AUTOIMMUNE DISEASE

WHAT IS THE IMMUNE SYSTEM AND WHY IS IT IMPORTANT?

The term immune is derived from the Latin word “immunis” which means free or untouched.  The immune system is responsible for protecting the body from things that can harm it.  Because it is comprised of different organs, cells, tissue, and proteins, it is the most complex system the body has besides the nervous system (1).

The main roles that the immune system play include:

• Neutralizing pathogens such as bacteria, viruses, parasites, or fungi that may have entered the body
• Recognizing and removing other harmful material that may have entered the body
• Fighting against the body’s own cells that may have changed as a result of a disease (e.g. cancerous cells) (1)

For protection to work effectively, the body must be able to tell the difference between “self” and “non-self” cells, organisms, and substances.  Generally, the immune system should not work against its own healthy cells. The “non-self” substances that activate the immune system are called antigens.  Antigens can bind to special receptors on defense cells causing a response from the body.  The immune system can also recall memories, so it can be able to respond to known pathogens more quickly.  There are surface proteins on the body’s own cells as well, but the body learns at an early stage to identify those cell proteins as “self.”  However, if the immune system identifies these cells as “non-self,” an autoimmune reaction occurs (2).

Autoimmune disease can affect almost any part of the body including the heart, brain, nerves, muscles, skin, eyes, joints, lungs, kidneys, glands, digestive system, and blood vessels (3).

RISK FACTORS AND SYMPTOMS OF AUTOIMMUNE DISEASE

The exact causes of autoimmune diseases remain unknown, but it is likely due to a combination of factors.  These include:

• Genes, which can predispose a person to the disease (3).  For example, certain autoimmune diseases such as lupus and multiple sclerosis have the tendency to run in families (4,5).
• Being overweight can increase the risk of developing rheumatoid arthritis or psoriatic arthritis.  It is thought that the extra weight increases the stress put on the joints or that fat produces substances that can result in inflammation (4).
• Smoking (4).
• Certain medications can trigger certain autoimmune diseases such as drug-induced lupus (4).
• Environmental factors (3).
• Women, particularly those that are African-American, Hispanic-American, and Native-American (6)

TYPES AND SYMPTOMS OF AUTOIMMUNE DISEASES (7)

Lupus

Systemic lupus erythematosus is a chronic autoimmune disease that involves multiple systems and is characterized by recurrent flares.  Lupus patients are at risk for developing and accumulating damage in several organs.  The musculoskeletal system is one of the most commonly involved systems in lupus patients (8).  Symptoms of lupus include joint pain or swelling, muscle pain, fever with an unknown cause, red rashes mostly on the face, chest pain when taking deep breaths, hair loss, pale or purple fingers or toes, sun sensitivity, swelling in legs or around eyes, mouth ulcers, swollen glands, and tiredness (9).

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic, inflammatory, autoimmune condition.  It causes joint pain, joint swelling, and destruction of synovial joints (10).  Persons who have rheumatoid arthritis experience morning stiffness that lasts one hour or more (11).

Sjögren’s syndrome

Sjögren’s syndrome is a systemic autoimmune rheumatic disease that affects the whole body and is found predominantly in females.  Symptoms of the disease may be extensive dryness all over the body, extreme fatigue, chronic pain, neuropathy, complications involving major organs, and lymphoma (12).

Multiple sclerosis

Multiple sclerosis is a heterogeneous disease that has three types: primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) relapsing-remitting multiple sclerosis (RRMS). PMSS is characterized by relapsing periods of systemic inflammation, while RMSS is characterized by progressive loss of the axons on neurons and neurodegeneration.  Only approximately 15% of patients present with PMSS at onset while a larger percentage of patients with RRMS are likely to switch to SPMS about 15-20 years after the onset of the disease.  In RRMS, symptoms include visual and sensory disturbances, while motor syndromes affecting the brainstem, cerebellum, and spinal cord are more common in PPMS.  Other symptoms common to both include impairment in mobility, tremors, bladder issues, fatigue, and disturbances in cognition (13).

