Osteoarthritis is one of the predominant causes of morbidity and disability worldwide. But of late, advanced technologies, metabolomics, proteomics, and genomics have helped in better understanding of the pathogenesis, development of clinically relevant markers and therapeutic targets for the disease.

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Characteristics of osteoarthritis

Osteoarthritis (OA) is the most prevalent and disabling arthritis worldwide due to its clinical heterogeneity and progressive nature of articular degradation.

1. It is characterised by low-grade inflammation and very slow progression.
2. Its risk factors include ageing, obesity, joint malalignment, polyarticular diathesis, injury, crystal deposition and high-impact physical activity.
3. It has 6 clinical phenotypes:
   1. Chronic pain (a prominent central mechanism)
   2. Inflammation
   3. Metabolic syndrome
   4. Bone and cartilage metabolism
   5. Mechanical overload
   6. Minimal joint disease

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Pathophysiology

The complete pathophysiology of OA remains unclear to date. The following is the current understanding of OA pathophysiology:

1. Cartilage breakdown is a central feature in pathogenesis.
2. In a healthy cartilage/joint, chondrocytes are in a state of physiological and metabolic homeostasis with robust redox control of differentiation and chondrogenesis.
3. Aberrant chondrocyte metabolism is a response to changes in the inflammatory microenvironment. It may play a key role in cartilage degeneration and OA progression.
4. Chondrocytes tend to adapt their metabolism to microenvironmental changes by shifting from one metabolic pathway to another.
5. Chondrocytes experience a pathological shift of metabolic homeostasis and cartilage remodelling characterised by
   1. Enhancement of the glycolytic pathway
   2. Disturbed mitochondrial function and chondro-senescence
   3. Process of cellular senescence in chondrocytes.

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Predictors of OA disease progression 

Hand OA

1. Baseline pain is a good clinical marker of OA progression.
2. Baseline erosive or swollen joints are a predictor of radiographic progression.

Knee OA- Newer MRI-based markers like subchondral trabecular biomarkers, meniscus morphology and positions can predict knee OA progression.

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Biomarkers: Current status & future

Early diagnosis, disease severity assessment, clinical and therapeutic monitoring are the major needs of the time. It will help to conduct better research trials for therapeutic intervention and management.

Advancing “omic” technology like metabolomics, proteomics and genomics have the potential to detect various metabolites involved in the process and be a future biomarker of interest.

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Physical therapies in OA

1. Physical therapy is the first-line strategy for OA management. It is grossly underutilised.
2. Very little data is available to show any benefit of high-intensity exercise over low-intensity exercises.
3. The American Foundation of Osteoarthritis recommends all forms of exercise regime (i.e aerobic therapy, high-intensity exercise programme, low-intensity exercise programme, aquatic therapy, neuromuscular therapy) as equipotent in improving the outcome.

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Current and newer therapeutics for OA management

Disease-modifying treatments for osteoarthritis (DMOADs)

DMOADs are drugs that modify the underlying OA pathophysiology and inhibit structural damage to prevent or reduce long-term disability and offer potential symptomatic relief. To date, no DMOADs have been approved. Progressive cartilage breakdown is a major therapeutic target for DMOADs. These drugs target inflammation, cartilage metabolism, and subchondral bone remodelling which lead to retardation of the structural progression and induce disease remission. For targeting pain, we can have the following 4 options:

• Nerve growth factor
• Intra-articular steroids
• NSAIDs
• Opioids

Therapies targeting cartilage metabolism and subchondral bone 

1. Sprifermin: It is a recombinant human fibroblast growth factor 18. The route of administration is intra-articular. It acts as an anabolic agent. It stimulates chondrocyte proliferation, increases cartilage thickness, volume and surface morphology. Subgroup analysis from FORWARD study has found that patients at risk of progression defined by baseline medial or lateral minimum joint-space width (mJSW) 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score of 40-90 units. In this population, sprifermin improved cartilage thickness and pain symptoms versus placebo. This subgroup is considered to be the therapeutic trial for future research.
2. Lorcevivint: It is a novel Wnt pathway modulator. The route of administration is a single intra-articular injection (0.07 mg). It is found to be effective in the unilateral knee symptom subgroup. In a phase IIa clinical trial, it was found to significantly improve medial joint space widening as compared to placebo.

Therapies targeting pain

Targeting nerve growth factor: Tanezumab & Fasinumab

The monoclonal antibodies bind with nerve growth factor - a major cytokine involved in the pain pathway. They are the proposed candidates for the treatment of chronic pain. The intravenous formulations can be given in a single dose every eight weeks. They have a Risk of Rapid progression of Osteoarthritis (RPOA) and hence have been rejected by FDA for their mitigation proposal considering safety concerns. These intra-articular steroids are mild to moderate symptomatic and give short term benefits in terms of pain and function.

Targeting inflammation: IL -1 antagonist- Canakinumab

Post-hoc analysis from the CANTOS trial; Canakinumab at a dose of 150 mg was associated with a reduced incidence of OA symptoms (reported as adverse events) and total knee and hip replacement surgeries. Other drugs like Hydroxychloroquine, Methotrexate, TNF inhibitors have failed to show any improvement in the treatment of knee OA.

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Over the years no drug has been approved for OA treatment. Newer drugs in line give us a strong hope for future trials, research and thereby improving societal morbidities and disability.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising Rheumatologist from Bangalore.