Rheumatic Manifestations of Systemic Diseases

Contributor: Deana Lazaro, MD and Richard Keating, MD 

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A 28 year old woman comes to clinic for evaluation of diffuse pain. The patient complains of widespread myalgias and arthralgias for the past 3 months. The pain is aching in quality and is becoming severe. It interferes with her activities such as cleaning the house and shopping. She also complains of fatigue but has no difficulty with sleep or morning stiffness. A review of systems is negative for weight loss, fever, rash, paresthesias, weakness, joint swelling, and Raynaud's phenomenon. The patient does complain of dry skin and mild constipation.

The patient has no significant prior medical history and takes no medications, but she takes many over the counter vitamins and supplements.

The general medical examination is unremarkable. There is some tenderness on palpation of the joints and muscles but no joint swelling, warmth, or effusion. There is no rash and the neurologic examination is intact except for a delay in the relaxation phase of the deep tendon reflexes.

What is the differential diagnosis?

The differential diagnosis of diffuse arthralgias and myalgias includes the onset of an inflammatory rheumatic disease such as systemic lupus erythematosus or rheumatoid arthritis, a soft tissue syndrome such as fibromyalgia, somatization disorder or depression, endocrinopathy, infection such as a viral arthritis or Lyme disease, and toxic or drug reaction.

What tests may be helpful in making a diagnosis?

Despite the broad differential diagnosis, there are several clues to a specific diagnosis in the history and physical examination of this patient. Dry skin, constipation, fatigue, myalgias, and arthralgias are possible manifestations of hypothyroidism. Delayed relaxation phase of the deep tendon reflexes is also consistent with a diagnosis of hypothyroidism. Thyroid function tests should be requested. Other useful tests may include ESR, CBC, Chemistry, CPK, anti-nuclear antibody (ANA), and Rheumatoid Factor (RF).


A 65 year old woman comes to clinic for follow-up of results of a bone density screening. Review of dual-energy x-ray absorbtiometry (DEXA) results show that she has osteoporosis with T-scores and Z-scores at the femoral neck and lumbar spine below -2.5. You counsel her to avoid smoking and alcohol, perform regular weight-bearing exercise, and to take adequate calcium with vitamin D and to start an oral bisphophosphonate.

What else is appropriate for the management of this patient's metabolic bone disorder?  

  • The abnormal Z-score indicates that a secondary cause for osteoporosis may be present. Screening for secondary causes such as hyperparathyroidism or thyroid disease is appropriate.  
  • You order additional tests and obtain the following results (normal values):

Ca=9.0 mg/dL (8.4-10.2 mg/dL)

Phosphorus=2.3 mg/dL (2.5-4.6 mg/dL)

TSH=1.9 µIU/ml (0.35-5.5)

Urinary Calcium=normal

Creatinine=2.0 mg/dL (0.4-1.2 mg/dL)

BUN=25 mg/dL (6-22 mg/dL)

Hemoglobin=12.0 g/dL (13-18 g/dL)

Hematocrit=34% (40-52%)

MCV=88 cmu (80-95 cmu)

Platelets=230,000 K/cmm (150-450,000 K/cmm)

ESR=90 mm/hr (0-20 mm/hr)

What is a likely cause for these findings? Would you order any additional tests?

  • The combination of osteoporosis, anemia, elevated ESR, and kidney disease suggests a diagnosis of multiple myeloma. Serum and urine protein electrophoresis should be performed. 
  • On further evaluation, the patient is diagnosed with multiple myeloma based upon an IgG kappa monoclonal gammopathy on protein electrophoresis and several lytic bone lesions in the femur and skull on a skeletal bone survey. The patient is referred to a hematologist for management of this disorder.
  • Several years later the patient complains of burning pain radiating from the wrist to the second and third fingers. The pain is especially bothersome at night and on awakening. Physical examination reveals a normal wrist exam, but a positive Tinel's sign bilaterally.
  •  Laboratories now reveal mild proteinuria.

What complication of her condition is the patient experiencing? How can you make the diagnosis?

The patient's history and physical findings suggest carpal tunnel syndrome. This disorder is associated with amyloidosis. Deposition of amyloid protein in the carpal tunnel may cause compressive neuropathy of the median nerve. AL variety of amyloidosis may complicate multiple myeloma. It is associated with carpal tunnel syndrome, arthropathy, periarthritis, and cystic bone disease.

