Let's learn the basis for early morning symptoms in chronic inflammatory rheumatic diseases like rheumatoid arthritis, ankylosing spondylitis, and polymyalgia rheumatica

1. Early morning stiffness
in
Rheumatoid arthritis

2. Introduction
• We have read that early morning joint stiffness is one of the
important diagnostic criteria for rheumatoid arthritis and also
observed clinically that early morning joint stiffness is a
common presenting complaint in rheumatoid arthritis
patients.
• But did we ever brainstorm why the symptoms of
rheumatoid arthritis (RA) like joint stiffness are more
prominent in early morning?
• If not, then lets learn the basis for early morning stiffness in
RA together.

3. Rheumatoid arthritis
• Rheumatoid arthritis is basically a chronic inflammatory
disease where proinflammatory cytokines (IL-1, TNF-α)
play a major role for the clinical presentation.
• These proinflammatory cytokines show diurnal rhythmicity
with peak levels during the night and early morning due to
which the symptoms are more prominent in the early
morning.
• But wait, why do the proinflammatory cytokines show
diurnal rhythmicity?

4. • This is because of the two circadian hormones:
a. Cortisol (anti-inflammatory)
which is secreted from the zona fasciculata layer of adrenal cortex
after stimulation from the hypothalamic-pituitary-adrenocortical
(HPA) axis
Anti inflammatory, suppresses the expression of proinflammatory
cytokines by immune cells
reach lowest level at around midnight, peaks at around 7 to 10 in the
morning, then slowly decreases as the day progresses and the 24 hrs
cycle continues
b. Melatonin (proinflammatory)
which is secreted from pineal gland
Proinflammatory action, activates immune cells and enhances Th1
type inflammatory cytokines (IL-1, IL-6, TNF-α, IFN-γ)
secretion starts at around 9 P.M and stops at around 7 in the
morning

5. Basis for early morning symptoms in RA
• So, at night time and early morning, plasma cortisol (anti-
inflammatory action) is lowest while melatonin
(proinflammatory action) is highest, which leads to the early
morning symptoms in RA.
• But as the cortisol secretion increases and that of melatonin
decreases, the symptoms become less prominent afterwards.
• Also chronic inflammation as in RA downregulates the HPA
axis activity leading to decreased cortisol secretion, that is
insufficient to suppress ongoing inflammation in RA.

6. Circadian sequence of hormone secretion

7. • Lets understand this from a simple example:
 What happens when your good friend who heals your suffering is
out of contact and the friend who adds misery to your life is in
contact with you? Just imagine that scenario.
 Similar is the situation in night time and early morning where
proinflammatory melatonin is increased and anti-inflammatory
cortisol is decreased due to circadian rhythmicity.
• The circadian increase in inflammation during night and
early morning accounts for the early morning stiffness in
rheumatoid arthritis.
• Similar is the basis for symptoms of early morning pain and
stiffness in other chronic inflammatory rheumatic diseases
like ankylosing spondylitis, and polymyalgia rheumatica
(PMR).

8. References
• https://pubmed.ncbi.nlm.nih.gov/15639059/
• https://pubmed.ncbi.nlm.nih.gov/16126979/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC48
00804/