Arthritis as a Manifestation of Systemic Disease

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Practice Essentials

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.[1] 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:

Post-acute sequelae of COVID-19 (PACS; "long COVID") is characterized by a wide spectrum of symptoms similar to fibromyalgia.[2] A chronic pain syndrome phenotype with primarily arthralgia and myalgia has been identified in 16-24% of patients.[3, 4]

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.

For patient education resources, see the Arthritis Health Center.

Pathophysiology

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.

Endocrine-associated arthropathies

Hypothyroidism: Muscle energy production is decreased due to reduction in glycogenolysis and mitochondrial oxidative metabolism, which probably contributes to myalgias, fatigue, and weakness.[5] Higher serum thyroid-stimulating hormone (TSH) levels have been suggested as the cause of a high prevalence of severe bilateral frozen shoulder in patients with hypothyroidism.[6]

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 important role in limited joint mobility syndromes.[7]

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.[8, 9]

Hematologic illness arthropathies

Hemophilia: Bleeding into the joint (hemarthrosis) may lead to synovial inflammation and joint deterioration.[10]

Sickle cell disease: Avascular necrosis may result from bone marrow infarction; gout may result from increased production of uric acid due to ineffective erythropoiesis and decreased clearance secondary to renal tubular damage.[11]

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[12] Patients who have C282Y homozygosity may be at higher risk for osteoarthritis than those with other genotypes.[13]

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 may occur as a paraneoplastic syndrome.

Epidemiology

Frequency

United States

Arthritis as a manifestation of systemic disease is rare. The frequency of selected disorders that can present as arthritis are listed below.

Hypothyroidism is an extremely common problem in the United States. The prevalence of hypothyroidism in the United States in 2012 has been estimated at approximately 9.5%—more than double the 2002 publication using National Health and Nutrition Examination Survey (NHANES) data from 1988 to 1994, which estimated that 4.6% of the US population suffered from hypothyroidism.[14]

In 2022, the US Centers for Disease Control and Prevention (CDC) estimated that 37.3 million people in the United States, or 11.3% of the population, had diabetes, and in 8.5 million of those, the disease was undiagnosed; in adults, 90% to 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.[15]

Cushing syndrome due to elevated levels of endogenous glucocorticoids (Cushing disease) 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.[16]

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 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.

The 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.

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 in women than in 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.[17]

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.

Prognosis

In arthritis due to systemic disease, successful treatment of the underlying illness usually results in improvement or complete resolution of the joint manifestations, unless permanent joint damage has occurred. The likelihood of that varies, however, depending on the underlying disorder. Acute sarcoid arthritis does not cause joint damage. In contrast, most patients with acromegaly have had the disease for many years prior to diagnosis and are left with cartilage hypertrophy and severe degenerative joint disease. The arthritis of hemochromatosis does not improve with phlebotomy.

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

Patients with hemochromatosis are at risk for developing 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 the diagnosis made before the onset of cirrhosis and treatment is instituted, 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 whites.[18]

History

Diabetes

Diabetic cheiroarthropathy is also known as diabetic hand syndrome. Patients present with insidious development of one or more of the following:

People with diabetes have more than 2 times the risk of carpal tunnel syndrome than those without diabetes; 6% of patients with carpal tunnel syndrome carry the diagnosis of diabetes. Diabetic hand syndrome is seen in both type 1 and type 2 diabetes. It is associated with duration of diabetes and control of blood sugar.[19]

Charcot joint occurs in < 1% of all individuals with diabetes. Most patients are older than 40 years and have had long-standing, poorly controlled diabetes. With progression of disease, patients can develop rocker bottom feet due to midtarsal collapse.

Diabetic osteolysis is a condition specifically occurring in people with diabetes. The osteolysis is characterized by osteoporosis and variable degrees of resorption of distal metatarsal bones and proximal phalanges in the feet.

Diabetic amyotrophy presents with severe pain and dysesthesia involving most commonly the proximal muscles of the pelvis and thighs. Patients are mostly men and may present with anorexia, weight loss, and unsteady gait. The etiology is unclear but inflammatory vasculopathy may play a role.

Diabetic periarthritis, or frozen shoulder, occurs in 10-33% of those with diabetes. It is more commonly seen in women with long-term type 2 diabetes. Up to 50% of the patients have bilateral involvement.

Diffuse idiopathic skeletal hyperostosis (DISH), also known as Forestier disease, occurs in up to 20% of those with type 2 diabetes. Affected individuals are typically obese and older than 50 years. They present with neck and back stiffness and radiographs show at least 4 fused vertebrae as a result of ossification of the anterior longitudinal ligament.