Type 1 diabetes

Type 1 diabetes is a disease characterized by the destruction of the beta cells in the pancreas which leads to insulin secretion in the body becoming completely deficient (14).  There are three symptoms typically associated with the disease: polydipsia, polyphagia, and polyuria, which along with overt hyperglycemia are typically used for diagnosis in children and adolescents and to a lesser extent in adults (15).

Psoriasis

Psoriasis is a chronic, inflammatory disease that causes dry, scaly patches on the skin.  The exact cause remains unknown, but it is suspected to be multifactorial including genetic predisposition, environmental factors combined with a disruption in the skin barrier, and immune dysfunction.  There are five types of psoriasis including vulgaris (plaque), guttate, pustular, inverse, and erythrodermic (16).

Inflammatory bowel disease

Inflammatory bowel disease is characterized by an amplified mucosal immune response to luminal gut contents in persons who may be genetically predisposed.  There are two main types:

• Crohn’s: inflammation may occur anywhere along the gastrointestinal tract.
• Ulcerative colitis: inflammation typically only occurs in the colon.  Patients with inflammatory bowel disease usually end up with a lifetime of debilitating symptoms including urgent diarrhea, rectal bleeding, vomiting, anorexia, and lethargy (17).

Addison’s disease (AD)

AD is a deficiency in the body’s glucocorticosteroids and mineral corticosteroids.  Symptoms associated with AD include fatigue, appetite loss, salt craving, nausea and/or vomiting, abdominal pain, postural lightheadedness and dizziness, musculoskeletal pain, diarrhea, loss of consciousness, and constipation.  Clinical signs that patients may present with include increased pigmentation, weight loss, hypotension, anemia, vitiligo, and shock (18).

Graves’ disease

Graves’ disease is defined as “acquired autoimmune hyperthyroidism with a diffuse goiter.”  Its major clinical symptoms in children include goiter, excessive sweating, fatigue, restlessness, and finger tremors.  In adults, common symptoms include goiter, ocular manifestations, weight loss, heat sensitivity, finger tremors and palpitations (19).

Myasthenia gravis

Myasthenia gravis is an autoimmune disorder which is caused by several different complex interactions of specific antibodies at the site of the postsynaptic membrane which leads to the function of the neuromuscular junction and neuromuscular transmission being impaired. The disease presents clinically with weakness and fatigue of a variety of specific muscle groups with characteristic distribution.  The weakness and fatigue increase with muscle activity and improve when the muscle is rested (20).

Others include hashimoto thyroiditis, vasculitis, pernicious anemia, celiac disease, autoimmune enteropathy, autoimmune colitis, immunological disorder, autoimmune endometrisis, autoimmune cirrhosis, autoimmune oophoritis, autoimmune vitiligo, autoimmune retinopathy autoimmune limbic encephalitis, autoimmune epilepsy, autoimmune uveitis, pernicious anemia and many others (7,21,22).

For more information on autoimmune diseases and diagnosis:  1. Talk to your doctor  2. Visit the American Autoimmune Related Diseases Association website   3. Visit the National Institutes of Health website.

AUTOIMMUNE DISEASE FACTS AND STATISTICS

A fact sheet from 2012 indicated that approximately 23.5 million Americans are affected by autoimmune diseases with the prevalence being highest among women (23).

Although the reason why autoimmune diseases are so prevalent among women is not clearly known, it is thought that hormones and other factors common among women play a role (24).  Antinuclear antibodies (ANA), which are serological markers of immunity and are often seen in autoimmune diseases, are more prevalent among older persons, African Americans and persons with normal weight (24).

