Overview

Are you passionate about science and would like to know more about diseases? Are you interested in arthritis in particular? In this article, we will discuss rheumatoid arthritis and its development, along with the role of monocytes in this disease. So, let us delve in.

What is rheumatoid arthritis (RA)? It is an autoimmune illness of unknown origin, and usually affects our joints.¹ It is multifactorial and can lead to extra-articular occurrences and is accompanied by chronic inflammatory conditions that can affect and damage other organs like the digestive and nervous systems, heart, skin, lungs, eyes and even kidneys.¹

It affects around 1% of the European population and is linked to premature death; a reduction in lifespan of 3 to 10 years.² RA is linked to multiple genes and genetics can play a role in this disease to about 60%.² It tends to affect women (assigned at birth) 3 times more than men (assigned at birth) and can appear at the ages of 40-50.³ Smoking seems to increase the risk of RA as well.⁴

Rheumatoid arthritis primarily affects the small joints of our hands, wrists, elbows, as well as the knees, neck and even the jaw.⁵ RA can lead to symptoms such as:⁴

• Pain in joints 
• Stiffness, warmth/redness and swelling of joints
• Poor appetite and weight loss 
• Fever and sweating 
• Fatigue and low energy
• Dry eyes 
• Chest pain (if the lungs or heart are being affected) 

Sometimes, complications in RA can occur and they include:⁴

• Carpal tunnel syndrome which is a common syndrome to occur in RA patients 
• Widespread inflammationof other body parts and includes:⁴
  • Heart: can lead to pericarditis and chest pain 
  • Lungs: can lead to pulmonary fibrosis, persistent cough and shortness of breath⁴
  • Blood vessels: can lead to vasculitis 

• Joint damage 
• Cardiovascular disease risk is increased if a person has RA, which can lead to strokes or heart attacks 
• Cervical myelopathy 

As we have discussed RA and its overview, now let us tackle monocytosis. To start off, what are monocytes? They are cells that are part of the immune system and can mature into macrophages to battle foreign microorganisms and keep our bodies safe.⁶ They also play a role in regulating the immune and inflammatory responses by communicating with other cells or differentiating into dendritic cells.⁶

The normal range of monocytes varies between different ages and sexes; with it being slightly higher and more sensitive to inflammation in males (assigned at birth).⁶ The normal range of monocytes in adults is between 0.2 to 0.8 x 10⁹/L.⁶ When the levels of monocytes increase above the normal range for a persistent period then this is known as monocytosis; for example, the World Health Organisation (WHO) defines this as monocyte count above 1x10⁹/L for 3 months or more, with 10% of leukocytes being monocytes.⁶

There are multiple causes for monocytosis, for example:

• Infections like tuberculosis, syphilis, protozoa, bacterial endocarditis or rickettsia⁷
• Autoimmune origin like RA, inflammatory bowel disease, sarcoidosis and systemic lupus erythematosus⁷
• Cancers and malignancies can increase monocyte levels such as monocytic leukaemia⁷
• Recovery from acute infection⁷
• Recovery from granulocytosis⁷
• Congenital agranulocytosis⁷

Pathophysiology of RA

RA is a systemic illness that is characterised by erosive symmetrical polyarthritis which leads to degeneration of the joints over time.⁸ Around 80% of patients with RA have autoantibodies like rheumatoid factor (RF) or anti-citrullinated protein antibodies.⁸ However, it is important to note that not all patients exhibit these antibodies and these antibodies can’t cause the disease on their own, but they can indicate a more aggressive form with stronger joint damage.⁸

RA is associated with genetics and heredity - with over 100 genetic loci being linked to this illness - however environmental factors seem to have a role too; for example, studies on identical twins showed that the consistency of RA between them was around 12-15%.⁸

To further explain RA, we have to look into the cells within the joint. This includes various types of cells such as peripheral blood mononuclear cells that get inside the tissue, fibroblast-like synoviocytes (FLS) that expand and cause a pannus, neutrophils that can release citrullinated proteins that are recognised by the anti-citrullinated protein autoantibodies.⁸ The mononuclear cells and FLS can become very active and release proinflammatory factors like interleukins 1, 6, 16, tumour necrosis factor, matrix metalloproteinases, and vascular endothelial growth factor.⁸ This causes the formation of an inflammatory environment which leads to joint damage – for example, FLS and activated osteoclasts can infiltrate the cartilage matrix and cause cartilage as well as bone degradation.⁸

