eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis

Arthritis as a Manifestation of Systemic Disease

Author: R Hal Scofield, MD, Professor, Department of Medicine, Section of Endocrinology, University of Oklahoma Health Sciences Center; Associate Member, Arthritis and Immunology Program, Oklahoma Medical Research Foundation
Coauthor(s): Linda A Zacharias, MD, Fellow, Department of Medicine, Section of Rheumatology, Oklahoma University Health Sciences Center
Contributor Information and Disclosures

Updated: Aug 29, 2006

Introduction

Background

A large number of conditions have musculoskeletal manifestations. However, among these, true arthritis is the initial manifestation of the underlying illness in only a few. This article focuses on systemic diseases in which an early, or even the initial, manifestation may be musculoskeletal in nature. These disorders include hypothyroidism, primary hyperparathyroidism, diabetes mellitus, Cushing disease, acromegaly, hyperlipidemia, hemochromatosis, and sarcoidosis.

Most patients complaining of joint pain or aches, muscle pain, or limited range of motion have a primary disorder of the joint, such as osteoarthritis. However, a few such persons have a systemic disorder that is affecting the joints, muscles, or both. The vigilant physician must be aware of these conditions, some of which are common and some of which are not so common, in order to make an appropriate diagnosis.

Pathophysiology

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

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

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 4.6% of patients (0.3% overt and 4.3% subclinical).
• The prevalence of hyperparathyroidism is 4 cases per 100,000 population.
• The estimated prevalence of diabetes in 2002 was 6.3%, 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.

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.
• Regarding hyperlipidemia, certain populations have a higher prevalence of particular genetic lipid disorders. For instance, familial hypercholesterolemia is significantly more common among French Canadians.
• 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.
• Untreated hyperparathyroidism may be associated with increased cardiovascular 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.
• Of course, the increased incidence of cardiovascular disease imparted by hypercholesterolemia and diabetes is well known.
• 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. Meanwhile, 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 (Helfand, 1990).
• 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.