Multiple sclerosis

• Multiple sclerosis has a high prevalence in central and northern Europe, North America, and Australia and a lower prevalence in Asia, Africa and Middle/South America (13).
• Women have a higher chance of developing the disease than men with a prevalence ratio of 1.6:1 although in its earlier stages and in PPMS, the gender ratio seems to reverse (13).
• Life expectancy among those who have MS is about 7-8 years shorter than the general population (25)

Rheumatoid arthritis

• Rheumatoid arthritis is the disease that most commonly affects the joints (11).
• A study from 2008 found that about 1 percent of the world’s population is affected by it being more prevalent among persons of European and Asian descent (11).
• The lifetime risk of developing rheumatoid arthritis in the United States is about 3.6 percent in women and 1.7 percent in men (11).
• The prevalence increases with age with the disease affecting 6 percent of the white population over 65 years of age (11).

Type 1 diabetes

• Type 1 diabetes is one the most common diseases in childhood (15)
• Type 1 diabetes is more common among males (15)
• Globally, it is most common in Finland with more than 60 cases per 100,000 annually.  It is less common in China, India, and Venezuela with 0-1 cases per 100,000 annually (15).

Psoriasis/psoriatic arthritis

• Approximately 2-4 percent of the world’s population is affected by psoriasis (2010) (26)
• Prevalence among adults is higher (0.91% to 8.5%) compared to children (0.2% to 2.1%) with two peak incidences of around 30-39 years of age and 60 years of age (26)

Lupus

• Approximately 1.5 million Americans and at least 5 million persons globally are affected by lupus (2012) (27)
• Mainly women of childbearing age are affected; however, lupus can affect men, children, and teenagers as well (27).

Inflammatory bowel disease

• Crohn’s disease and ulcerative colitis affect about 1 in 200 persons in developed countries with a rising incidence in developing countries (2012) (17)
• The disease is estimated to cost the USA more than 2.2 billion dollars each year (17)
• Both Crohn’s disease and ulcerative colitis develop at young ages with persons being more likely to develop it between their late teens and early 30s (28)

Addison’s disease

• The most common cause of AD worldwide is tuberculosis while the most common cause in the developed world is autoimmunity (18)
• It is estimated that 1 in 10,000 people are affected in the UK and across Europe (2014) (18)
• More females than males are affected with a ratio of female to male ratio of 1.8 (18)

Graves’ disease

• Graves’ disease is common among adults with a prevalence of about 0.5-1% (19)

Sjögren’s syndrome

• After rheumatoid arthritis, it is considered to be the most common rheumatic autoimmune disorder with worldwide prevalence rates ranging from 0.03% in Japan and 0.09% in Greece to 2.7% in Sweden (12).

Myasthenia gravis

• Patients with myasthenia gravis have a higher incidence of having other autoimmune diseases (20)

MEDICAL TREATMENTS OF AUTOIMMUNE DISEASES

Each autoimmune disease presents itself in a different manner causing standardized treatments difficult.  Some common treatments for them include medication such as analgesics, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biological agents, and glucocorticoids.  With an early diagnosis, the main goal of treatment would be remission without inflammation and functional deterioration (29).  Another treatment option includes replacing end organ function such as in the case of insulin in diabetes and thyroxine in autoimmune thyroid disease (30).

The current “gold standard” for treating autoimmune diseases are immunosuppressive medication which inhibit immune responses.  Although they are highly effective, patients require long-term treatment with high doses which can leave them susceptible to potentially life-threatening opportunistic infections and long-term risk of malignancy.

Along with this, there has been toxicity associated with these drugs along with serious side effects.  Due to this, there has been some push to develop new strategies to treat autoimmune diseases that do not suppress the immune system as much and are more tolerated by patients.  These new therapies include co-stimulation blockade, regulatory T cell therapy, antigen-specific immunotherapy, and manipulating the interleukin-2 pathway (31).

Some disease-specific treatments include:

Rheumatoid arthritis

Managing rheumatoid arthritis is primarily done with the use of disease-modifying antirheumatic drugs (DMARDs).  These drugs are characterized by their ability to reduce or reverse signs or symptoms, disability, impairment of quality of life, inability to work and progression of joint damage; therefore, they disrupt the disease process (32).