Monocytes and their link to RA

Monocytes are part of the immune system and play an important role in antimicrobial protection through various actions such as phagocytosis, cytokine production, and regulating other cells that are part of the immune system.⁹ These cells have an important role in protecting our bodies during inflammation, but also play a pathological role where they can have a hand in inflammatory diseases such as atherosclerosis by forming foam cells and production of pro-inflammatory factors.⁹

There are 3 subsets of monocytes: classical, intermediate and non-classical:¹⁰

• Classical: These cells produce high concentrations of tumour necrosis factor, interleukin 1,6 and 10, and can differentiate into inflammatory macrophages and osteoclasts.¹⁰ These cells function as scavengers and promote synovial inflammation as well as bone erosion through osteoclastic activity.¹⁰
• Intermediate: These cells are seen to be elevated in the blood and synovia of RA patients.¹⁰ They can also secrete a lot of tumour necrosis factor, interleukin 1 and 6 in the joints.¹⁰ These cells transform into proinflammatory macrophages (M1) and can maintain the inflammation in the joint which can lead to further damage.¹⁰
• Non-classical: These cells are known to have ‘patrolling behaviour’ in cases of tissue damage or injury.¹⁰ This subset of cells can resolve inflammation; however, they can change into a phenotype that can lead to inflammation and is age related.¹⁰

Hence, once RA starts and inflammation rises, monocytes can respond to the surrounding area by changing into M1 macrophages that can lead to further damage and maintain the inflammation.¹⁰ Therefore it is not surprising to see that RA and monocytosis go hand in hand.

Diagnosis

To diagnose RA or monocytosis, there are multiple approaches that can be done as mentioned below.

Rheumatoid arthritis

The steps include:

• Physical examination⁴
• Blood tests including:⁴
  • Erythrocyte sedimentation rate: it is used to check for the level of inflammation in the body 
  • C-reactive protein: this test is also done to assess the levels of inflammation 
  • Full blood count which is done to help rule out other conditions for the symptoms at hand, as well as an overview of the general health 
• Testing for antibodies through checking for the rheumatoid factor antibodies and the anti-cyclic citrullinated peptide (anti-CCP) test. People who have anti-CCP are highly likely to develop RA, however not every RA patient has these antibodies present⁴
• Joint scans like x-rays or MRIs⁴

Monocytosis

The approach as follows:

• Blood smear to assess the morphology of these cells as it is a critical step in diagnosis and classification¹¹
• Differential diagnosis of monocytosis and its cause is quite difficult as it occurs in a broad spectrum like chronic conditions or infections. Hence, multiple tests can be done to differentiate monocytosis for the specific disease at hand (e.g. physical assessment, blood tests, checking for infections etc)⁷

Treatment 

Rheumatoid arthritis

Treatment of RA can be a mix of things:¹²

• Medication like corticosteroids, NSAIDs 
• Reduction of stress to the joint 
• Physical therapy 
• Occupational therapy 
• Surgery 
• Disease- modifying anti-rheumatic drugs (DMARDS) can be used such as methotrexate, hydroxychloroquine, tumour necrosis factor inhibitors, or interleukin 1 receptor antagonist therapy 

Monocytosis

Monocytosis in itself does not require treatment as it's considered a sign. Its treatment is addressed by treating its underlying cause.⁷ Once the illness or causing factor is addressed, monocytosis will resolve.⁷

FAQs

What foods should you avoid if you have RA?

There are several foods that we can avoid to help reduce inflammation such as grilled or fried meats, sugars and refined carbs, fatty foods rich in omega-6 fatty acids like margarine or vegetable oil, preservatives and alcohol.¹³

Is bed rest good for RA?

Resting and conserving energy can improve inflamed joints, however, doing this long term can potentially lead to bad side effects such as decreased strength and motion range and lowered aerobic capacity.¹⁴

Summary

RA can be a tough and painful illness to deal with, especially if left untreated. It can affect anyone and is a polygenic illness. It is classed as an autoimmune disease, where our immune cells play a role in the deterioration of our joints. One fraction of these cells are the monocytes that show an elevation in RA causing monocytosis, which gives a feedback loop to promote this illness further. Hence, it is important to diagnose and treat this condition early on to keep it controlled and maintained as this can affect our daily life as well as mental well-being long-term.