Unlike DISH, the predisposition of diabetic patients to the development of osteopenia is not clearly defined. To the extent that it does exist, osteopenia is more common in type 1 diabetes than in type 2, and it is reportedly associated with poor disease control.[20]

Hypothyroidism

Hypothyroidism can present as 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.

Myxedematous arthropathy usually affects large joints such as knees. Patients present with swelling and stiffness. Synovial thickening, ligamentous laxity, and effusions are seen but radiographs are frequently normal.

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 enzyme levels, proximal weakness (especially in the hip flexors) and polymyositis-like syndrome to a constellation of muscle cramps, stiffness, and pseudohypertrophy, referred to as Hoffmann syndrome.[21]

There can be mild elevations of creatine phosphokinase (CPK), but few patients actually show muscle weakness.

Carpal tunnel syndrome is observed in up to 10% of patients with hypothyroidism.

Raynaud phenomenon may be seen in hypothyroidism.

Aching muscles with findings indistinguishable from fibromyalgia can be seen but are less common.

Hypothyroidism is also a common cause of trigger finger.

Frozen shoulder is more likely to be severe and bilateral than in patients without hypothyroidism.[6]

Hyperparathyroidism

The classic musculoskeletal manifestation of primary hyperparathyroidism is osteitis fibrosa cystica, which consists of bone pain, osteopenia, and bony cysts. 

Painless proximal muscle weakness with normal CPK and a neuropathic or myopathic electromyography (EMG) findings is seen in hyperparathyroidism.

Chondrocalcinosis has been described in up to 30% of patients with primary hyperparathyroidism. Acute pseudogout attacks occasionally may occur, especially after parathyroidectomy. While some patients with hyperparathyroidism and chondrocalcinosis are asymptomatic, many of them have other symptoms, including depression, fatigue, constipation, and joint pain. The joint pain is widespread and nonspecific.

Diffuse osteopenia is commonly seen and erosions may be seen in the joints of hands and at the end of the clavicles. Spinal compression fractures are common.

Discrete lytic lesions due to focal aggregates of osteoclastic giant cells known as Brown tumors may be seen, although these are rare.

Advanced kidney disease and associated secondary hyperparathyroidism can lead to metastatic calcification of muscles and soft tissues.

Hyperthyroidism

Thyroid acropachy is a rare (1%) complication of Graves disease. It consists of soft tissue swelling of hands, digital clubbing, and periostitis. Radiographs show the characteristic findings of periosteal reaction along the shafts of the metacarpals and phalanges. Thyroid acropachy is strongly associated with ophthalmopathy and pretibial myxedema.

Patients can present with myopathy, with dramatic increases in CPK and severe proximal muscle weakness, similar to disease seen in polymyositis.

Cushing syndrome

The presenting musculoskeletal manifestation of Cushing syndrome may be osteoporosis with fracture. It is not uncommon for patients with Cushing syndrome to present with a vertebral compression fracture. Occurrence of osteoporotic fractures in young adults may be the manifestation that triggers a workup for excess glucocorticoid production. Proximal myopathy with muscle wasting is common.

Patients can also present with osteonecrosis. Iatrogenic Cushing syndrome is more likely to cause osteonecrosis than endogenous Cushing syndrome (Cushing disease).

Acromegaly

Arthropathy is common and is seen in 70% of the patients with 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 overgrowth of cartilage and joint space widening. Most commonly, osteoarthritis of the first metacarpal joint is seen early in the disease.

Carpal tunnel syndrome, osteoarthritis, and proximal muscle weakness with normal CPK and normal EMG often occur.

Hyperlipidemia

Familial hypercholesterolemia and mixed hypercholesterolemia lead to tendon xanthomas, particularly of the Achilles tendon, as well as Achilles tendonitis.[22] An association may exist between hyperlipidemia and oligoarthritis or a migratory polyarthritis.[23]

Hemochromatosis

Chronic arthropathy occurs in approximately two thirds of patients with hereditary hemochromatosis.[24] 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.[25] Chondrocalcinosis is present in as many as two thirds of patients with hemochromatosis.

Hemochromatosis may be associated with an increased incidence of osteoporosis. One study reported that 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. 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, but are rare.

Advanced disease can show lytic lesions in the bones of peripheral joints.

Malignancies

Muskuloskeletal manifestations of malignancy include the following:

HIV disease

Patients with HIV disease may report osteomyelitis, osteonecrosis, reactive arthritis, and/or psoriatic arthritis.