Type 1 diabetes

Management of type 1 diabetes typically involves using insulin analogs along with mechanical technologies such as insulin pumps and glucose monitors (15).

Psoriasis

Classic therapies for psoriasis range from topical treatments (emollients, topical corticosteroids, vitamin D analogs) for mild-moderate cases to UVA/UVB phototherapy or systemic therapies for more severe cases (26).

Lupus

Patients with lupus are typically treated with glucocorticoids but this puts them at risk for bone loss.  Osteoporosis is a common comorbidity of lupus patients and low bone mineral density frequently occurs among this population (8).

Inflammatory bowel disease

Pharmacological treatment of inflammatory bowel disease involves five main categories: anti-inflammatory drugs, immunosuppressants, biologic agents, antibiotics, and drugs for relief of symptoms (33).

Addison’s disease

Management of AD involves lifelong supplementation and replacement of glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) (18).

Graves’ disease

There are several different treatment options for Graves’ disease including antithyroid drug therapy, surgery, 131I (Iodine) therapy (19).

Sjögren’s syndrome

Multiple drugs are used for the treatment of Sjögren’s syndrome.  These include pilocarpine, NSAIDs, hydroxychloroquine, methotrexate, glucocorticoids, and rituximab (34).

Myasthenia gravis

Treating early with immunosuppressive drugs such as corticosteroids or azathioprine can potentially reduce the progression of the disease into secondary generalization (35).

However, these drugs have been shown to have poor efficacy and safety and have side-effects that can occur in the long-term.  Another drug, tacrolimus, is a potential treatment option for myasthenia gravis and its dosage can be gradually reduced once the disease symptoms improve until there is complete withdrawal from the drug (36).

NATURAL WAYS FOR SUPPORTING A HEALTHY IMMUNE SYSTEM

Practices to Support a Healthy Immune System:

• Exercising
• Limiting some environmental factors like UV exposure
• Eating a well-balanced diet
• Limiting stress (5)

Natural Supplements That Support a Healthy Immune System:

• Andrographis leaf extract (Andrographis paniculate) (37,38,39).
• Arabinogalactans (Larch laricina) (40,41)
• Echinacea leaf (Echinacea purpurea) (42,43,44)
• Echinacea root extract (Echinacea angustifolia) (42,45)
• Olive leaf extract (Olea europaea) (46)
• Shilajit extract (47)

