Manifestations of Systemic Diseases

Fig. 18.1

Avascular necrosis of the left hip in a patient with sickle cell disease (Reprinted with permission from Springer [2])

Acromegaly is characterized by hypersecretion of growth hormone (GH) and insulin growth factor-1 (IGF-1), usually the result of a hyperfunctioning pituitary adenoma. Hypothalamic tumors and ectopic production are possible but rare. The disease affects middle-aged men and women. Increased somatomedins secreted by hepatocytes under the influence of GH stimulate bone and cartilage leading to chondrocyte replication, increased proteoglycans, collagen, osteoblastic proliferation, and increased bone collagen leading to increased bone mass, large joint arthralgias, and proximal muscle weakness. Fibrous synovial thickening and bony overgrowth of PIPs and DIPs may be seen on physical examination. Muscle enzymes will be normal, and muscle biopsy will show variation in fiber size without active inflammation. Musculoskeletal imaging may identify an enlarged sella turcica, increased thickness of enlarged frontal sinuses, an elongated mandible, soft tissue thickening, broad metacarpals and phalanges, prominent distal tufts, widened joint spaces due to cartilage hypertrophy, increased thickness of the heel pad, broadening of the sternal ends of ribs, kyphosis, and enlarged vertebral bodies (Fig. 18.2). Arthralgia is one of the most commonly reported symptoms, and axial involvement may resemble diffuse idiopathic skeletal hyperostosis syndrome (DISH). Morning stiffness and joint swelling are not characteristic. Bilateral carpal tunnel syndrome may be seen in over half of patients. Surgical resection of the adenoma is used to treat acromegaly, but musculoskeletal symptoms often persist. BMD is often normal or elevated; however, patients remain at increased risk of vertebral fracture [1].

../images/464721_1_En_18_Chapter/464721_1_En_18_Fig2_HTML.jpg — Fig. 18.2

Elongated mandible (a) and broad metacarpals and phalanges (b) characteristic of acromegaly (Reprinted with permission from Springer [3])

Diabetes mellitus type 2 (DM2) leads to altered connective tissue, increased fibrosis, and tendinopathies, and neuropathy can lead to severe osteoarthropathy. In the shoulder, there is increased risk of adhesive capsulitis. Calcific tendinitis often develops due to deposition of calcium hydroxyapatite within rotator cuff tendons. Common hand pathology includes flexor tenosynovitis and trigger finger, Dupuytren’s contracture, carpal tunnel syndrome, and diabetic cheiroarthropathy (limited joint mobility related to thickened skin in longstanding diabetics). In the feet patients may suffer from diabetic osteoarthropathy or Charcot’s arthropathy as a result of neurovascular disease. In Charcot’s, increased blood flow to subchondral bone is associated with increased osteoclastic activity and bone resorption. Resulting osteopenia leads to osteolysis of bone, fragmentation, and sclerosis (Fig. 18.3). MRI or bone scintigraphy is used to evaluate extent of disease. Sudden muscle infarction is also described in uncontrolled patients with DM2. Ossification of the anterior longitudinal ligament of the spine often with osteophyte formation, a condition known as DISH, is associated with DM2; the condition characteristically spares the intervertebral disc spaces and sacroiliac (SI) joints allowing clinicians to differentiate DISH from axial spondyloarthritis [1].

../images/464721_1_En_18_Chapter/464721_1_En_18_Fig3_HTML.jpg — Fig. 18.3

Example of Charcot’s arthropathy (Reprinted from Springer with permission [4]), (a) Hypertrophic form of neuroarthropathy on radiography. Lateral image of the foot shows the hypertrophic form of neuroarthropathy, characterized by sclerosis, osteophytosis, and radiographic appearance of extreme degenerative change. (b) Midfoot deformity related to neuroarthropathy on radiography. Lateral radiograph demonstrates dorsal dislocation of the tarsometatarsal joints

Hyperthyroidism and hypothyroidism can both present with musculoskeletal symptoms. In hypothyroid states, patients manifest with symmetric arthropathy involving stiffness of the hands and knees with “gelling” phenomenon. Synovial fluid is non-inflammatory and viscous with increased hyaluronic acid. CPPD crystals may be present. Myopathy will present with cramps, myalgia, stiffness, proximal muscle weakness, fatigue, and elevated CK, and muscle biopsy will show type 2 fiber atrophy with increased type 1 fibers. Carpal tunnel syndrome has been described as a result of excess glycosaminoglycan deposition. Hoffman syndrome describes a rare condition of hypothyroidism manifesting as increased muscle mass (pseudohypertrophy). Kocher-Debre-Semelaigne syndrome describes infants with muscle pseudohypertrophy in iodine-deficient mothers [1].