Patient Care

  1. Recognize rheumatic manifestations of diabetes mellitus including syndromes of limited joint mobility such as diabetic hand syndrome (diabetic cheiroarthropathy), trigger finger (flexor tenosynovitis), dupytren’s contracture, adhesive capsulitis, diffuse idiopathic skeletal hyperostosis, neuropathies such as carpal tunnel syndrome, neuropathic arthritis (Charcot joint), complex regional pain syndrome, and diabetic muscle infarction (amyotrophy).
  2. Recognize rheumatic manifestations of hyperthyroidism including osteoporosis, myopathy, periarthritis, and acropachy.
  3. Recognize rheumatic manifestations of hypothyroidism including arthralgias, scleromyxedema, symmetrical polyarthritis, joint laxity, carpal tunnel syndrome, calcium pyrophosphate deposition disease, and myopathy.
  4. Recognize rheumatic manifestations of hyperparathyroidism including osteoporosis, osteitis fibrosa cystica, subperiosteal resorption, erosive arthritis, joint laxity, calcium pyrophosphate deposition disease, and myopathy.
  5. Recognize rheumatic manifestations of acromegaly including osteoarthritis, bursal enlargement, joint laxity, compression neuropathy, and tendon and joint capsule calcification.
  6. Recognize rheumatic manifestations of hemophilia including hemarthrosis, hemophilic arthropathy, chronic joint contractures, and septic arthritis.
  7. Recognize rheumatic manifestations of hemoglobinopathy such as sickle cell disease including painful crisis, dactylitis, osteonecrosis, and osteomyelitis.
  8. Recognize rheumatic manifestations of multiple myeloma including lytic bone lesions, osteoporosis, amyloidosis, and sclerotic bone lesions.
  9. Recognize the paraneoplastic rheumatic syndromes.
  10. Recognize rheumatic manifestations of hypertrophic osteoarthropathy.
  11. Recognize rheumatic manifestations of sarcoidosis including Lofgren’s syndrome, arthritis, periarthritis, dactylitis, and lytic and cystic bone lesions.
  12. Recognize rheumatic manifestations of leukemia including arthritis due to acute myeloid leukemia, Sweet’s syndrome, tumor lysis syndrome and gout.
  13. Recognize rheumatic manifestations of hemochromatosis including calcium pyrophosphate dehydrate deposition disease and osteoarthritis of the metacarpal joints.
  14. Recognize rheumatic manifestations of amyloidosis including arthropathy, carpal tunnel syndrome, scapulohumeral periarthritis, and cystic bone disease.

Medical Knowledge

  1. Describe the inflammatory, degenerative, and autoimmune etiologies for the rheumatic manifestations of systemic diseases.
  2. Understand the basic underlying principles and technical considerations in the use of plain radiographs, computed tomography, magnetic resonance imaging, ultrasonography, and radionuclide scanning of bones, joints, and periarticular structures to diagnose rheumatic manifestations of systemic diseases.
  3. Understand the use of synovial fluid analysis including cell count, differential, Wright's stain, and crystal identification for evaluation of rheumatic manifestations of systemic diseases.
  4. Formulate appropriate differential diagnoses and therapeutic plans based on an ability to critically analyze the clinical data and integrate this analysis with the basic fund of medical knowledge.
  5. Recognize the need for appropriate consultation and the reasonable expectations from a consultant.

Interpersonal Skills

  1. Discuss musculoskeletal manifestations of systemic diseases with a patient in a way that incorporates the patient's perspectives.
  2. Communicate appropriately with peers and paramedical personnel.


  1. Provide compassionate care and serve all patients with respect to their cultural, emotional, spiritual, and social needs.
  2. Recognize importance of patient privacy and informed consent.
  3. Demonstrate integrity and honesty in discussing patient care issues and management with the patient and family.

Practice-Based Learning and Improvement

  1. Set learning goals for the musculoskeletal manifestations of systemic diseases.
  2. Monitor outcomes to ascertain whether clinical decisions and therapeutic interventions are effective and adhere to accepted standards of care in managing patients with rheumatic manifestations of systemic diseases.
  3. Utilize information technology to search, retrieve, and interpret medical information relevant to the care of patients with rheumatic manifestations of systemic diseases.
  4. Consider creating a quality improvement project to address rheumatic manifestations of systemic diseases in patient care.
  5. Integrate and apply information from the history and physical, laboratory, and diagnostic testing to make informed decisions about patient care.