REFERENCES

1. Immune System – National Library of Medicine – PubMed Health. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0025680/. Accessed March 11, 2018.
2. Institute for Quality and Efficiency in Health Care. How does the immune system work? September 2016. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072548/. Accessed March 11, 2018.
3. National Institutes of Health. Autoimmune Diseases | NIAMS. https://www.niams.nih.gov/health-topics/autoimmune-diseases/advanced#tab-overview. Accessed March 12, 2018.
4. Orbai A-M. What Are Common Symptoms of Autoimmune Disease? https://www.hopkinsmedicine.org/health/healthy-woman/conditions/what-are-common-symptoms-of-autoimmune-disease. Accessed April 3, 2018.
5. Shepshelovich D, Shoenfeld Y. Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity. Lupus. 2006;15(3):183-190. doi:10.1191/0961203306lu2274rr
6. National USL of M. Autoimmune Diseases. https://medlineplus.gov/autoimmunediseases.html. Accessed March 12, 2018.
7. Murrel D. Autoimmune Diseases: Types, Symptoms, Causes and More. https://www.healthline.com/health/autoimmune-disorders. Published 2017.
8. Cramarossa G, Urowitz MB, Su J, Gladman D, Touma Z. Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus. Lupus. 2017;26(4):365-372. doi:10.1177/0961203316664597
9. Lupus. https://medlineplus.gov/lupus.html. Accessed April 9, 2018.
10. Guo G, Fu T, Yin R, et al. Sleep quality in Chinese patients with rheumatoid arthritis: contributing factors and effects on health-related quality of life. Health Qual Life Outcomes. 2016;14(1):151. doi:10.1186/s12955-016-0550-3
11. Davis JM, Matteson EL, American College of Rheumatology EL, European League Against Rheumatism. My treatment approach to rheumatoid arthritis. Mayo Clin Proc. 2012;87(7):659-673. doi:10.1016/j.mayocp.2012.03.011
12. Hammitt KM, Naegeli AN, van den Broek RWM, Birt JA. Patient burden of Sjögren’s: a comprehensive literature review revealing the range and heterogeneity of measures used in assessments of severity. RMD open. 2017;3(2):e000443. doi:10.1136/rmdopen-2017-000443
13. Beer S, Khan F, Kesselring J. Rehabilitation interventions in multiple sclerosis: an overview. J Neurol. 2012;259(9):1994-2008. doi:10.1007/s00415-012-6577-4
14. Kawasaki E, Maruyama T, Imagawa A, et al. Diagnostic criteria for acute-onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 Diabetes Mellitus. J Diabetes Investig. 2014;5(1):115-118. doi:10.1111/jdi.12119
15. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet (London, England). 2014;383(9911):69-82. doi:10.1016/S0140-6736(13)60591-7
16. Ayala-Fontánez N, Soler DC, McCormick TS. Current knowledge on psoriasis and autoimmune diseases. Psoriasis (Auckland, NZ). 2016;6:7-32. doi:10.2147/PTT.S64950
17. Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet (London, England). 2016;387(10014):156-167. doi:10.1016/S0140-6736(15)00465-1
18. Burton C, Cottrell E, Edwards J. Addison’s disease: identification and management in primary care. Br J Gen Pract. 2015;65(638):488-490. doi:10.3399/bjgp15X686713
19. Committee on Pharmaceutical Affairs, Japanese Society for Pediatric Endocrinology, and the Pediatric Thyroid Disease Committee, Japan Thyroid Association (Taskforce for the Revision of the Guidelines for the Treatment of Childhood-Onset Graves’ Disease) TC on P, Minamitani K, Sato H, et al. Guidelines for the treatment of childhood-onset Graves’ disease in Japan, 2016. Clin Pediatr Endocrinol case reports Clin Investig  Off J Japanese Soc Pediatr Endocrinol. 2017;26(2):29-62. doi:10.1297/cpe.26.29
20. Tanovska N, Novotni G, Sazdova-Burneska S, et al. Myasthenia Gravis and Associated Diseases. Open access Maced J Med Sci. 2018;6(3):472-478. doi:10.3889/oamjms.2018.110
21. Autoimmune Disorders | Peer reviewed | High Impact Articles List. http://autoimmunediseases.imedpub.com/. Accessed March 20, 2018.
22. American Autoimmune Related Diseases Association. Autoimmune Disease List • AARDA. https://www.aarda.org/diseaselist/. Accessed April 3, 2018.
23. National Institute of Environmental Health Sciences. Autoimmune Disease. https://www.niehs.nih.gov/health/materials/autoimmune_diseases_508.pdf. Accessed March 29, 2018.
