Arthritis as a Manifestation of Systemic Disease 

A large number of systemic conditions have musculoskeletal manifestations. 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 hypothyroidism, hyperthyroidism, primary hyperparathyroidism, diabetes mellitus, Cushing disease, acromegaly, hyperlipidemia, hemochromatosis, syphilis, infections, certain malignancies, and sarcoidosis.

Some rheumatologic illnesses like polymyalgia rheumatica, polymyositis can also present with arthralgias without true arthritis.

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

In many cases, the pathophysiologic basis of joint disease in these systemic illnesses is not known.

Endocrine-associated arthropathies

• Hypothyroidism: Muscle energy production is decreased due to reductions 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 to cancellous bone.
• Diabetes: Glucose-induced collagen modifications and microvascular disease may play an important 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.

Hematologic illness arthropathies

• Hemophilia: Bleeding in the joint and hemearthrosis
• 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. The underlying cause of arthritis in patients with hemochromatosis is unknown, though iron deposition and defects in cartilage and immunologic function have been implicated.

Other systemic illnesses

• 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.

Malignancy-associated arthropathies

• Seronegative polyarthritis from paraneoplastic syndrome

Frequency

United States

• 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 5 cases per 100,000 population.
• The estimated prevalence of diabetes in 2008 was 8%, with over 80% of cases consisting of type 2 diabetes mellitus.
• Cushing disease is an uncommon disease.
• The incidence of acromegaly is low: 3 to 4 per million people.
• Hyperlipidemias are common disorders. For instance, heterozygous familial hypercholesterolemia is found in approximately 1 out of 500 individuals.
• Hemochromatosis is an autosomal recessive disease; the prevalence of homozygosity for the mutation is 1 in 200 to 300 persons. However, only a fraction of these persons 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.
• Arthritis as a manifestation of these diseases is rare but certainly seen.

International

• Hypothyroidism is more common in areas of the world where the population has a low iodine intake.
• The incidence of hyperparathyroidism, Cushing disease, and acromegaly globally is 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 a 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. The hemochromatosis gene is found almost exclusively in persons of northern European origin.
• The diversity of the prevalence of sarcoidosis among certain ethnic and racial groups is remarkable, with a range of less than 1 case to 64 cases per 100,000 population worldwide. In Sweden, 64 out of 100,000 persons are affected; in France, 10 out of 100,000 persons are affected; and in Poland, 3 out of 100,000 persons are affected. In contrast, the disease is very rare among Canadian Indians, New Zealand Maoris, and Southeast Asians.

Mortality/Morbidity

If left undiagnosed, significant morbidity and mortality exist for each of the diseases discussed is this article.

• 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 cerebral vascular accident. 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.

Race

• 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.

Sex

• 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.

Age

• 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.^[1]
• 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 lipids 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.