In Graves’ disease (autoimmune hyperthyroid state), patients can develop several musculoskeletal manifestations. Proximal muscle weakness, adhesive capsulitis of the shoulder, loss of muscle mass, and weight loss are all expected to improve after treatment. Onycholysis, clubbing, and thyroid acropachy related to periostitis surrounding MCPs may not resolve. Associated osteopenia and osteoporosis are most commonly associated with hyperthyroidism [1].

Hypoparathyroidism results in altered calcium homeostasis leading to altered bone structure and turnover. This can result in enthesopathy and paravertebral and subcutaneous calcifications [1].

Renal osteodystrophy is seen in patients with chronic kidney disease and is characterized by abnormal bone remodeling with or without abnormalities in bone mineralization in the setting of untreated secondary hyperparathyroidism. Chronic renal insufficiency and hemodialysis contribute to biochemical disturbances in calcium and phosphate metabolism leading to a wide spectrum of bone and soft tissue abnormalities. Patients present with osteomalacia, osteitis fibrosa cystica, osteosclerosis, and osteoporosis. Occasionally axial symptoms mimic ankylosing spondylitis or DISH with characteristic morning stiffness and gait posture. Serum testing for PTH, vitamin D, serum calcium or phosphorus, and bone imaging may help to characterize the underlying disease, and bone biopsy remains the gold standard as bone turnover may be increased or decreased in these patients. Arthralgia in these patients will not respond to NSAIDs but may respond to calcitriol. CKD leading to hyperphosphatemia and secondary hyperparathyroidism may also increase the risk of crystal deposition diseases. Long-term dialysis may also be complicated by beta-2 microglobulin amyloid deposition, destructive spondyloarthropathy, osteonecrosis, and musculoskeletal infections [7].

Hyperparathyroidism presents with arthralgia, osteitis fibrosa cystica (OFC), and subperiosteal resorption along radial side of phalanges. OFC is a skeletal disorder resulting in loss of bone mass due to replacement of calcified structures with fibrous tissue and formation of cyst-like brown tumors in and around the bone (Fig. 18.4). Brown tumors are lytic lesions in the skeleton resulting from localized areas of fibrous tissue as a result of increased osteoclastic activity, giant cells, and decomposing blood. Arthritis involves small joints of hands and typically spares the PIPs. While symptoms may mimic rheumatoid arthritis, subperiosteal resorption is distinctive and acute-phase reactants RF and CCP will not be elevated. Radiocarpal, inferior radioulnar, and MCP joints are most commonly involved. Patients with hyperparathyroidism are also at increased risk of CPPD, gout, or both. Hyperparathyroidism can also lead to proximal muscle weakness with normal muscle enzymes; EMG and muscle biopsy will show denervation [1].

../images/464721_1_En_18_Chapter/464721_1_En_18_Fig4_HTML.jpg — Fig. 18.4

Example of brown tumor associated with hyperparathyroidism (Reprinted with permission from Springer [5]) (a) Osteolytic lesion on X-ray examination of tibia, (b) Osteolytic lesion on transverse section of tibia on CT scan

Metabolic Disorders

Wilson’s disease (WD) is a rare autosomal recessive genetic disorder defined by excess copper deposition in tissues, particularly the liver and nervous system. Mutations in ATP7B lead to abnormal copper transport, and symptoms usually present between 6 and 20 years of age. In addition to the characteristic hepatic and neurologic manifestations, a significant proportion of patients may first present with musculoskeletal symptoms. Early osteoarthritis, chondrocalcinosis, and spinal osteochondritis have been described. Otherwise unexplained arthralgia or effusion or early radiographic features of osteoarthritis warrant copper survey. Diagnosis is based on clinical, biological, radiographic, and sometimes histologic findings including the characteristic blue-green or red-brown peripheral deposit surrounding the cornea known as the Kayser-Fleischer ring. Of note, D-penicillamine, a chelating agent commonly used in the treatment of WD, has been associated with drug-induced lupus [6].