Systems Based Practice

  1. Demonstrate the ability to collaborate with other health care providers in addressing rheumatologic manifestations of systemic diseases including orthopedic surgeons, physiatrists, primary care physicians, and medical subspecialists.
  2. Demonstrate the ability to perform as a consultant or a health-care team leader when summoned.
  3. Determine cost-effectiveness of management plans for addressing rheumatic manifestations of systemic diseases.


Endocrine Diseases

Hematologic and Malignant Disorders




(Answer questions 1 – 5 on a piece a paper. Find Answer Key at the bottom on the page.)

1) Sarcoidosis can present with fever, hilar lymhphadenopathy, ankle swelling (arthritis and/or periarthritis), and erythema nodosum. Which of the following is true:

  1. This presentation is named Lofgren’s syndrome.
  2. This presentation is named lupus pernio.
  3. This presentation is named Heerdfort syndrome. 
  4. This presentation is named Koebner phenomenon.

2) AL (immunoglobulin light chain) amyloidosis is a plasma cell disorder characterized by tissue deposition of monoclonal immunoglobulin light chains or fragments.  Amyloid deposition in AL can involve the synovium. Presentations for AL amyloidosis may include all of the following except:

  1. a chronic, progressive monoarthritis
  2. subcutaneous nodules, macroglossia, & submandibular swelling
  3. carpal tunnel syndrome
  4. a polyarthropathy involving the shoulders, knees, wrists, and small joints of the fingers

Hemochromatois can lead to manifestations in multiple organ systems, including the MSK system.  

3) A clinically distinct form of arthropathy seen in hemochromatosis is:

  1. dactylitis of the toes
  2. carpal tunnel syndrome
  3. arthritis of the 2nd and 3rd MCPs resembling osteoarthritis (OA)
  4. sacroiliitis

Patients with autoimmune thyroid disease (AITD) includes chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) and Grave’s disease.  

4) The most common serologic abnormality not directed against thyroid tissue seen in this population of patients is:

  1. anti-double stranded DNA antibody
  2. ANA
  3. ANCA
  4. Anti-smooth muscle antibody

5) The least common musculoskeletal manifestation of diabetes is which of the following:

  1. limited hand mobility (cheiropathy)
  2. tendon rupture
  3. adhesive capsulitis
  4. Charcot joint - hand
  5. flexor tendon tenosynovitis of the fingers
  6. Charcot joint – foot

Answer Key

1) The correct answer is A.

Lofgren’s syndrome (fever, hilar lymphadenopathy, ankle swelling, and erythema nodosum) has about 95% specificity for sarcoidosis.  It is more common in Europeans than African-Americans.  Lupus pernio is a distinctive rash of sarcoidosis, often seen about the nares, that is violaceous and may take the form of plaques or nodules.  Heerdfordt syndrome, also called uveoparotid fever, consists of fever, uveitis, and parotitis with or without CN VII involvement.  It is a relatively rare presentation for sarcoidosis.  Koebner phenomenon can occur in sarcoidosis when sarcoid skin lesions develop on old scars or tattoos. 

2) The correct answer is A.

AL amyloidosis can present with soft tissue involvement.  This may take the form of carpal tunnel syndrome, a polyarthropathy, subcutaneous nodules that might resemble rheumatoid nodules, submandibular gland involvement, and macroglossia.  A monoarthritis would be very extremely unusual. 

3) The correct answer is B.

There is a predilection for the finger MCP joints, variably accompanied by chondrocalcinosis, in the arthropathy of hemochromatosis.  It is a chronic and progressive arthropathy with a low-grade inflammation.

4) The correct answer is B.

Physicians should appreciate that a positive ANA is seen in almost 50% of patients with autoimmune thyroid disease (AITD) – a much higher prevalence than is seen in the general population and these patients do not usually have a classifiable rheumatic disorder.

5) The correct answer is D.

Diabetes can have a number of MSK manifestations.  Limited hand mobility, also called diabetic cheiropathy, results from increased stiffness and thickening of the finger tendons.  Adhesive capsulitis can affect 30% of diabetics and flexor tenosynovitis in the hands can affect 10-20% of patients.  Charcot joint, also known as neuropathic arthritis, usually affects the foot, and is characterized by fracture, dislocation, and subluxation of the affected joint in the presence of a significant sensory deficit.   A Charcot joint of the hand is distinctly unusual.

Last updated February 2015.

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