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I remember learning in biology that we’re made out of cells. That’s true, but not all the way true. We’re also made out of the stuff in between cells This stuff is called the extracellular matrix. Extracellular means outside of the cells and matrix in this context means the environment that is occupied. Though the extracellular matrix isn’t a dystopian cyberworld made by robots, it can be dangerous if parts of it start getting out of control. Systemic sclerosis, a type of scleroderma, is a disease that results in excess material being deposited in the extracellular matrix, causing body-wide problems.

Systemic sclerosis is a rare, chronic, and progressive autoimmune disease. It affects women in their 60s, though men and African Americans have the worst outcomes from the disease. Around one in four people with systemic sclerosis also have another autoimmune disease. The biggest risk factor for systemic sclerosis is family history; and genetics. It is thought that some people have a genetic predisposition to the disease and that environmental factors cause it to “kick on.”

As an autoimmune disease, systemic sclerosis is complex. It may present differently in each patient who has it. One of the easiest ways to differentiate types is by how it affects skin. Sclerosis comes from Greek and means to harden or a tumor. Systemic sclerosis is hard, tumor-like skin that affects the whole body (or system). There are three categories based on how widespread the condition is. Systemic Sclerosis sine scleroderma is when skin is unaffected, though fingers may experience discoloration. Limited cutaneous systemic sclerosis is, as the name suggests, limited. The skin on the fingers and face is affected. It tends to progress slower and may be less dangerous. Diffuse cutaneous systemic sclerosis is quite the opposite. It is diffuse, meaning it spreads far and wide. It may affect the arms and legs up to knees and elbows, the chest, stomach area, and back. It progresses quickly and is associated with poorer outcomes.

Beyond the hardening of the skin, there are other symptoms, and (unsurprisingly) none are great. Patients may experience:

• Pain
• Joint abnormalities
• Itching
• Fatigue
• Digestive issues
• Heart, lung, and kidney problems
• Psychological problems like anxiety and body image concerns

All of these can be annoying and painful, but many are very dangerous. Systemic sclerosis, in fact, is the most deadly of all rheumatic diseases. Let’s dig into how systemic sclerosis works to find out why.

As stated before, systemic sclerosis is an autoimmune disease. Some environmental factors like smoke, alcohol, viruses, solvents, or chemicals activate our epithelial cells. Epithelial cells interact with the outside world and are located on the skin, in our lungs and digestive tract, and around organs. The cells send out danger signals in the form of cytokines. There are several cytokines, but one of the most prevalent in this system is type 1 interferon (IFN). If this were The Matrix these guys would be the Agents, good at getting rid of unwanted intruders but dangerous when they get out of control. They are usually sent out in viral infections and put the immune system into a general state of alert. When there are too many cytokines, they start causing damage that needs to be repaired. The body responds to high IFN in a couple of ways: alerting immune cells, starting inflammation, and – in people with systemic sclerosis, by activating fibroblasts. Fibroblasts make the connective tissue between cells (you may see where this is going). These guys go into overdrive and spew extra collagen, elastin, and other connective tissues between cells. They try to repair damage from the cytokines, but the excess tissue signals problems and creates a deadly feedback loop.

When this is bad enough, normal cells are replaced by this dense tissue in the extracellular matrix. The skin on the fingers and toes thickens, and the vascular (circulatory) system starts getting crushed. Small blood vessels called capillaries die. The tissue around your vital organs thickens and causes damage. The body can’t deliver enough oxygen to organs, which is bad. If this happens to the blood vessels of the lungs, it’s even worse. The thickening on the fingers, toes, arms, legs, and face may be debilitating, but the real danger is what’s happening inside.

So what can be done? Doctors can try to treat the symptoms and complications to keep people comfortable. They may treat vascular, skin, kidney, arthritic, and gastrointestinal problems. If the lungs are affected, specific monoclonal antibodies may be prescribed. Some patients also find that general immunosuppressors help, but these can come with myriad side effects. The best bet for patients is to discover and treat systemic sclerosis early, before damage spreads, if possible. Medications may slow the decline, possibly until the disease becomes stable. On the horizon, clinical researchers are looking at medications that may cut the feedback loop and help patients break free from the matrix.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Harrison, D. G., Coffman, T. M., & Wilcox, C. S. (2021). Pathophysiology of hypertension: the mosaic theory and beyond. Circulation research, 128(7), 847-863. https://doi.org/10.1161/CIRCRESAHA.121.318082 

Myat, A., Redwood, S. R., Qureshi, A. C., Spertus, J. A., & Williams, B. (2012). Resistant hypertension. Bmj, 345. https://doi.org/10.1136/bmj.e7473

Sarafidis, P. A., Georgianos, P., & Bakris, G. L. (2013). Resistant hypertension—its identification and epidemiology. Nature Reviews Nephrology, 9(1), 51-58. https://www.nature.com/articles/nrneph.2012.260