Systemic lupus erythematosus natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2]

Overview

Common complications of systemic lupus erythematosus include dermatitis, nephritis, and arthritis. Prognosis is generally poor, and the 10-year mortality rate of patients with systemic lupus erythematosus is approximately 40%. The disease's course can be divided into 4 subcategories: developmental phase, preclinical phase, clinical phase, and comorbid complication phase.

Natural History

Systemic lupus erythematosus (SLE) is an autoimmune disease. Several flare-ups may happen in the course of the disease. SLE usually develops in the second and third decades of life, although it can present at any age. It usually starts with mild symptoms such as fatigue, fever, and skin rashes. Without treatment, the patient will develop symptoms of end organ damage, which will eventually lead to death in most patients.

The disease course can be divided into 4 subcategories based on the course of the disease:^[1]^[2]^[3]

Developmental phase:

Genetic mutations
UV radiation exposure
Smoking

Preclinical phase:

Mostly associated with auto-immune antibody production
Autoantibodies common to other systemic autoimmune diseases
Proceeds with a more disease-specific clinically overt autoimmune phase

Clinical phase:

The phase due to damages of the autoantibodies to the body tissues (mostly related to disease itself)
Inflammation
Involvement of first organs
Flares
Involvement of additional organs
Early damages (e.g. alopecia, fixed erythema, cognitive dysfunction, valvular heart disease, avascular necrosis, tendon rupture, Jaccoud’s arthropathy, and osteoporosis)

Comorbidity-complication phase

The phase of damages due to complications of longstanding disease, immunosuppressive therapy, and end organ damage (irreversible damages and complications)

Factors associated with flare up: ^[4]^[3]^[5]

Stress (emotional, etc.)
Sunlight
Ultraviolet light
Infection
Injuries
Surgery
Pregnancy
Abrupt discontinuation of medications
Treatment noncompliance
Medications
Immunizations
Lupus nephritis
Presence of neurologic complications
Presence of vasculitis
Elevated anti-dsDNA
Low C3 level

Complications

Complications that can develop as a result of prolonged activation of systemic lupus erythematosus or the SLE therapy are:^[6]^[7]^[8]^[9]^[10]^[11]^[12]^[13]^[14]^[15]^[16]

(Up arrows represent higher frequencies and down arrows represent lower frequencies)

