2. T-cell activation and suppression of intercellular adhesion molecule expression by T-cells
  3. methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function.

Rationale

There is very low-quality evidence from one small trial of 56 participants who used 7.5 mg of methotrexate weekly versus placebo for painful knee OA, which did not find a reduction in pain at four months (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). Another open-label study evaluated the effects of methotrexate for pain relief in participants with knee OA. At 24 weeks, 13/30 participants (43%) achieved ≥30% reduction in Visual Analogue Scale (VAS) pain, of whom, seven (23%) had achieved ≥50% reduction. Conversely, four participants (13%) experienced a flare. Thirteen of 30 (43%) participants achieved Osteoarthritis Research Society International’s responder criteria.115 An ongoing pragmatic phase III trial (ISRCTN77854383) has been designed to confirm these inconsistent findings. In terms of cost and access, methotrexate is a relatively cheap and widely available. Currently, there is no direct evidence for hip OA.
Methotrexate does not currently have an indication via the TGA for OA, and should be considered as an investigational medication only.

Harms

The side effects of methotrexate can include gastrointestinal side effects, haematological abnormalities and elevated liver transaminases. Side effects resulting in discontinuation of the drug vary in frequency from 15% to 17%, but have been shown to reduce to 4% in the second year of treatment.116,117

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