Physical Examination

Hypothyroidism

Patients complain of generalized muscle pains similar to fibromyalgia. Frank myxedematous arthropathy can also exist, classically involving the large peripheral joints such as the knees. The metacarpophalangeal (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. Patients can present with joint swelling and have chondrocalcinosis. Charcot-like destructive process in joints has been reported.

Hyperparathyroidism

The joints are not swollen, red, or tender, except with acute chondrocalcinosis, which is frequently seen in these patients. Bony erosions, especially in metacarpal and carpal bones, can be seen. In advanced stages, osteitis fibrosa cystica can be seen. Proximal muscle weakness and calciphylaxis can be seen with hyperparathyroidism.

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.

Patients with diabetic cheiroarthropathy present 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, and this condition can be confused with osteomyelitis on radiographs.

Thyroid acropachy with periosteitis and diffuse soft tissue swelling is seen and can look like scleredema.

DISH and osteopenia are rare but may occur.

Cushing syndrome

The patient may have the classic features of Cushing syndrome, such as striae, truncal obesity, plethora, and bruising. 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. 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 calcium pyrophosphate deposition. 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.

Laboratory Studies

Several laboratory studies may be useful in patients presenting with arthritis. These tests include erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), rheumatoid factor (RF), uric acid level, and an antistreptolysin O (ASO) titer. However, in patients with arthritis as a manifestation of one of the illnesses considered herein, the findings from these tests are generally negative or normal. Thus, if no rheumatic disease cause can be determined, the syndrome of arthritis as a manifestation of a systemic illness should be entertained. In patients with monoarticular arthritis, initial diagnostic considerations are gout, pseudogout, and infectious causes.

Hypothyroidism is usually readily diagnosed by measuring serum thyroid-stimulating hormone (TSH) and free thyroxine.

Hyperparathyroidism is usually suspected because of an elevated serum calcium level, but this value can be within the reference range. In most cases, simultaneous measurement of serum calcium and parathyroid hormone (PTH) is sufficient to obtain a diagnosis. Serum PTH must be measured by a proper assay, such as an intact molecule immunoradiometric assay. Serum calcium levels must be interpreted in light of the serum albumin level. An ionized calcium test can be useful in patients with low serum albumin or in patients with borderline-high total serum calcium.

Diabetes is diagnosed with fasting blood sugars. Cholesterol levels, hemoglobin A1c, and urine studies are important lab tests in the evaluation of diabetes.

Cushing disease diagnostic considerations include the following:

Acromegaly screening tests include serum growth hormone testing or serum insulinlike growth factor–1 (IGF-1) testing, although provocative testing sometimes is required to make a definitive diagnosis.

For hyperlipidemia, total serum cholesterol without regard to eating restrictions can be used as a screening test. Fractionated cholesterol values should be measured on a specimen obtained after an overnight fast.

For hemochromatosis, serum transferrin saturation and ferriitin assays are the recommended initial screening tests; patients with transferrin saturation of 45% or higher, elevated ferritin, or both should undergo HFE genotyping; full guidelines on diagnosis have been published by the American Association for the Study of Liver Diseases[27]  and the European Association for the Study of the Liver (EASL).[28]

Hemochromatosis can be misdiagnosed as rheumatic disease and a high degree of suspicion should be present in cases of rheumatoid arthritis not responding to treatment or lacking signs of active synovitis.[29]

No definitive laboratory test is available for sarcoidosis. Leukopenia (WBC count < 4000 cells/µL), mild eosinophilia (> 5%), elevated ESR, hyperglobulinemia, an elevated level of angiotensin-converting enzyme, and mild hypercalcemia all are possible laboratory abnormalities. Synovial fluid white blood cell (WBC) count ranges from 250-6200 cells/µL with 56-100% mononuclear cells.

A detailed review of the diagnostic workup of each of the illnesses discussed is beyond the scope of this article. The reader is referred to other Medscape articles that specifically deal with these diseases. See the following:

Imaging Studies

Plain radiographs of the hands and feet or of the affected joints may be obtained. Findings consistent with rheumatoid arthritis, such as erosions, may eliminate the need to search for nonrheumatic illnesses.

Hypothyroidism has no characteristic radiographic features.

Hyperparathyroidism may lead to the discovery of abnormalities of osteitis fibrosa cystica that are striking, but these are rarely seen today. Other features include subperiosteal resorption in the hands, wrists, and feet and resorption in the sacroiliac joints, symphysis pubis, diskovertebral junctions, and peripheral joints. Chondrocalcinosis may also be seen.

Diabetes may lead to changes in the spine. Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by flowing ossification along the anterior aspect of the vertebral column, most prominent in the thoracic spine. Though present in only a few patients, Charcot joint is illustrated radiographically by sclerosis, osteophytosis, bony fractures, subluxation, and dislocation.