Organ	Disease	Description	Frequency
Gastrointestinal	Dysphagia	Usually due to an underlying esophageal motility disorder Concomitant gastroesophageal reflux disease	↑↑↑
	Peptic ulcer disease	Due to: The disease itself The adverse effect of SLE treatment	↑
	Intestinal pseudo-obstruction	May lead to mechanical obstruction of the small or large bowel in the absence of an anatomic lesion Obstructing the flow of intestinal contents	↓↓
	Protein-losing enteropathy	Occurs in patients with clinically severe SLE with multi-organ involvement Characterized by: Profound edema Hypoalbuminemia The absence of nephrotic range proteinuria	↓↓
	Hepatitis	May be due to: Drug-induced damage Steatosis Viral hepatitis (concomitant with SLE) Vascular thrombosis Overlap with autoimmune hepatitis due to SLE itself	↑
	Acute pancreatitis	Occurs usually in the setting of active SLE	↓
	Mesenteric vasculitis	Mostly involve: Medium-sized branches of the celiac artery Superior mesenteric artery Inferior mesenteric artery Features of mesenteric vasculitis include: Abdominal pain Gastrointestinal bleeding Intestinal ischemia, infarction, perforation Pancreatitis Primary spontaneous peritonitis: An infection that develops in the peritoneum mainly due to lupus vasculitis	↓↓
	Acute cholecystitis	Due to periarterial fibrosis and acute vasculitis May progress to gangrene, perforation, and sepsis	↓↓
Pulmonary	Pleural disease	May lead to: Pleuritic chest pain with or without radiographic evidence of a pleural effusion Inflammation of the pleura, the lining of the pleural cavity, surrounding the lungs Pneumothorax: a collection of air within the pleural cavity	↑
	Acute pneumonitis	Fulminant form of diffuse lung injury Characterized by rapid onset with fever, cough, and shortness of breath	↓↓
	Pulmonary hemorrhage	Pulmonary alveolar hemorrhage: Acutely ill patients with hemoptysis, fever, cough, and hypoxemia Extensive blood loss Associated with high mortality rates of 70%–90%	↓↓
	Pulmonary hypertension	Increased pressure in the pulmonary artery or lung vasculature Characterized by shortness of breath, dizziness, and faint	↑
	Thromboembolic disease	Chronic inflammation that increase the risk of thromboembolic events	↑
	Shrinking lung syndrome	Characterized by dyspnea and shortness of breath (estimated prevalence approximately 0.5%)	↓↓
Cardiac	Cardiomegaly	Due to: Myocarditis Libman-Sacks endocarditis Subacute bacterial endocarditis Uremia Pulmonary arterial hypertension with right-sided heart failure Corticosteroid-related cardiomyopathy	↑↑
	Valvular disease	Different valvular complications include: Libman-Sacks vegetations Valve thickening Valve regurgitation Mainly due to immunoglobulin and complement deposition in valvular structure Affect the mitral valve more frequently	↑↑
	Pericardial disease	Acute pericarditis Pericardial effusion	↓
	Myocarditis	Characterized by: Chest pain ST segment elevation Elevated biomarkers of myonecrosis Heart failure Sudden death Myonecrosis may happen as a consequence of autoimmune reaction	↓
	Coronary artery disease	Mainly as a result of increased risk of atheromatous plaques due to autoimmune status of SLE	↑↑
Neurological	Cognitive dysfunction	May be temporarily affected by multiple, transient metabolic and systemic processes	↑
	Stroke	Increase risk of thrombotic stroke due to small vessel vasculopathy	↓
	Seizures	May happen secondary to increased intracranial pressure: Hypercoagulability state (due to inflammation) Thrombosis within the cerebral venous	↑
	Psychosis	Can indirectly influence cognitive performance Mostly accompanied by hallucinations in SLE	↑↑
	Neuropathies	Peripheral neuropathy Mostly related to disease activity Central nervous system involvement association A predilection for asymmetric and lower extremities involvement, especially peroneal and sural nerves	↑↑
Musculoskeletal	Arthritis	Mostly symmetrical and non-erosive arthritis Arthralgias Effusions Decreased range of motion of both small and large joints Morning stiffness	↑↑↑↑
	Osteonecrosis (Avascular necrosis)	Most common in the femoral head Can involve humeral head, tibial plateau, and scaphoid navicular Usually bilateral Often asymptomatic Glucocorticoids treatment is associated with the greatest risk of developing the disease	↓
	Subcutaneous nodules	Associated with active disease and flare ups	↑
	Osteoporosis	Mostly due to glucocorticoid usage Loss of height Sudden back pain	↑
Skin	Cutaneous lupus erythematosus	Erythema in a malar distribution over the cheeks and nose (but sparing the nasolabial folds), which appears after sun exposure	↑
	Photosensitivity	Common theme for skin lesions associated with SLE	↑↑↑
	Non-scarring alopecia	May occur at some point during the course of their disease	↑
	Oral and nasal ulcers	Usually painless	↑↑
	Discoid lesions	More inflammatory Have a tendency to scar	↑
Very rare disorders	Malignancy	Non-Hodgkin’s lymphoma Lung cancer Liver cancer Vulvar/vaginal cancer Thyroid cancer	↓↓↓
Very rare disorders	Diabetes mellitus	Increase predisposition to: Lupus nephritis Peripheral neuropathy Retinal disease	↓

Prognosis

The prognosis of systemic lupus erythematosus ranges from a benign illness to an extremely rapid progressive disease that can lead to a fulminant organ failure and death. Without treatment, systemic lupus eryhtematosus will result in a very high mortality rate, with a report of higher than a 60% mortality rate during the mid-20th century. The presence of nephritis is associated with a particularly poor prognosis among patients with SLE; SLE is associated with a 10-year mortality of more than 50% among patients with nephritis. The increase in survival rate of patients and better prognosis may be due to increased disease recognition with more sensitive diagnostic tests, earlier diagnosis or treatment, the inclusion of milder cases, increasingly judicious therapy, and prompt treatment of complications. Although improvements in SLE diagnosis have led to better prognosis, the mortality rate among SLE patients is still 5 times higher than the normal population.^[17]^[18]^[19]^[20]

Poor prognostic factors for SLE survival:^[21]

Presence of nephritis (especially diffuse proliferative glomerulonephritis)
Hypertension
Male sex
Young age
Older age at presentation
Low socioeconomic status
Black race: Higher rate of nephritis
Presence of antiphospholipid antibodies
High overall disease activity

Prognosis markers: ^[21]