Alkaptonuria is a rare autosomal recessive disorder caused by abnormal tyrosine and phenylalanine metabolism. Deficiency in the enzyme homogentisate 1,2-dioxygenase (HGD) leads to excess circulating homogentisic acid (HGA) which accumulates as pigment in connective tissues including cartilage, heart valves, and sclera of the eyes. Clinical symptoms begin in early adult life and become prominent in the fourth and fifth decade and may include blue-black pigmentation of the ear cartilage and sclera of the eyes, cardiac valvular disease, and osteoarthropathy. The clinical syndrome associated with pigment-related diseases is known as ochronosis.

Osteoarthropathy in ochronosis leads to premature joint and spinal disease in the peak of adulthood. Patients often require multiple joint replacements and suffer from degenerative disc disease and progressive kyphoscoliosis. Tendon and ligament ruptures, osteopenia, and fractures have also been described. Osteoarthropathy is thought to be the result of pigmented deposits in the hyaline cartilage disrupting normal load distribution with subsequent damage to the subchondral plate. Therapeutic options remain limited [7].

Hemochromatosis (HHC) is a disorder defined by excess iron deposition in body tissues as a result of increased iron absorption. Hereditary hemochromatosis is inherited in an autoimmune recessive fashion. In addition to skin pigmentation iron deposition leads to endocrine dysfunction as well as liver failure with alternate terminology including “bronze diabetes” or “pigmented cirrhosis.” Phenotype is highly variable, and several extra-articular manifestations including hepatic and cardiac abnormalities, hyperpigmented skin, diabetes mellitus, erectile dysfunction, and increased susceptibility to certain infections have been defined. Risk of liver carcinoma is significantly increased as well. Phlebotomy in early disease may prevent or postpone complications. Arthralgia and arthritis have been described in the majority of patients and are often a late manifestation but rarely can be the presenting symptom in undiagnosed cases. Often the 2nd and 3rd MCP are involved, but arthritis may also be seen in the PIPs, wrists, shoulder, hip, knee, and ankle. Patients develop pain and stiffness but not synovitis. Studies have shown an increased risk of prosthesis loosening after hip arthroplasty. Patients are seronegative, and radiographs show characteristic joint space narrowing of 2nd and 3rd MCP, hook-like osteophytes, and chondrocalcinosis of the triangular fibrocartilage adjacent to the ulnar styloid. Unlike many of the extra-articular manifestations of hemochromatosis, arthritis usually does not respond to phlebotomy. NSAIDs, colchicine, and intra-articular steroids can be effective [8].

Hematologic Disorders

Hemophilia and other bleeding disorders may lead to hemarthrosis. Intra-articular bleeding can cause a range of musculoskeletal symptoms as highlighted below, including hemophilic arthrosis which presents with features resembling rheumatoid arthritis or osteoarthritis.

Acute hemarthrosis usually involves the large joints. Early symptoms include tingling and tightness of the joint with subsequent rapidly progressive swelling, reduced range of motion, pain, and warmth. Flexion is often the most comfortable position, and symptoms should respond with administration of clotting factor. Arthrocentesis is not recommended in the setting of acute hemarthrosis unless symptoms do not respond to conservative treatment and should only be performed after clotting factor replacement. Embolization remains an option in severe or recurrent cases.

Synovitis results from incomplete clearance of blood products after recurrent hemarthrosis. Subsequent angiogenesis further increases the risk of repeat bleeding leading to a vicious cycle. Painless swelling may be visible but will not be tense (in contrast to acute hemarthrosis), and symptoms will not respond to acute administration of clotting factor in the acute setting. Long-term factor replacement can prevent recurrent hemarthrosis and improve symptoms. Treatment of acute synovitis includes COX-2 inhibitors but other NSAIDs should be avoided as they may increase the risk of bleeding. Synovectomy may be indicated in severe cases.

Hemophilic arthropathy in the setting of recurrent hemarthrosis is the result of progressive degeneration of cartilage, synovial inflammation, and bone changes. Symptoms include chronic pain, joint stiffness, and severe limitations in range of motion. Deformity, subluxation, laxity, malalignment, and spontaneous arthrodesis can develop (Fig. 18.5). Treatment options include those available in other degenerative arthritis.

