This document discusses calcinosis, a complication of scleroderma where calcium deposits form in the soft tissues. It outlines that calcinosis most commonly affects the hands, joints, knees and muscles. While the calcium levels in the blood are normal, inflammation and low blood flow in tissues are thought to contribute to calcinosis formation. The deposits contain bone-like proteins and crystals. 18F-NaF PET imaging may help detect early or active calcinosis. Treatments discussed include protecting joints, surgical removal of deposits, topical or injected sodium thiosulfate, medications like tofacitinib, NSAIDs, colchicine and minimizing scleroderma complications to reduce calcinosis risk over

1. Calcinosis in Scleroderma
October 21st
Carrie Richardson, MD MHS
Co-Director, Northwestern Scleroderma Program

2. Disclosures
• Consultant for Cabaletta Pharmaceuticals

3. Presentation Outline
• Part 1 – Calcinosis Overview
• Part 2 – The Science of Calcinosis
• Part 3 – Treatments We Use for Calcinosis

4. Key Questions
• What is scleroderma-related calcinosis?
• What do we know about what causes
calcinosis?
• What do we know about how to treat
calcinosis?

5. Part 1 – Calcinosis Overview

6. What Is Scleroderma-Related
Calcinosis?
• Calcium-phosphate crystal deposition in the
soft tissue
• Not exactly bone but shares some similarities
• Calcium and phosphorous levels in the
bloodstream are NORMAL
Pai et al. Mod Rheumatol 2018
Bartoli et al. Rheumatol 2016

7. Calcinosis Most Commonly Affects the
Hands
Thumb of
the
dominant
hand is the
most likely
to be
affected – A
VERY BAD
SPOT!!!
Calcinosis

8. Calcinosis Commonly Occurs At Joints
This can
make it hard
to bend!!!
Or it can
pinch nerves
at the elbow

9. The Knee is Another Area Where We
Commonly See Calcinosis
These can take a
VERY long time to
heal if they open
up

10. Calcinosis May Also Encase the
Muscles
These
deposits can
be VERY
extensive and
can feel like a
plate

11. Why Are These Specific Areas So
Affected?
• Tendon insertions (which are located in or near
joints) and muscles are prone to calcification,
especially with pressure or injury
• If the joints, tendons, and/or muscles get
inflamed, the inflammation can eventually result
in calcinosis as the body tries to heal
• People with scleroderma are especially prone to
this calcification process

12. Who Is Affected by Calcinosis?
• Affects to 40% of patients with scleroderma
• People with LONGER disease duration and
more scleroderma-related damage have more
calcinosis
• Myositis and PM/Scl antibodies increase the
risk of calcinosis

13. More Scleroderma Complications for a
Longer Time Period => More Calcinosis
Scleroderma
Complications
People with
the Most
Complications
have the most
Calcinosis
Richardson et al. Rheumatology
(Oxford) 2022

14. What Do We Think Causes Calcinosis?
• Scleroderma-related inflammation…
• PLUS low blood flow in the tissue and
scarring…
• Causes tissue-resident stem cells to behave
like bone cells as the body tries to repair
damage

15. A Simple Schematic of Calcinosis
Inflammation
Tissue Hypoxia (Low
Oxygen State)
Fibrosis
Tissue-level
factors (cytokines/
chemokines/
adipokines,
resident stem
cells,
loss of calcification
inhibitors)
Calcinosis

16. Why Does Calcinosis Matter?
• No known effective medication to prevent or
treat this
• Disabling and disfiguring
• Understanding calcinosis in scleroderma may
help us understand common problems like
”hardening of the arteries” or rotator cuff
problems

17. Calcinosis Can Get Infected and
Require Surgery

18. Calcinosis May Make it Hard to Feel
Comfortable

19. Part 2 – The Science of Calcinosis

20. Calcinosis Does Not Look Quite Like
Bone …
Vs.

21. …But Calcinosis Shares Some
Similarities With Bone Formation
• Bone-associated proteins are present in
calcinosis deposits
• Mechanical loading important
Lian et al. Biochem Biophys Res Comm 1976
Hughes et al. Semin Arthritis Rheum 2020
Urganus et al. Arthritis Rheumatol 2009

22. Calcinosis Lesions And the Blood
Vessels Near Them Contain Bone-
Associated Proteins
OPN
ON
OC
RUNX2
MGP
ALP
BSP
DPP
DMP1
OC
ON
MGP
DPP
BSP
ALP
OPN
DMP1
Vasculature
OPN
DPP
DMP1
BSP
ALP
RUNX2
Deposits
TRAP
Urganus et al. Arthritis Rheum 2009

23. The Calcium Crystal in Calcinosis is the
Same as in Bone
Hydroxyapatite – Ca10(PO4)6(OH)2
Cochrane and Davies Ann Rheum Dis 1965

24. What Does Calcinosis Look Like Under
the Microscope?
• “Morphea with dystrophic calcification”
• Some look disorganized, some liquid, others
grossly resembling bone
• Some have tissue macrophages (“big eater”
inflammatory cells), some have few cells

25. Calcinosis Under the Microscope
Images from Olsen et al. AJR Am J Roentgenol 2004
Macrophages Irregular calcification
Fibrosis

26. How Can We Measure Calcinosis?
Xray – fine for
identifying
calcinosis but
gives a 2D image
CT –
Provides a 3D view but
does not tell us how
“active” calcinosis is
NaF PET CT-
Could this give us an
indicator of calcinosis
activity?