Patients with Cushing syndrome may present with osteopenia (or osteoporosis) as determined by bone mineral density measurement or with vertebral compression fractures.

Acromegaly has several characteristic radiographic features. These include increased thickening of the heel pad and widening of the articular space, which is best seen at the knee.

Hyperlipidemia has no characteristic radiographic features.

Hemochromatosis commonly manifests with cystic lesions on the metacarpal heads. Squared-off bone ends and hooklike osteophytes in the metacarpophalangeal (MCP) joints, particularly in the second and third MCP joints, are characteristic findings. Chondrocalcinosis may also be visualized.

Although conventional radiography is the gold standard method for the detection of structural changes in hemochromatosis, magnetic resonance imaging (MRI) has been applied in a few case series and small studies with mixed results. In a series of three patients with hemochromatosis with pain and swelling of the ankles, for example, MRI identified advanced degenerative changes without notable inflammation. In another MRI study of patients with hemosiderosis (caused by regular blood transfusions due to beta-thalassemia), synovial inflammation of wrists was reported in 23% of cases.[24]  

Sarcoidosis may affect the skeleton in a focal or generalized fashion, and either osteolytic or osteosclerotic involvement may be evident (see the images below). Phalangeal cysts are often considered a helpful diagnostic clue when considering sarcoidosis.



View Image

Focal osteolytic changes seen in the phalanges in a patient with chronic sarcoid arthritis.

Chest radiography should be performed to rule out lung carcinomas.

Hypothyroidism, hyperparathyroidism, and hemochromatosis are associated with calcium pyrophosphate deposition (CPPD), which may be seen radiographically as chondrocalcinosis.

Histologic Findings

Sarcoidosis may have a synovial histology that is often less inflammatory in nature than rheumatoid arthritis, but, occasionally, noncaseating granulomas are observed.

Approach Considerations

A complete discussion of the therapy for each of these diseases that may have arthritis as a manifestation may be found in the article concerning that particular disease. See the following:

With hemochromatosis, note that phlebotomy is used to reduce the level of total body iron to the reference range, but has little effect on the clinical and radiologic progression of arthropathy.

Aspects of sarcoidosis treatment relevant to the musculoskeletal manifestations of the disease include the following:

Consultations

Hypothyroidism and diabetes usually do not mandate a consultation.

With hyperparathyroidism, consultation with an endocrinologist may be useful to ensure the diagnosis is correct; consultation with a surgeon experienced in neck exploration is essential.

With Cushing disease, an endocrinologist likely will be needed to guide the patient through the maze of diagnostic tests that are required. These include provocative testing, such as high-dose dexamethasone suppression testing and petrosal sinus sampling. An interventional radiologist experienced in petrosal sampling likely will be needed. If pituitary-dependent Cushing disease is confirmed, consultation with a neurosurgeon experienced in transsphenoidal hypophysectomy is indicated.

With acromegaly, provocative testing of growth hormone will be required in many cases, and should be supervised by an endocrinologist. Surgical therapy requires a neurosurgeon who is an expert in pituitary surgery. Late in the disease, joint problems can cause significant morbidity, and consultation with a rheumatologist or orthopedic surgeon may be needed.

With hyperlipidemia that is poorly controlled, especially in patients requiring multiple drugs, consultation with an endocrinologist or other lipidologist may be appropriate.

With hemochromatosis, many patients require a liver biopsy obtained by a gastroenterologist. Prolonged phlebotomy is required, during which several dozen units of blood are removed over months to years. Such specialized therapy should be monitored by a gastroenterologist or hematologist with experience in this procedure.

With sarcoidosis, a pulmonologist should be consulted when chest findings are abnormal. Patients may need bronchoscopic biopsy or mediastinoscopy for definitive diagnosis. A rheumatologist may be consulted for the management of joint disease. Patients need a thorough eye examination by an ophthalmologist to determine whether evidence of uveitis is present.

Medication Summary

For an in-depth discussion of drug therapy, see the following:

Author

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

Disclosure: Nothing to disclose.

Specialty Editors

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

Disclosure: Stock ownership for: Johnson & Johnson.

Chief Editor

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

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Nothing to disclose.

Acknowledgements

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.

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Focal osteolytic changes seen in the phalanges in a patient with chronic sarcoid arthritis.

This picture shows a 42-year-old white man who was admitted with acute back pain. In this frontal view, note the lower-face fullness that obscures his ears and the plethora of his cheeks.

Focal osteolytic changes seen in the phalanges in a patient with chronic sarcoid arthritis.

Osteolysis has left a lacy trabecular pattern in this phalanx (arrow).