Clinical

History

• Hypothyroidism
  • Hypothyroidism can present with an arthritis that resembles early rheumatoid arthritis (RA). Patients complain of pain and stiffness, including morning stiffness, in a symmetrical distribution similar to that found in RA affecting small joints of the hands and wrists. Unlike most cases of RA, this is not a deforming arthritis.
  • There is a well-known association between the occurrence of hypothyroidism and muscular disease. The spectrum of thyroid myopathy is broad, ranging from asymptomatic elevation in muscle enzymes, proximal weakness (especially in the hip flexors), polymyositislike syndrome, to a constellation of muscle cramps, stiffness, and pseudohypertrophy, referred to as Hoffmann syndrome.
  • Carpal tunnel syndrome is observed in up to 10% of patients with hypothyroidism.
  • Patients may have associated symptoms of fatigue, weight gain, and cold intolerance.
• Hyperparathyroidism
  • The classic musculoskeletal manifestation of primary hyperparathyroidism is osteitis fibrosa cystica, which consists of bone pain, osteopenia, and bony cysts.
  • Hyperparathyroidism with kidney stones and osteitis fibrosa cystica is rare today because most patients with primary hyperparathyroidism are diagnosed after their serum calcium is found to be high on multiple automated chemistries.
  • Chondrocalcinosis has been described in up to 30% of patients with primary hyperparathyroidism. Acute pseudogout occasionally may occur, especially after parathyroidectomy. While some patients discovered in this manner are asymptomatic, many of these patients have other symptoms. These include depression, fatigue, constipation, and joint pain. The joint pain is widespread and nonspecific. The joints of the hands most commonly are affected.
• Diabetes
  • Musculoskeletal disorders of the hand and shoulder occur more commonly in patients with diabetes. One study reports the disorder as occurring 4 times more frequently in patients with diabetes than in those without the disease. These syndromes include adhesive capsulitis of the shoulder, Dupuytren contracture, and flexor tenosynovitis. Adhesive capsulitis can be seen in up to 20% of people with diabetes and tends to occur at a younger age in these individuals. The presence of hand or shoulder syndromes is associated with longer duration of disease. The risk of such syndromes is also higher in women.
  • Diabetic cheiroarthropathy (limited joint mobility of the hands characterized by thick, tight, waxy skin over the dorsum of the hands) is most commonly seen in people with type 1 diabetes.
  • People with diabetes have more than 2 times the risk of carpal tunnel syndrome, compared with those without diabetes. Six percent of patients with carpal tunnel syndrome carry the diagnosis of diabetes.
  • A higher prevalence of diffuse idiopathic skeletal hyperostosis (DISH) exists in patients with diabetes. This illness is manifested by excessive new bone growth predominantly in entheseal regions of the thoracolumbar spine.
  • Neuropathic arthropathy, also known as Charcot joint, can be seen in long-standing diabetes. The most commonly affected joints are the metatarsophalangeal, tarsometatarsal, tarsus, ankle, and interphalangeal joints.
  • Diabetic muscle infarction is a rare complication of diabetes, presenting as a painful swelling, usually in the thigh.
• Cushing disease
  • The presenting musculoskeletal manifestation of Cushing disease may be osteoporosis with fracture. Proximal myopathy with muscle wasting is common in Cushing disease.
  • In the authors' experience, it is not uncommon for patients with Cushing disease to present with a vertebral compression fracture. Of course in the past, many of these patients have seen physicians for obesity, diabetes mellitus, hypertension, infection, or a combination of these disorders. But the occurrence of osteoporotic fractures in young adults may be the manifestation that triggers a workup for excess glucocorticoid production.
• Acromegaly
  • Rarely does a patient present with complaints of coarsening facial features, increasing shoe size, or enlarging hands.
  • Most patients with acromegaly present with headache or visual-field abnormalities related to the size and position of the pituitary tumor that is producing growth hormone. At this point, the patient undoubtedly has had the disease for many years.
  • A substantial fraction of patients with acromegaly are diagnosed serendipitously, usually when they accompany their spouse to see the doctor or seek care for matters unrelated to acromegaly.
  • Peripheral arthropathy is common in the large joints, such as the shoulders and knees. Severe osteoarthritis with crepitus and, eventually, pain, limited range of motion, and deformity can occur.
  • An early manifestation may be involvement of the first carpometacarpal joint.
  • Symptoms of carpal tunnel syndrome often occur.
• Hyperlipidemia
  • Familial hypercholesterolemia and mixed hypercholesterolemia are associated with tendon xanthomas, particularly of the Achilles tendon, as well as Achilles tendonitis.
  • An association may exist between hyperlipidemia and oligoarthritis or a migratory polyarthritis.
• Hemochromatosis
  • Approximately 40-60% of patients with hemochromatosis have arthropathy. With some patients, the arthropathy is the first manifestation of the underlying disease.
  • Any joint may be affected, but osteoarthritislike symptoms and changes in the second and third metacarpophalangeal (MCP) joints are involved most commonly.
  • Pain and stiffness in the affected joints are common.
  • Chondrocalcinosis is present in as many as two thirds of patients with hemochromatosis.
  • One study found a prevalence rate of 1.5% for hemochromatosis in a rheumatology clinic.
  • Hemochromatosis may be associated with an increased incidence of osteoporosis. One study reported 45% of patients with hemochromatosis also have osteoporosis, especially those patients with coexisting hypogonadism.
• Sarcoidosis
  • The clinical features of sarcoidosis may mimic those of many rheumatic diseases.
  • Sarcoidosis may also coexist with autoimmune diseases.
  • Patients may present with an acute polyarthritis, especially involving ankles and knees. This arthritis may occur in isolation or as part of Lofgren syndrome, which is defined as a triad of hilar lymphadenopathy, acute polyarthritis, and erythema nodosum.
  • Less commonly, a chronic arthritis may occur (typically involving the ankles, knees, and hands) that is rarely deforming.
  • Occasionally, patients may have enthesitis, especially in the Achilles tendon, or granulomatous myopathy with pain, proximal muscle weakness, or both.
  • Granulomatous bony lesions may occur, especially in the fingers.
• Association with calcium pyrophosphate deposition disease
  • Hypothyroidism, hyperparathyroidism, and hemochromatosis are associated with calcium pyrophosphate deposition disease (CPPD).
  • This may occur as asymptomatic chondrocalcinosis or as episodes of acute monoarthritis (pseudogout) or chronic polyarthritis.
  • See Calcium Pyrophosphate Deposition Disease.
• Association with carpal tunnel syndrome
  • Hypothyroidism, acromegaly, and diabetes are associated with carpal tunnel syndrome.
  • See Nerve Entrapment Syndromes.

