Arthritis as a Manifestation of Systemic Disease

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Musculoskeletal manifestations can be part of the presentation in many systemic conditions, but true arthritis is the initial manifestation of the underlying illness in some systemic diseases. This article focuses on systemic diseases in which an early or even the initial manifestation may be musculoskeletal in nature. These disorders predominantly include the following:

Some rheumatologic illnesses (eg, polymyalgia rheumatica, fibromyalgia, polymyositis) can also present as arthralgias without true arthritis.

Most patients who complain of joint pain and swelling, muscle pain, or limited range of motion have a primary disorder of the joint, such as rheumatoid arthritis or osteoarthritis. Less commonly, joint pains may be the chief complaint in a patient with a systemic disorder that is affecting the joints, muscles, or both. A vigilant physician must be aware of these conditions, some common and some not so common, to make an appropriate diagnosis and early referral and appropriate treatment.

Systemic illnesses can cause musculoskeletal manifestations through a variety of mechanisms. However, in many cases, the pathophysiologic basis of joint disease in these systemic illnesses is not known.

See the list below:

Hypothyroidism: Muscle energy production is decreased due to reduction in glycogenolysis and mitochondrial oxidative metabolism, which probably contributes to myalgias, fatigue, and weakness

Hyperparathyroidism: Excess parathyroid hormone (PTH) results in increased bone resorption with preferential loss of cortical bone, as compared with cancellous bone

Diabetes: Glucose-induced collagen modifications and microvascular disease may play an role in limited joint mobility syndromes

Cushing disease: Excess glucocorticoid production induces osteoporosis by multiple mechanisms, including direct effects on the osteoclast and osteoblast unit and secondary effects mediated through vitamin D and PTH

Acromegaly: Excess growth hormone and insulinlike growth factor I (IGF-I) stimulate proliferation of articular chondrocytes; this proliferation leads to cartilage hypertrophy, and the thickened cartilage is subject to rapid and early degeneration that leads to acromegalic arthropathy

See the list below:

Hemophilia: Bleeding into the joint (hemarthrosis), which may lead to synovial inflammation and joint deterioration [1]

Sickle cell anemia: Avascular necrosis and hyperuricemia secondary to renal tubular damage

Hemochromatosis: This genetic disease results in an iron overload secondary to excess absorption of iron from the GI tract; iron deposition and defects in cartilage and immunologic function have been implicated in the arthritis; deposition of ferritin in joints can cause pain and swelling; elevated serum levels of vascular adhesion molecule 1 (VCAM-1) correlate with clinical measures of arthropathy [2] Patients who have C282Y homozygosity may be at higher risk for osteoarthritis than those with other genotypes. [3]

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Hyperlipidemia: The pathogenesis of rheumatic manifestations of this disease is not well understood

Sarcoidosis: Although the cause of this disease is unknown, the host immune response clearly plays a central role in its pathogenesis; sarcoidosis is characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas that are widely distributed in involved tissues, including in the muscles and synovium

Seronegative polyarthritis may occur as a paraneoplastic syndrome

United States

Arthritis as a manifestation of systemic disease is rare. The frequency of selected disorders that can present as arthritis is as follows:

Hypothyroidism is an extremely common problem in the United States; the Third National Health and Nutrition Examination Survey (NHANES III) reports hypothyroidism in 5% of the population

The prevalence of hyperparathyroidism is five cases per 100,000 population

The US Centers for Disease Control and Prevention (CDC) estimates that in the United States in 2012, 29.1 million people, or 9.3% of the population, had diabetes, and in 8.1 million of those, the disease was undiagnosed; in adults, 95% of cases consisted of type 2 diabetes mellitus, and at current rates, at least one in three people in the US will develop the disease in their lifetime [4]

Cushing syndrome is uncommon; most cases are due to exogenous steroids

The incidence of acromegaly is low: three to four per million population

Hyperlipidemias are common disorders; for example, heterozygous familial hypercholesterolemia is found in approximately one of 500 individuals

Hemochromatosis is an autosomal recessive disease; the prevalence of homozygosity for the mutation is one in 200 to 300 persons, but only a fraction of those develop clinical disease; frequency of the carrier state is estimated to be 10% in whites in the United States and Western Europe

The prevalence of sarcoidosis is 5-40 cases per 100,000 population in the United States


The frequency of selected systemic disorders that can present as arthritis is as follows:

Hypothyroidism is more common in areas of the world where the population has a low iodine intake

The incidences of hyperparathyroidism, Cushing syndrome, and acromegaly globally are not known to differ from that in the United States

Type 2 diabetes is less common in non-Western countries, with the exception of India, where it is extremely prevalent and on the rise

Regarding hyperlipidemia, certain populations have a higher prevalence of particular genetic lipid disorders; familial hypercholesterolemia is significantly more common among French Canadians; hyperlipidemia is also diet related and more frequently seen in developed nations with the obesity epidemic

