Rheumatic Manifestations of Endocrine Diseases

Joseph A. Markenson

Disclosures

Curr Opin Rheumatol. 2010;22(1):64-71. 

In This Article

Diabetes Mellitus

Patients with diabetes mellitus have several rheumatic syndromes, many of which are associated with the severity of the disease. These include diabetic neuropathy and its associated arthropathy. The pathogenesis is neurovascular[45] instead of the generally thought neurotraumatic (resulting from decreased sensitivity of nerve endings) or reduced flow secondary to arterial sclerosis of small vessels. Patients with diabetes have increase blood flow (secondary to neuropathy involving the sympathetic nervous system) to subchondral bone, resulting in increased osteoclastic activity and bone resorption. This occurs even in the absence of peripheral vascular disease, resulting in bone fatigue and disorganization. It appears radiographically as progression from localized osteopenia to osteolysis of subchondral bone, fragmentation of bone and cartilage (part of which may be come embedded in synovial tissue) and sclerosis.[46] Joints involved in order of frequency include ankle, metatarsophalangeal and tarsometatarsal. This distribution differentiates diabetic arthropathy from tabes dosalis in which the knee is more commonly involved. The pathogenic mechanism which may be active in diabetes mellitus causing tissue damage is unknown; however, advanced glycation end products bind to RAGE receptors (increased in diabetes and thought to be responsible for inflammation and increased atherosclerosis) on chondrocytes up-regulating matrix metalloproteinase which are involved in inflammation.[47–50]

There are relationships between gout, hyperuricaemia and the metabolic syndrome. The metabolic syndrome increases the risk for atherosclerotic cardiovascular disease (CVD) and type 2 diabetes. A recent study looked at the relationship between gout and the development of type 2 diabetes by prospectively studying a cohort of 11 351 male participants from the Multiple Risk Factor Intervention Trial (MRFIT). After adjusting for age, body mass index (BMI), smoking, family history of type 2 diabetes, alcoholic intake, dietary factors, and presence of individual components of the metabolic syndrome the multivariate risk for type 2 diabetes among men with gout at baseline compared to men without gout was 1.34 [95% confidence interval (CI) 1.09–1.64]. These findings from men with a high cardiovascular risk suggests that men with gout are at a higher future risk of developing type 2 diabetes independent of the other known risk factors.[51••]

The evidence for co-occurrence of two autoimmune diseases RA and diabetes mellitus type 1 has been reported. RA has been linked with the premature development of cardiovascular disease which is related to the inflammatory burden and predisposes to the development of atherosclerosis in these patients. Systemic inflammation has also been implicated in predisposition to developing diabetes mellitus type 2 as well as insulin resistance. Since systemic inflammation is increased in RA it is possible that the prevalence of diabetes is increased in RA. Simard and Mittleman,[52] however, reported a population-based study utilizing data collected from the National Health and Nutrition Examination Study (NHANES) III (included 5302 patients > 60 years of age) in which there was no association between RA and diabetes mellitus. There were several problems with this study including too few patients with RA and diabetes mellitus, a mix of mild and severe RA (also failure to look at anti-CCP positive and negative RA patients), and lastly a concentration of patients with type 2 diabetes mellitus. One established genetic risk factor, the 620W allele of the protein tyrosine phosphate N22gene (PTPN22), is shared by both RA and type 1 diabetes mellitus. In a recent study the presence of this association was again investigated utilizing the Swedish data base. Patients from the RA registry (1419) were compared with matched controls (1674) from the Swedish national population registry during the period 1996–2003. All patients had blood samples that were tested for antibodies to cyclic citrullinated peptide (anti-CCP), rheumatoid factor, and the 620W PTPN22 risk allele. Type 1 diabetes mellitus was associated with an increased risk of RA [odds ratio (OR) 4.9, 95% CI 1.8–13.1]. This association was specific for anti-CCP + RA (OR 7.3, 95% CI 2.7–20.0) and attenuated to an OR of 5.3 when looking further for the presence of the 620W PTPN22 allele (OR 5.3, 95% CI 1.5–18.7), concluding that the association of RA and type 1 diabetes mellitus was limited and specific to one subset (anti-CCP + RA) and the risk in patients with type 1 diabetes mellitus of developing RA in later life was attributed partly to the presence of the 620WPTPN22 allele (possibly representing a common pathway for both auto immune diseases).[53••]

Further investigations looking for a genetic locus for susceptibility to multiple autoimmune diseases focused on the discovery that a common single-nucleotide polymorphism (SNP) rs6822844p was found in linkage-disequilibrium on chromosome 4q27 with genes KIAA1109, Tenr, IL2, and IL21. IL21 (MIM695384), IL2, KIAA and Tern have been reported to be a strong genetic factor in celiac disease in humans and type 1 diabetes mellitus in mice. Zhernakova et al.[54] investigating common genes for autoimmune disease tested SNP rs6822844 from this region for association with disease in 350 type 1 diabetic patients, 1047 patients with RA and 929 controls in a Dutch population. Her results replicated the association found in the KIAA1109/Tenr/IL2/IL21 gene region with type 1 diabetes mellitus and found a similar association with RA implying that this locus may be a general risk factor for multiple auto immune diseases.[54]

Diffuse idiopathic skeletal hyperostosis (hyperostosis or DISH) originally described as confined to the axial skeleton involves calcification of tendon and ligament attachments in both spinal and extraspinal locations as well as hyperostosis at bony prominences. Forty to fifty percent of patients with this condition also have diabetes mellitus. Elderly patients with diabetes mellitus have an increased prevalence of DISH over age-matched controls; however, the severity of the diabetes is not related to the extent of DISH present.[55,56]

Periarthritis and adhesive capsulitis (frozen shoulder) presenting with shoulder pain (often awaking the patient at night) progressing sometimes to progressive limitation of motion over months is associated with several medical conditions including diabetes mellitus.[57] Abnormality of the involved joint demonstrates thickening and fibrosis of the glenohumeral capsule with the exact mechanism unknown except that proliferating fibroblasts and fibrosing syndromes are seen in diabetes mellitus.

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