27. 18F-NaF PET Deposits in Areas of
Growing Calcinosis
CT of knee shows calcinosis
(white arrow) but no
calcinosis in the back of the
knee
Radiotracer lights up the calcinosis
but also an area in the back of the
knee – is this a very early calcinosis
deposit?

28. 18F-NaF PET Can Show Active
Calcinosis in Areas Where We Cannot
See Calcinosis Yet on CT
Calcinosis (white markings) looks pretty
minimal
The whole pelvic area
lights up with the
radiotracer

29. 18F NaF PET Might Be a Way to
Identify Calcinosis Before We Can Even
Feel It
Are calcinosis
deposits THIS
big….
…going to turn into
calcinosis deposits THIS
big?

30. Part 3 – Calcinosis Treatments

31. Treatments We Use for Calcinosis*
• Protection from mechanical injury
• Treatment of any ongoing inflammatory activity in the joints or muscles
• Surgical resection in select cases
• Sodium thiosulfate (topical or injected)
• Tofacitinib (Xeljanz)
• Anakinra (Kineret)
• Non-steroidal anti-inflammatories like celecoxib, ibuprofen
• Minocycline
• Colchicine
• Low-dose prednisone
• Methotrexate
• Sulfasalazine
*Note: There are NO FDA-approved medications for calcinosis

32. Would Treating Scleroderma Better
Eliminate Calcinosis?!!!!!
Could we reduce or eliminate calcinosis by decreasing scleroderma complications????
People with the most
scleroderma
complications have
the most calcinosis
People with fewer
scleroderma
complications have
less calcinosis

33. How Do We Treat Scleroderma Better?
• Check for myositis with a CK level and strength
exam and treat (consider IVIG or rituximab) if
myositis is present
• Treat for arthritis if exam shows joint swelling
or if an ultrasound shows joint inflammation
• Maximize Raynaud’s medications to improve
blood flow

34. Protection from
Mechanical Injury
• Finger cots
• Adhesive bandages
• Arm rest cushions
• Chair cushions

35. Surgical Removal
• Helpful for SMALL
deposits in inconvenient
spots, like the hand
• Also helpful for infected
deposits or areas that are
causing pinched nerves
• Deposits are often
connected to muscle,
tendons and can be
difficult to remove
• Removal can leave chronic
open wounds

36. Sodium
Thiosulfate
• Prevents calcium crystals from
clumping together
• ~75% of patients notice some
benefit based on a Mayo Clinic
study
• Can be used as a cream on the
skin or injected into calcinosis
• Often makes deposits liquify and
come to the surface or pop out

37. How Do You Get
Sodium
Thiosulfate?
• Compounded
preparation, requires
prescription
• We use Petranek’s
Pharmacy in Illinois or
Mayo Clinic Pharmacy
• 25% sodium
thiosulfate,
compounded in zinc
oxide or Vanicream

38. Tofacitinib (Xeljanz)
• Inhibitor of Jak1 and 3
(inflammatory proteins)
• Oral medication,
typically 5 mg twice
daily but higher doses
can be used

39. Xeljanz
Considerations
• Infection risk,
particularly shingles
(see picture)
• Elevated liver
enzymes, high
cholesterol, low white
blood cell count

40. Minocycline
• Oral medication
• Typical dose is 50-100 mg daily
• May have some benefits for inflammatory
arthritis

41. Minocycline
Considerations
• Causes permanent
blue/gray skin and
nail discoloration
• Can also turn
calcinosis deposits
blue/gray
• Risk of development
of drug-induced
autoimmune disease

42. Colchicine
• Common treatment for
gout and pseudogout
(other disorders caused
by crystals)
• Anti-inflammatory,
blocks cells called
neutrophils from
migrating to cause
inflammation
• Typical dose is 0.6-1.2
mg daily

43. Anakinra
• Also used for gout, pseudogout
• Daily injection, typically 100 mg
daily
• Causes injection site reactions
• Expensive, difficult to get insurance
to cover

44. Non-Steroidal Anti-
Inflammatories
• Examples: Ibuprofen/Motrin,
naproxen/Aleve,
celecoxib/Celebrex
• Can cause issues with GI tract,
kidney, and heart especially
with regular use
• Diclofenac gel/Voltaren gel is
a topical NSAID that is gentler
on the body

45. A Note On Calcinosis and Osteoporosis
• People with calcinosis are at increased risk of
osteoporosis (low bone density)
• If you have calcinosis, consider getting screened
for osteoporosis!!!
• We generally try to avoid using
teriparatide/Forteo (bone-building osteoporosis
medication) in people with calcinosis

47. Special Thank You to Stephanie
Gresh for Organizing!