Hemochromatosis gene is found almost exclusively in persons of northern European origin

The prevalence of sarcoidosis among certain ethnic and racial groups shows remarkable diversity, with a range of less than one to as many as 64 cases per 100,000 population worldwide. In Sweden, 64 of 100,000 persons are affected; in France, 10 of 100,000 persons are affected; and in Poland, three of 100,000 persons are affected. In contrast, the disease is very rare among Canadian aboriginal peoples, New Zealand Maoris, and Southeast Asians

If left undiagnosed, each of the diseases discussed in this article may result in significant morbidity and mortality, as follows:

Untreated hypothyroidism can result in myxedema coma, which has a high mortality rate. Fortunately, this is now a rare presentation of hypothyroidism.

Hyperthyroidism can lead to atrial fibrillation and stroke. Osteoporosis from hyperthyroidism can lead to increased risk of hip fractures and increased mortality.

Untreated hyperparathyroidism may be associated with increased cardiovascular mortality. Osteoporosis from hyperparathyroidism can lead to increased risk of hip fractures and increased mortality.

Without proper diagnosis and treatment, Cushing disease also leads to premature cardiovascular disease.

Acromegaly is associated with increased mortality from both cardiovascular causes and cancer.

There is increased incidence of cardiovascular disease imparted by hypercholesterolemia and diabetes.

Patients with hemochromatosis are at risk for developing liver cirrhosis, hepatocellular cancer, diabetes, and heart disease. Patients with hemochromatosis who are diagnosed after the onset of cirrhosis die prematurely from end-stage liver disease or primary liver cancer. If diagnosed before the onset of cirrhosis, life expectancy is normal.

Sarcoidosis is associated with increased mortality from both cardiac and lung disease. The age-adjusted mortality rate for African Americans was 12 times higher than for Caucasians. [1]

See the list below:

Hypothyroidism: This disease may be more common among whites than other races.

Hyperparathyroidism: No known racial differences exist.

Diabetes: In the United States, type 2 diabetes is more prevalent amongst Native Americans, Hispanics, Asians, and blacks than other races.

Cushing disease: This disease may be more common among whites than other races.

Acromegaly: No known racial differences exist.

Hyperlipidemia: The incidence of arthritis and tendon xanthomas is not known to differ among races, but some populations have a low incidence of lipid abnormalities.

Hemochromatosis: This disease is found in northern Europeans and their descendants.

Sarcoidosis: The condition is most common in African Americans and Northern European whites.

See the list below:

Hypothyroidism: Women are affected more commonly than men, with the disorder occurring up to 8 times more frequently in women than men.

Hyperparathyroidism: Women are affected more commonly than men by a ratio of 2:1.

Diabetes: Men and women appear to be affected equally.

Cushing disease: Women are affected 5 times more often than men.

Acromegaly: Men and women are affected equally.

Hyperlipidemia: Men are affected more commonly than women, but the gene frequency is equal between men and women.

Hemochromatosis: The gene frequency is equal between men and women, but men are diagnosed with the disease more frequently than women. This may relate to iron loss in women through menstruation as well as iron loss and increased iron needs during pregnancy.

Sarcoidosis: The disorder is slightly more common amongst women than men.

See the list below:

Hypothyroidism: This disease affects individuals of all ages, with the frequency of hypothyroidism increasing with age. Hypothyroidism is so common in women that the 1990 American College of Physicians Clinical Practice Guidelines recommend screening for hypothyroidism in women older than 40 years. [5]

Hyperparathyroidism: The most common age at onset is in the fifth and sixth decades.

Diabetes: The total prevalence of diabetes increases with age.

Cushing disease: The most common age at onset is in the third and fourth decades.

Acromegaly: Onset usually occurs in young adulthood from 20-40 years. As this is an insidious disease, the mean age of diagnosis is 40-45 years.

Hyperlipidemia: Elevated may be noted early in life, even in childhood.

Hemochromatosis: In men, hemochromatosis manifests in those aged approximately 40-50 years. Onset in women usually is later, in those aged approximately 60 years. Similar to the diagnosis itself, this delay in women is likely related to iron loss during the reproductive years.

Sarcoidosis: Most patients present with sarcoidosis when aged 20-40 years, but this disorder can occur in children and in elderly individuals.

Most of the arthritis get better with treatment of the underlying condition unless permanenet damage has been done due to a chronic condition.

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Ritu Khurana, MD Chief of Rheumatology, Crozer Chester Medical Center, Upland, PA

Ritu Khurana, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Lawrence H Brent, MD Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology

Disclosure: Stock ownership for: Johnson & Johnson.

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Interim Chief, Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors R Hal Scofield, MD and Linda A Zacharias, MD to the development and writing of this article.

Arthritis as a Manifestation of Systemic Disease

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