24. Satoh M, Chan EKL, Ho LA, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum. 2012;64(7):2319-2327. doi:10.1002/art.34380
25. Ziemssen T, Derfuss T, de Stefano N, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016;263(6):1053-1065. doi:10.1007/s00415-015-7986-y
26. Di Meglio P, Villanova F, Nestle FO. Psoriasis. Cold Spring Harb Perspect Med. 2014;4(8). doi:10.1101/cshperspect.a015354
27. America LF of. No Title. https://resources.lupus.org/entry/facts-and-statistics. Published 2018.
28. Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53(3):305-353. doi:10.1007/s00535-018-1439-1
29. Konforte D, Diamandis EP, van Venrooij WJ, Lories R, Ward MM. Autoimmune diseases: early diagnosis and new treatment strategies. Clin Chem. 2012;58(11):1510-1514. doi:10.1373/clinchem.2012.189480
30. Autoimmune diseases – Australasian Society of Clinical Immunology and Allergy (ASCIA). https://www.allergy.org.au/patients/autoimmunity/autoimmune-diseases. Accessed April 9, 2018.
31. Rosenblum MD, Gratz IK, Paw JS, Abbas AK. Treating human autoimmunity: current practice and future prospects. Sci Transl Med. 2012;4(125):125sr1. doi:10.1126/scitranslmed.3003504
32. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509. doi:10.1136/annrheumdis-2013-204573
33. Triantafillidis JK, Merikas E, Georgopoulos F. Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Devel Ther. 2011;5:185-210. doi:10.2147/DDDT.S11290
34. Both T, Dalm VASH, van Hagen PM, van Daele PLA. Reviewing primary Sjögren’s syndrome: beyond the dryness – From pathophysiology to diagnosis and treatment. Int J Med Sci. 2017;14(3):191-200. doi:10.7150/ijms.17718
35. Wang L, Zhang Y, He M. Clinical predictors for the prognosis of myasthenia gravis. BMC Neurol. 2017;17(1):77. doi:10.1186/s12883-017-0857-7
36. Tao X, Wang W, Jing F, et al. Long-term efficacy and side effects of low-dose tacrolimus for the treatment of Myasthenia Gravis. Neurol Sci. 2017;38(2):325-330. doi:10.1007/s10072-016-2769-5
37. Bertoglio JC, Baumgartner M, Palma R, et al. Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study. BMC Neurol. 2016;16:77. doi:10.1186/s12883-016-0595-2
38. Sandborn WJ, Targan SR, Byers VS, et al. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. Am J Gastroenterol. 2013;108(1):90-98. doi:10.1038/ajg.2012.340
39. Okhuarobo A, Ehizogie Falodun J, Erharuyi O, Imieje V, Falodun A, Langer P. Harnessing the medicinal properties of Andrographis paniculata for diseases and beyond: a review of its phytochemistry and pharmacology. Asian Pacific J Trop Dis. 2014;4(3):213-222. doi:10.1016/S2222-1808(14)60509-0
40. Dion C, Chappuis E, Ripoll C. Does larch arabinogalactan enhance immune function? A review of mechanistic and clinical trials. Nutr Metab (Lond). 2016;13:28. doi:10.1186/s12986-016-0086-x
41. Udani JK. Immunomodulatory effects of ResistAidTM: A randomized, double-blind, placebo-controlled, multidose study. J Am Coll Nutr. 2013;32(5):331-338. doi:10.1080/07315724.2013.839907
42. Zhai Z, Liu Y, Wu L, et al. Enhancement of innate and adaptive immune functions by multiple Echinacea species. J Med Food. 2007;10(3):423-434. doi:10.1089/jmf.2006.257
43. Kim LS, Waters RF, Burkholder PM. Immunological activity of larch arabinogalactan and Echinacea: a preliminary, randomized, double-blind, placebo-controlled trial. Altern Med Rev. 2002;7(2):138-149.
44. Melchart D, Linde K, Worku F, et al. Results of Five Randomized Studies on the Immunomodulatory Activity of Preparations of Echinacea. J Altern Complement Med. 1995;1(2):145-160. doi:10.1089/acm.1995.1.145
45. Echinacea angustifolia – an overview | ScienceDirect Topics. https://www.sciencedirect.com/topics/medicine-and-dentistry/echinacea-angustifolia. Accessed April 9, 2018.
46. Omar SH. Oleuropein in olive and its pharmacological effects. Sci Pharm. 2010;78(2):133-154.doi:10.3797/scipharm.0912-18
47. Carrasco-Gallardo C, Guzmán L, Maccioni RB. Shilajit: a natural phytocomplex with potential procognitive activity. Int J Alzheimers Dis. 2012;2012:674142. doi:10.1155/2012/674142