Serum anti ds-DNA titres correlated with:

Lupus nephritis
Progression to end-stage renal disease
Increased disease severity
Damage or poor survival

Antiphospholipid antibodies correlated with:

Features of the antiphospholipid syndrome (APS)
CNS involvement
Severe lupus nephritis
Increase in mortality rate

SLE in men compared to women: ^[22]

Less photosensitivity
More serositis
Older age at diagnosis
Higher 1 year mortality compared to women

SLE in the elderly (>65) compared to middle age prevalency: ^[23]

Lower incidence of:
- Malar rash
- Photosensitivity
- Purpura
- Alopecia
- Raynaud’s phenomenon
- Nephritis
- Central nervous system involvement
Greater prevalence of:
- Serositis
- Pulmonary involvement
- Sicca syndrome
- Musculoskeletal manifestations

References

↑ Iwata Y, Furuichi K, Kaneko S, Wada T (2011). "The role of cytokine in the lupus nephritis". J. Biomed. Biotechnol. 2011: 594809. doi:10.1155/2011/594809. PMC 3199078. PMID 22028590.
↑ Rahman A, Isenberg DA (2008). "Systemic lupus erythematosus". N. Engl. J. Med. 358 (9): 929–39. doi:10.1056/NEJMra071297. PMID 18305268.
↑ ^3.0 ^3.1 Deguchi Y, Kishimoto S (1991). "Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice". Clin. Exp. Immunol. 85 (3): 392–5. PMC 1535595. PMID 1893619.
↑ Crow MK, Olferiev M, Kirou KA (2015). "Identification of Candidate Predictors of Lupus Flare". Trans. Am. Clin. Climatol. Assoc. 126: 184–96. PMC 4530671. PMID 26330673.
↑ Josić D, Hofmann W, Habermann R, Schulzke JD, Reutter W (1988). "Isolation of immunoglobulins and their use in immunoaffinity HPLC". J. Clin. Chem. Clin. Biochem. 26 (9): 559–68. PMID 3199078.
↑ Gurevitz SL, Snyder JA, Wessel EK, Frey J, Williamson BA (2013). "Systemic lupus erythematosus: a review of the disease and treatment options". Consult Pharm. 28 (2): 110–21. doi:10.4140/TCP.n.2013.110. PMID 23395811.
↑ Zubair A, Frieri M (2013). "Lupus nephritis: review of the literature". Curr Allergy Asthma Rep. 13 (6): 580–6. doi:10.1007/s11882-013-0394-4. PMID 24234325.
↑ Torres A, Askari AD, Malemud CJ (2009). "Cardiovascular disease complications in systemic lupus erythematosus". Biomark Med. 3 (3): 239–52. doi:10.2217/bmm.09.14. PMID 20477476.
↑ Cortes S, Chambers S, Jerónimo A, Isenberg D (2008). "Diabetes mellitus complicating systemic lupus erythematosus - analysis of the UCL lupus cohort and review of the literature". Lupus. 17 (11): 977–80. doi:10.1177/0961203308091539. PMID 18852220.
↑ Doria A, Canova M, Tonon M, Zen M, Rampudda E, Bassi N, Atzeni F, Zampieri S, Ghirardello A (2008). "Infections as triggers and complications of systemic lupus erythematosus". Autoimmun Rev. 8 (1): 24–8. doi:10.1016/j.autrev.2008.07.019. PMID 18703174.
↑ Zizic TM, Classen JN, Stevens MB (1982). "Acute abdominal complications of systemic lupus erythematosus and polyarteritis nodosa". Am. J. Med. 73 (4): 525–31. PMID 6127033.
↑ Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD (2011). "Manifestations of systemic lupus erythematosus". Maedica (Buchar). 6 (4): 330–6. PMC 3391953. PMID 22879850.
↑ Clowse ME, Jamison M, Myers E, James AH (2008). "A national study of the complications of lupus in pregnancy". Am. J. Obstet. Gynecol. 199 (2): 127.e1–6. doi:10.1016/j.ajog.2008.03.012. PMC 2542836. PMID 18456233.
↑ Bhattacharyya S, Helfgott SM (2014). "Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis". Semin Neurol. 34 (4): 425–36. doi:10.1055/s-0034-1390391. PMID 25369438.
↑ Alves SC, Fasano S, Isenberg DA (2016). "Autoimmune gastrointestinal complications in patients with systemic lupus erythematosus: case series and literature review". Lupus. 25 (14): 1509–1519. doi:10.1177/0961203316655210. PMID 27329649.
↑ Kang I, Park SH (2003). "Infectious complications in SLE after immunosuppressive therapies". Curr Opin Rheumatol. 15 (5): 528–34. PMID 12960476.
↑ Ren Y, Feng X, Zou Y, Pan W, Wang X, Pan J, Zhang M, Tao J, Zhang Y, Tan K, Li J, Ding X, Qian X, Da Z, Wang M, Chen Z, Sun L (2014). "[Clinical features and prognosis of patients with lupus nephritis]". Zhonghua Yi Xue Za Zhi (in Chinese). 94 (13): 973–6. PMID 24851681.
↑ Ugarte A, Ruiz-Irastorza G (2016). "SLE: the changing prognosis". Lupus. 25 (12): 1285–7. doi:10.1177/0961203316652948. PMID 27307448.
↑ Matsuyama N, Morimoto S, Tokano Y, Amano H, Nozawa K, Isonuma H, Hashimoto H, Takasaki Y (2010). "The long-term prognosis of lupus nephritis patients treated with intravenous cyclophosphamide". Intern. Med. 49 (9): 823–8. PMID 20453401.
↑ Sabio JM (2016). "[Systemic lupus erythematosus today]". Med Clin (Barc) (in Spanish; Castilian). 146 (4): 160–2. doi:10.1016/j.medcli.2015.08.001. PMID 26434992.
↑ ^21.0 ^21.1 Lisnevskaia L, Murphy G, Isenberg D (2014). "Systemic lupus erythematosus". Lancet. 384 (9957): 1878–88. doi:10.1016/S0140-6736(14)60128-8. PMID 24881804.
↑ de Carvalho JF, do Nascimento AP, Testagrossa LA, Barros RT, Bonfá E (2010). "Male gender results in more severe lupus nephritis". Rheumatol. Int. 30 (10): 1311–5. doi:10.1007/s00296-009-1151-9. PMID 19784840.
↑ Feng X, Zou Y, Pan W, Wang X, Wu M, Zhang M, Tao J, Zhang Y, Tan K, Li J, Chen Z, Ding X, Qian X, Da Z, Wang M, Sun L (2014). "Associations of clinical features and prognosis with age at disease onset in patients with systemic lupus erythematosus". Lupus. 23 (3): 327–34. doi:10.1177/0961203313513508. PMID 24297642.