../images/464721_1_En_18_Chapter/464721_1_En_18_Fig5_HTML.jpg — Fig. 18.5

Example of hemophilic arthropathy before and after joint replacement (Reprinted with permission from Springer [9]) (a) Knees kept in mild flexion which is the position of minimum discomfort; chronic synovitis evident on exam, (b) Destruction of articular cartilage with severe narrowing of the joint space, (c) Knee XRs status post total bilateral knee arthropasty

Extra-articular manifestations in patients prone to bleeding can be subtle or at times dramatic. Intramuscular hemorrhage presents with painful swelling, worse with active contraction or stretching, and may result in spasm and flexed position. Palpable tender hematoma can be present on examination but deeper bleeds can be difficult to identify and carry a risk of potentially life-threatening compartment syndrome. Muscular hemorrhage can also lead to the formation of a pseudotumor which can erode into adjacent bone, compress neurovascular structures, rupture, lead to fistula, and contribute to pathologic fracture requiring surgical excision [10].

Hemoglobinopathies are inherited diseases caused by mutations in globin genes. They include thalassemias and sickle cell anemia, both of which afflict the musculoskeletal system. They are common in the Mediterranean basin and tropical regions of Asia and Africa.

Thalassemia refers to inherited defects in globin chain biosynthesis. Abnormal globin chains lead to reduced function of hemoglobin tetramers which display as anemia, hypochromia, and microcytosis on complete blood count. Osteoporosis is commonly observed as a result of bone marrow hyperplasia, resorption of bone cortex, decreased cancellous bone, and coarsened trabeculae. In the spine reduced BMD and cortical thinning are associated vertebral compression fractures and subsequent scoliosis and kyphosis. MRI shows predominance of red marrow in vertebrae and early degeneration of intervertebral discs in the lower thoracic and lumbar spine. Abnormal intravertebral iron deposition may be seen. Extramedullary hematopoiesis is radiographically evident in the paravertebral and presacral spaces as a symmetric extra-osseous spread of marrow. Spinal cord compression has been described as a rare complication of marrow expansion. Marrow changes in the skull will cause a characteristic “hair-on-end” appearance (Fig. 18.6). Frequent blood transfusions in these patients may lead to iron overload and contribute to mild arthralgias or arthritis. Symptoms are often self-limited or responsive to NSAIDs [11].

../images/464721_1_En_18_Chapter/464721_1_En_18_Fig6_HTML.jpg — Fig. 18.6

“Hair-on-end” appearance of skull on radiography in beta-thalassemia major (Reprinted with permission from Springer [12])

Sickle cell disease (SCD) is a single gene disorder caused by homozygous inheritance for sickle hemoglobin (Hb S). Affected Hb units polymerize to form rigid rods distorting normal morphology of red blood cells. Disease flares are precipitated by dehydration or hypoxia and are accompanied by hemolytic anemia and acute vaso-occlusive episodes defined by bouts of pain and progressive organ damage.

Vaso-occlusive crisis of the bone is a common complication of SCD and a frequent cause of hospitalization in children with SCD. Painful episodes often involve the chest, lower back, or extremities and may be accompanied by leukocytosis, fever, or abdominal pain. Acute painful crises are the result of microvascular occlusion in low flow vascular areas including bone marrow leading to bone thrombosis. Vertebral body infarction may lead to collapse with typical fish mouth deformity on plain radiography. Infarcts have a predilection for the long bones and may be identified with MRI. Dactylitis can be seen in children under 7 years old and has been termed “hand foot syndrome” defined by painful swelling of one or more digits. Subperiosteal new bone formation leads to a characteristic moth-eaten pattern on radiography. Epiphyseal involvement can lead to premature fusion and shortened digits [11].

Osteomyelitis is more common in SCD than the general population as these patients are predisposed to infection with encapsulated organisms. Infection of the bone can be difficult to differentiate from bone infarcts, particularly as bony infarcts commonly involve the epiphysis and can clinically resemble synovitis, and appearance on MRI may be indistinguishable. Synovial analysis and bone biopsy may be required to confirm the diagnosis.

Arthritis resembling RA has been described in sickle cell patients with polyarticular symmetric synovitis affecting the knees and ankles. Symptoms are self-limited and radiography may show periarticular osteopenia, bony erosions, and joint space narrowing.

SCD in children causes growth disturbances including delayed puberty by 12–24 months and delayed skeletal age.

Osteonecrosis is common in SCD patients often presenting as avascular necrosis of the femoral head. Concurrent hemoglobinopathy (alpha thalassemia) or frequent vaso-occlusive crises are risk factors for avascular necrosis. Multiple joints can be affected, and clinical clues include chronic joint pain and progressive decreased range of motion to the joints.

