Rheumatoid manifestations of endocrine and metabolic diseases and treatments

Acromegaly

The articular manifestations of acromegaly are a leading cause of morbidity and functional disability in affected patients. At the time of diagnosis, most patients have signs or symptoms of joint disease. The duration of acromegaly does not appear to correlate with the severity of the arthropathy. The initial endocrine changes secondary to acromegaly are followed over time by the development of mechanical changes in the joints and the spine. Joint damage in patients with acromegaly occurs in three stages. The first is characterized by continued, excessive proliferation and regeneration affecting chondrocyte activity and cartilage matrix growth. In the early course of the disease, elevated growth hormone and insulin-like growth factor type I levels promote the growth of articular cartilage and periarticular ligaments, leading to cartilage thickening and joint space congestion. In this phase, joint space widening and periarticular soft tissue hypertrophy occur. Hyaline cartilage becomes thickened with clusters of large active basal chondrocytes; marginal osteophyte formation becomes excessive; and periosteal fibrocartilaginous attachments hypertrophy and ossify. These changes account for the clinical features of acromegaly: large bones with remodeled shafts; thickened cartilage, tendon, and capsule attachments; and large marginal osteophytes ( Fig. 209.1 ). The second stage consists of the development of specific cartilage ulcers at weight-bearing sites, presumably because of unequal cell proliferation and matrix formation in the cartilage midzone, which creates stress in the interterritorial areas and ultimately causing cartilage fissuring and ulceration. In the third stage, localized loss of cartilage substance takes place. During the repair mechanism, the regenerating fibrocartilage layer is excessive and forms a layer covering the old hyaline cartilage on the exposed bone. These structural alterations result in eburnation of subchondral bone and cyst formation that resembles severe forms of osteoarthritis.

Clinical Features

Joint pain is a common finding in patients with acromegaly ( Box 209.1 ). Affected joints include those of the jaw, hands, shoulders, hips, knees, cervical and lumbar spine, and sacroiliac joints ( Fig. 209.2 ). Joint effusions are uncommon; rarely, some patients may experience episodes of pseudogout. Physical examination shows evidence of bony enlargement and soft tissue prominence surrounding affected joints. Radiographs may demonstrate the hallmark features of acromegaly, namely widened joint spaces with chondrocalcinosis, osteophyte formation, and calcification of ligamentous insertions, or may show osteophytes and enthesitis. Sacroiliac x-rays may be abnormal in up to one third of patients, and acromegaly may clinically mimic spondyloarthritis. Prognathism is seen commonly and usually accompanied by widening of the interdental spaces. Bilateral carpal tunnel syndrome is often present and symptomatic at initial evaluation. Magnetic resonance imaging has demonstrated increased edema of the median nerve in the carpal tunnel rather than extrinsic compression, and ultrasound imaging has demonstrated increased median nerve stiffness and cross-sectional area. The Raynaud phenomenon has been described in about a quarter of patients. Another characteristic feature is vertebral enlargement with widened intervertebral spaces and osteophyte formation; however, facet joint hypertrophy is unusual. A high prevalence of vertebral fractures has been observed in men and postmenopausal women with acromegaly, correlating with length of disease activity. This risk is independent of bone mineral density scores and persists even when acromegaly treatment is initiated.

Box 209.1

Musculoskeletal Features Of Acromegaly

Adapted from Bluestone R, Bywaters E, Hartog M, et al. Acromegalic arthropathy. Ann Rheum Dis 1971;30:243-58.

• Clinical features of acromegaly include large bones with remodeled shafts, thickened cartilage, enlarged tendon and capsule attachments, and large marginal osteophytes.

• Pain and crepitus are common but rarely accompanied by restricted motion.

• Despite frequent back pain, back mobility is maintained even with aging because the thickened intervertebral disk cartilage, together with lax hypertrophied paraspinal ligaments, contribute to increased spinal mobility.

• A higher incidence of vertebral fractures may be observed.