[pmid22028590-1] Iwata Y, Furuichi K, Kaneko S, Wada T (2011). "The role of cytokine in the lupus nephritis". J. Biomed. Biotechnol. 2011: 594809. doi:10.1155/2011/594809. PMC 3199078. PMID 22028590.

[pmid18305268-2] Rahman A, Isenberg DA (2008). "Systemic lupus erythematosus". N. Engl. J. Med. 358 (9): 929–39. doi:10.1056/NEJMra071297. PMID 18305268.

[pmid1893619-3] 3.0 ^3.1 Deguchi Y, Kishimoto S (1991). "Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice". Clin. Exp. Immunol. 85 (3): 392–5. PMC 1535595. PMID 1893619.

[pmid26330673-4] Crow MK, Olferiev M, Kirou KA (2015). "Identification of Candidate Predictors of Lupus Flare". Trans. Am. Clin. Climatol. Assoc. 126: 184–96. PMC 4530671. PMID 26330673.

[pmid3199078-5] Josić D, Hofmann W, Habermann R, Schulzke JD, Reutter W (1988). "Isolation of immunoglobulins and their use in immunoaffinity HPLC". J. Clin. Chem. Clin. Biochem. 26 (9): 559–68. PMID 3199078.

[pmid23395811-6] Gurevitz SL, Snyder JA, Wessel EK, Frey J, Williamson BA (2013). "Systemic lupus erythematosus: a review of the disease and treatment options". Consult Pharm. 28 (2): 110–21. doi:10.4140/TCP.n.2013.110. PMID 23395811.

[pmid24234325-7] Zubair A, Frieri M (2013). "Lupus nephritis: review of the literature". Curr Allergy Asthma Rep. 13 (6): 580–6. doi:10.1007/s11882-013-0394-4. PMID 24234325.

[pmid20477476-8] Torres A, Askari AD, Malemud CJ (2009). "Cardiovascular disease complications in systemic lupus erythematosus". Biomark Med. 3 (3): 239–52. doi:10.2217/bmm.09.14. PMID 20477476.