Iron overload due to repeat transfusions results in a symmetric polyarticular arthropathy with bony enlargement and minimal inflammation affecting the MCPs, PIPs, wrists, elbows, shoulders, and hips mimicking hemochromatosis. Compared to the latter, patients have less severe iron-induced cardiac and endocrine dysfunction.

Crystal arthritis as a consequence of hyperuricemia due to increased red blood cell turnover is common in SCD.

Primary Immunodeficiencies (PIDs)

Several primary immunodeficiencies (PIDs) have been associated with rheumatologic disorders. Thought to be a consequence of immune dysregulation, rheumatologic manifestations may even precede characteristic infectious complications of PID. Incidence of primary PID may be as high as 22% in the rheumatology clinic population, and it is confounded prospectively by concomitant immunosuppressive medications predisposing patients to infections. Red flags for PIDs include personal or family history of recurrent infections, family history of PID, as well as with concomitant rheumatologic diseases.

Systemic lupus erythematosus has been associated with C1q, C1r/C1s, C4, C3, and C2 deficiencies, chronic granulomatous disease (CGD), selective IgA deficiency (SIgAD), and common variable immune deficiency (CVID). Early complement deficiencies are more strongly associated with development of autoimmune disease, as well as risk of infection with encapsulated organisms (late complement more associated with Neisseria infection). Autoimmune lymphoproliferative syndrome (ALPS) is associated with serologic evidence of lupus but not with clinical disease.

Arthritis pattern in PID is highly variable and can be mono-, oligo-, or polyarticular with or without rheumatoid nodules. Any monoarticular arthritis especially in this population is considered septic until proven otherwise. Arthritis is more strongly associated with hypogammaglobulinemia or agammaglobulinemia. The large joints of the lower extremities are more commonly affected in X-linked agammaglobulinemia (XLA), whereas SIgAD and CVID are associated with RA and juvenile inflammatory arthritis (JIA). DiGeorge syndrome (DS) is linked to a chronic early-onset polyarticular arthritis. Other PIDs afflicted by arthritis include Wiskott-Aldrich syndrome (WAS), hyper-IgM syndrome, ALPS, and CGD. Treatment of the underlying disease usually leads to symptomatic benefit; corticosteroids and steroid-sparing immunosuppressants are rarely required posing challenges.

Vasculitis has been described with WAS, C4 deficiency, autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED), ALPS, CVID, and SIgA and is thought to be mediated by impaired clearance of immune complexes. Treatment is the same for PID and PID-unrelated vasculitis.

Sarcoidosis must be differentiated from the typical caseating inflammatory lesions seen in CGD. Granulomatous lesions have also been described in CVID. GLILD or granulomatous and lymphocytic interstitial lung disease is characterized by non-necrotizing pulmonary granuloma with radiographic findings that mimic sarcoidosis. In the syndrome of immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) sarcoid-like granulomas responsive to immunosuppression have been described.

Dermatomyositis-like syndromes have been described in association with XLA, WAS, and CVID, and Sjögren’s syndrome has been associated with APECED, as well as CVID and C4 deficiency. Several organ-specific manifestations may mimic rheumatologic conditions and should be considered in the differential of autoimmune manifestations. For example, patients with hyper-IgM syndrome and WAS have been reported to have uveitis and optic neuritis [13].

Rheumatic Diseases and Malignancy

Musculoskeletal symptoms may be first manifestation of underlying malignancy. At times cause and effect is difficult to define, as some cancers present more frequently in patients with underlying autoimmune disease, while some autoimmune diseases are associated with underlying malignancy. To further complicate the matter, various medications used to treat autoimmune diseases have been associated with an increased risk of malignancy. Finally, musculoskeletal symptoms may be the result of a paraneoplastic process.

Common musculoskeletal manifestations of solid tumors include carcinomatous polyarthritis, reflex sympathetic dystrophy, digital necrosis, palmar fasciitis, multicentric reticulohistiocytosis (Fig. 18.7), osteogenic osteomalacia, and sarcoidosis. Vasculitis, mixed cryoglobulinemia, lymphomatoid granulomatosis, and erythromelalgia are more commonly associated with underlying lymphoproliferative disorders. Panniculitis, polymyalgia rheumatica, remitting seronegative symmetric synovitis with pitting edema (RS3PE), lupus-like syndromes, and antiphospholipid production have been attributed to a variety of underlying malignancies.