Physical

• Hypothyroidism
  • Physical findings are minimal.
  • The MCP and proximal interphalangeal (PIP) joints may be slightly tender. Soft tissues may be slightly swollen, though redness and increased warmth are unlikely.
  • Signs of carpal tunnel syndrome may be present.
  • Proximal muscle weakness may be present.
• Hyperparathyroidism
  • The joints are not swollen, red, or tender, except with acute pseudogout.
• Diabetes
  • Adhesive capsulitis of the shoulder is more common in patients with diabetes. The capsulitis is characterized by progressive, painful restriction of shoulder motion.
  • Dupuytren contracture and flexor tenosynovitis may be present.
  • Diabetic cheiroarthropathy presents with thick, tight skin over the dorsum of the hands and with flexion deformities of the MCP joints and interphalangeal joints. This condition can be shown clinically by the inability of the palms to come completely together with the wrists fully flexed, which is known as the prayer sign.
  • Findings consistent with carpal tunnel syndrome may be present.
  • Neuropathic arthropathy, also known as Charcot joint, is characterized by a painless, swollen, deformed joint. The most commonly affected joints are the metatarsophalangeal, tarsometatarsal, tarsus, ankle, and interphalangeal joints.
• Cushing disease
  • The patient may have the classic features of Cushing disease, such as striae, truncal obesity, plethora, and bruising (see Image 1).
  • On the other hand, most or even all of these findings may be absent.
  • Proximal weakness with muscle wasting may be present.
• Acromegaly
  • Hypertrophy of the joint, including thickening of bursae (eg, olecranon or prepatellar bursae), can be present.
  • In later stages, patients may have a limited range of motion at the large joints, such as the shoulder.
  • Physical findings of carpal tunnel syndrome may be present.
• Hyperlipidemia
  • The critical physical finding is the presence of tendon xanthomas. These appear in childhood in individuals with a complete defect in the low-density lipoprotein (LDL) particle receptor (ie, homozygous familial hypercholesterolemia).
  • In heterozygous familial hypercholesterolemia, tendon xanthomas begin to develop in the second or third decade of life.
• Hemochromatosis
  • Bony swelling and mild tenderness of the second and third MCP joints may develop, though usually without redness or increased warmth.
  • Shoulder, hip, and knee joints may be involved in a low-grade synovitis, especially in patients with CPPD.
  • Full extension or full flexion may not be possible.
• Sarcoidosis
  • Acute sarcoid arthritis is often periarticular, with tenderness, erythema, and swelling. The ankles and knees are almost invariably involved, often with coexistent erythema nodosum. Other joints, such as the wrists, elbows, PIP joints, or MCP joints, are commonly involved. Joint motion is usually normal, and pain is absent or minimal. The axial skeleton is usually spared.
  • The presence of erythema nodosum, acute arthritis, and bilateral hilar adenopathy is called Lofgren syndrome.
  • Enthesitis may be observed upon physical examination.
  • Chronic sarcoid arthritis can be evanescent, recurrent, or chronic. The knees, ankles, and PIP joints are most commonly involved. The chronic form often manifests as dactylitis, frequently with overlying cutaneous sarcoid.
  • Other potential rheumatic manifestations of sarcoidosis are uveitis, proptosis, keratoconjunctivitis sicca, parotid gland enlargement, and upper airway disease including laryngeal inflammation and sinusitis.

Causes

• Hypothyroidism
  • The common cause of hypothyroidism is autoimmunity, with destruction of the gland's functional capacity due to chronic inflammation.
  • Other causes include surgical removal of the thyroid, radioiodine therapy for hyperthyroidism, or pituitary failure.
• Hyperparathyroidism
  • The great majority of primary hyperparathyroidism cases are caused by a parathyroid adenoma. This has been proven to be of monoclonal origin.
  • Hyperplasia, a polyclonal process involving all 4 glands, is less common.
  • Still less common, parathyroid carcinoma rarely produces hyperparathyroidism.
• Diabetes
  • Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to absolute insulin deficiency.
  • Type 2 diabetes is characterized by variable degrees of insulin deficiency and insulin resistance, with a strong genetic influence.
• Cushing disease
  • Approximately 85% of endogenous hypercortisolism is caused by pituitary overproduction of adrenocorticotropic hormone (ACTH).
  • In at least 90% of these cases, a basophilic microadenoma ( <1 cm by definition, but usually 1-2 mm) of the pituitary is present.
  • In the remainder, corticotroph hyperplasia is present without a discrete tumor.
• Acromegaly
  • A pituitary tumor secreting growth hormone is the only common cause of acromegaly.
  • These tumors are almost always macroadenomas (ie, > 1 cm in diameter).
• Hyperlipidemia
  • Familial hypercholesterolemia is caused by a genetic mutation in the LDL receptor gene.
  • In heterozygotes, this results in half the normal number of these receptors and serum cholesterol values of nearly 500 mg/dL.
• Hemochromatosis: This is a genetic disorder resulting in iron overload.
• Sarcoidosis: While much speculation exists, the etiology of sarcoidosis is unknown.

• Search for CME/CE on This Topic »

• Arthritis Center
• Muscle Disorders Center
• Knee Pain Introduction