[pmid18852220-9] Cortes S, Chambers S, Jerónimo A, Isenberg D (2008). "Diabetes mellitus complicating systemic lupus erythematosus - analysis of the UCL lupus cohort and review of the literature". Lupus. 17 (11): 977–80. doi:10.1177/0961203308091539. PMID 18852220.

[pmid18703174-10] Doria A, Canova M, Tonon M, Zen M, Rampudda E, Bassi N, Atzeni F, Zampieri S, Ghirardello A (2008). "Infections as triggers and complications of systemic lupus erythematosus". Autoimmun Rev. 8 (1): 24–8. doi:10.1016/j.autrev.2008.07.019. PMID 18703174.

[pmid6127033-11] Zizic TM, Classen JN, Stevens MB (1982). "Acute abdominal complications of systemic lupus erythematosus and polyarteritis nodosa". Am. J. Med. 73 (4): 525–31. PMID 6127033.

[pmid22879850-12] Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD (2011). "Manifestations of systemic lupus erythematosus". Maedica (Buchar). 6 (4): 330–6. PMC 3391953. PMID 22879850.

[pmid18456233-13] Clowse ME, Jamison M, Myers E, James AH (2008). "A national study of the complications of lupus in pregnancy". Am. J. Obstet. Gynecol. 199 (2): 127.e1–6. doi:10.1016/j.ajog.2008.03.012. PMC 2542836. PMID 18456233.

[pmid25369438-14] Bhattacharyya S, Helfgott SM (2014). "Neurologic complications of systemic lupus erythematosus, sjögren syndrome, and rheumatoid arthritis". Semin Neurol. 34 (4): 425–36. doi:10.1055/s-0034-1390391. PMID 25369438.

[pmid27329649-15] Alves SC, Fasano S, Isenberg DA (2016). "Autoimmune gastrointestinal complications in patients with systemic lupus erythematosus: case series and literature review". Lupus. 25 (14): 1509–1519. doi:10.1177/0961203316655210. PMID 27329649.

[pmid12960476-16] Kang I, Park SH (2003). "Infectious complications in SLE after immunosuppressive therapies". Curr Opin Rheumatol. 15 (5): 528–34. PMID 12960476.

[pmid24851681-17] Ren Y, Feng X, Zou Y, Pan W, Wang X, Pan J, Zhang M, Tao J, Zhang Y, Tan K, Li J, Ding X, Qian X, Da Z, Wang M, Chen Z, Sun L (2014). "[Clinical features and prognosis of patients with lupus nephritis]". Zhonghua Yi Xue Za Zhi (in Chinese). 94 (13): 973–6. PMID 24851681.

[pmid27307448-18] Ugarte A, Ruiz-Irastorza G (2016). "SLE: the changing prognosis". Lupus. 25 (12): 1285–7. doi:10.1177/0961203316652948. PMID 27307448.

[pmid20453401-19] Matsuyama N, Morimoto S, Tokano Y, Amano H, Nozawa K, Isonuma H, Hashimoto H, Takasaki Y (2010). "The long-term prognosis of lupus nephritis patients treated with intravenous cyclophosphamide". Intern. Med. 49 (9): 823–8. PMID 20453401.

[pmid26434992-20] Sabio JM (2016). "[Systemic lupus erythematosus today]". Med Clin (Barc) (in Spanish; Castilian). 146 (4): 160–2. doi:10.1016/j.medcli.2015.08.001. PMID 26434992.

[pmid24881804-21] 21.0 ^21.1 Lisnevskaia L, Murphy G, Isenberg D (2014). "Systemic lupus erythematosus". Lancet. 384 (9957): 1878–88. doi:10.1016/S0140-6736(14)60128-8. PMID 24881804.

[pmid19784840-22] Carvalho JF, do Nascimento AP, Testagrossa LA, Barros RT, Bonfá E (2010). "Male gender results in more severe lupus nephritis". Rheumatol. Int. 30 (10): 1311–5. doi:10.1007/s00296-009-1151-9. PMID 19784840.

[pmid24297642-23] Feng X, Zou Y, Pan W, Wang X, Wu M, Zhang M, Tao J, Zhang Y, Tan K, Li J, Chen Z, Ding X, Qian X, Da Z, Wang M, Sun L (2014). "Associations of clinical features and prognosis with age at disease onset in patients with systemic lupus erythematosus". Lupus. 23 (3): 327–34. doi:10.1177/0961203313513508. PMID 24297642.

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