Diabetes Mellitus

Diabetes mellitus is associated with a range of musculoskeletal and rheumatologic problems ( Table 209.1 ). Many studies have observed that the symptoms of hand pain and dysfunction occur more frequently in diabetic patients. A longer duration of diabetes rather than hemoglobin A _1C levels appears to correlate with a higher frequency of hand and shoulder syndromes. A study of adolescents with type I diabetes mellitus found that plantar fascia thickness, as measured by ultrasound imaging, was a significant predictor of the subsequent development of complications in type I diabetes mellitus, thus suggesting that glycation and oxidation of collagen in soft tissues may be independent risk factors for microvascular complications. Similarly, the finding of limited joint mobility of the hands in patients with type I diabetes may indicate an increased risk for microvascular disease. Patients with limited joint mobility typically have limited extension of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, generally beginning in the ulnar digits and spreading radially. Patient are asked to hold their hands opposed to one another with the wrists extended and the elbows flexed (prayer sign); a positive test is indicated by the inability of patients to completely approximate the palmar surface of the digits. Dupuytren’s contracture consists of palmar and digital nodules and cords, palmar skin tethering, and digital contractures. In contrast to nondiabetics, the condition is milder, the ring and middle digits are predominantly involved as opposed to the small and ring digits, and few patients complain of symptoms. Carpal tunnel syndrome has similar findings in diabetic and nondiabetic patients. However, many authors believe that diabetic patients have poorer outcomes following carpal tunnel release than nondiabetic patients do.

There may be subtle distinctions between the clinical manifestations of stenosing tenosynovitis (trigger finger) in diabetic versus nondiabetic patients. When compared with a nondiabetic population, trigger finger in diabetics is more commonly seen in females and more often bilateral and involving multiple digits with relative sparing of the index and small fingers. Corticosteroid injection is less effective in diabetics, and these patients require surgery more frequently. Adhesive capsulitis of the shoulder can be defined as unilateral shoulder pain of greater than 3 months’ duration with an associated reduction in range of motion in all planes by at least 50%.

A study attempting to quantify the prevalence of painful or stiff shoulder in diabetic patients found that shoulder pain was present in about a quarter of the patients compared with just 5% of nondiabetic individuals. Frozen shoulder was observed in about 4% of patients vs less than 1% in the nondiabetic cohort.

Neuropathic (Charcot) arthropathy is typically characterized by pain and swelling of the midfoot in a patient with underlying peripheral neuropathy. Over time, evidence of severe osteolysis may be seen, and bone and joint destruction may follow. The condition is sometimes self-limited and one sided even though the neuropathy is usually permanent and symmetric. It has been proposed that activation of proinflammatory cytokines, including tumor necrosis factor-α and interleukin (IL)-1β, together with RANKL–NF-κB signaling, may result in bone lysis and calcification of the media of the arterial walls of blood vessels supplying the feet.

Stiff person syndrome is an uncommon disorder seen in some type I diabetic patients. The condition is characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles with severe impairment of ambulation. In severe cases, a fixed spinal deformity with pronounced lordosis is evident. The hallmark feature is the presence of superimposed, severe episodic muscle spasm precipitated by sudden movement, noise, or emotional upset (startle reflex). Stiff person syndrome and type I diabetes share some immunologic features, including the presence of antibodies to glutamic acid decarboxylase, although the magnitude of the antibody response and the selected epitopes that are recognized differ in these two diseases.

Diabetic myonecrosis, also referred to as diabetic muscle infarction (DMI), is a rare condition of unclear pathogenesis. It most frequently affects the quadriceps and thigh muscles, though it has been reported in the calves and upper extremities and is only rarely bilateral. It occurs more often in patients with advanced diabetes with end-organ dysfunction. In one review, the mean age of onset was 42 years of age. Characteristic MRI features include a “patchwork pattern” of multifocal areas that demonstrate interfascial and intramuscular edema, and muscle enlargement. DMI may be considered in the differential diagnosis of a focal myositis and is notable for the presence of pain and a normal serum CK value.

A number of antihyperglycemics have been associated with musculoskeletal manifestations including myalgias and elevated fracture risk ( Table 209.2 ). Metformin, a commonly used biguanide that inhibits gluconeogenesis and therefore decrease hepatic production of glucose, has been associated with myalgias. The mechanism is unknown, but potentially related to reduced levels of Vitamin D. Gliptins, a newer class of antihyperglycemic agents that inhibit dipeptidyl peptidase-4, have also been associated with myalgias and arthralgias through an unclear mechanism. Thiazolidinediones, which stimulate adipogenesis and fatty acid uptake, are associated with increased fractures in women, independent of both age and length of exposure to the drug. The gliflozins (SGLT2 inhibitors), which promote glucosuria, may also be associated with increased fracture risk though a recent metaanalysis did not confirm this finding. Finally, in one murine study and several human case studies, both sulfonylureas and meglitinides were associated with muscle-type dependent atrophy.