VIMS Journal: December 2015

Special Article

Rheumatological Disorders in Diabetes Mellitus (Based on an Article Published in RSSDI Update 2015)

Dr. Sudip Chatterjee

It is well recognised that there is an increased incidence of rheumatological disorders in diabetes. Crispin [1] classified these disorders into four types: those that were a consequence of complications; those that were a result of metabolic consequences of diabetes; syndromes that shared pathogenesis with microvascular complications; and associations of diabetes. Research in the field is hampered by poor characterisation of subjects and lack of uniformity in definitions. Perhaps as a consequence, there is a wide reported variation in the incidence of various rheumatological complications. For example, a study from Jordan on 1000 type 2 diabetes patients found limited joint mobility (LJM) in 63% of patients [2] while a study from Kolkata on 100 patients found an incidence of only 29 % [3] . A study on type 1 diabetes patients, comprising the follow up of the DCCT trial cohort, the EDIC group of 1217 subjects, looked at cheiroarthropathy and functional disability after an average of 24 years of follow up [4] . Cheiroarthropathy was present 64 % of subjects in the erstwhile intensive group and 68% in the erstwhile conventional group (non significant). The affected subjects were significantly more likely to have functional disability as well.

The association of diabetes and rheumatological disease has its underpinning in the nature of collagen itself. Collagen fibers tend to form an increased number of crosslinks when exposed to oxidative stress and hyperglycemia. The reactive carbonyl group of a sugar attaches to a nucleophilic amino group of an amino acid to form complex series of molecules. This is the basis of the Maillard Reaction, first described in 1912. In vivo, this reaction is best studied with the help of a pentose sugar, pentosidine which forms an arginine - lysine crosslink. The resulting compounds exhibit autofluorescence between wavelengths of 420 and 600 nm, a fortuitous finding which allows the process to be studied in exposed tissues like skin. Hyperglycemia induced collagen crosslinkages have widespread and deleterious consequences in long lasting collagen tissues. These include the arterial wall, periarticular soft tissue and the lens of the eye. The products of the Maillard Reaction are collectively called advanced glycation end products or AGE. These products make the tissues more stiff, and in the case of joints, limit their movement, causing disability.

Various pharmaceutical methods to avoid the deleterious effects of AGE have been tried. For example, aminoguanidine to inhibit AGE formation and ligands to block the AGE receptor. None of these approaches have yielded desired results. Poor glycemic control and long duration of diabetes correlate well with the incidence and severity of musculoskeletal disorders, while on the other hand patients with good control of their diabetes are likely to have fewer musculoskeletal problems. A few of the commonest disorders will be discussed in the following paragraphs.

Adhesive capsulitis of the shoulder is a painful and usually self limiting disorder where external rotation and abduction are principally affected. The joint volume is reduced due to thickening of the capsule and its adherence to the head of the humerus. Non diabetic associations include stroke, myocardial infarction and shoulder trauma. Patients with diabetes are affected at a younger age, and the condition takes longer to resolve. The condition is self limiting. Management consists of gentle stretching, analgesics and in severe cases, intra articular corticosteroids and manipulation under anesthesia.

Diabetic cheiroarthropathy has been used synonymously with limited joint mobility (LJM) by most authors. However a study on the EDIC cohort used the term LJM to include carpal tunnel syndrome, tenosynovitis and Duputreyn's contracture [4] . LJM has a strong association with microvascular complications.

In the carpal tunnel syndrome (CTS) the median nerve is compressed as it passes through the fibro osseous carpal tunnel. Sensory symptoms usually occur first with tingling and numbness of the first to 4 th digits especially at night. This is followed by motor symptoms with weakness of the thenar muscles. Initial treatment is with rest, splints and gabapentin. Invasive treatments include local corticosteroid injection and surgical decompression. Electrophysiological criteria for diagnosis in Indian subjects have been formulated [5] . Using electrophysiologic criteria the author found asymptomatic CTS in 58.2 % of a series of 62 unselected type 2 diabetes patients (unpublished data).

Duputryen's contracture typically affects the third and fourth digits of patients with diabetes as opposed to a predilection for the fifth digit in non diabetic patients. Treatment depends on disease severity. Tenosynovitis of the flexor tendons of the fingers typically responds to local corticosteroid infiltration.

Diffuse idiopathic skeletal hyperosteosis (DISH) is a non inflammatory disease of the spine primarily involving calcification of the anterior longitudinal ligament at the level of the thoracic spine. The condition has been associated with diabetes and with several components of the metabolic syndrome. There is ossification of the points of attachment of tendons and muscles to bone and may occur anywhere in the body. As the condition is often asymptomatic, prevalence of the condition varies widely [6].

Type 1 and type 2 diabetes are both associated with attenuation of bone trabecular architecture, poor osteoblast function, accelerated bone resorption leading to poor quality of bone. Although earlier studies showed increased bone mineral density in type 2 diabetes, current data show that patients (and animals) with both types of diabetes have similar bone defects. Also glycation of collagen leads to formation of AGE in the bone matrix which decreases its mechanical strength [7] . Osteoarthritis appears to be more common in patients with diabetes. In vitro evidence comes from cultured knee cartilage harvested during knee replacement surgery. Cartilage from diabetes patients showed a higher responsiveness to inflammation induced by interleukin 1b [8] .

In type 1 diabetes there is an increased incidence of rheumatoid disease [9] . Also, there are type 1 DM patients with no arthropathy who are positive for anti CCP antibodies (author's unpublished data). Hydroxychloroquine and sulfasalazine, often used in RA, have been shown to increase insulin sensitivity in non diabetic subjects [10] and several studies are underway to explore this finding and turn it to clinical benefit.

A large series from Jaipur looked at 5632 patients with type 2 DM and found musculoskeletal manifestations in 57.01% of them. The commonest conditions were adhesive capsulitis, carpal tunnel syndrome, LJM with a slightly higher incidence in type 1 DM patients [11] .

Summary:
It is evident from the literature that musculo- skeletal disorders are common in patients with diabetes, and these problems diminish their quality of life. At the same time it is an area which has received less attention than other co- morbidities of diabetes. One of the reasons for this is that the conditions are poorly defined leading to lack of agreement among investigators. Also there is lack of recognition of the fact that these disorders are more common in diabetes. Specialists in the subject should actively seek out and treat musculoskeletal problems in their patients. Also a common nomenclature and classification needs to evolve.

This article is based on a article written by the author and published in RSSDI Update 2015, edited by Dr. Sarita Bajaj and published by Jaypee Brothers Medical Publishers (P) Ltd, New Delhi. This is with the kind permission of the Editor and Publishers.

References
  1. Crispin JC, Alcocer-Varela J.
    Rheumatologic manifestations of diabetes mellitus. Am J Med. 2003 Jun 15;114(9):753-7.

  2. Mustafa KN, Khader YS, Bsoul AK, Ajlouni K. Musculoskeletal disorders of the hand in type 2 diabetes mellitus: Prevalence and its associated factors. Int J Rheum Dis. 2015 Aug 10. doi: 10.1111/1756- 185X.12617. [Epub ahead of print]

  3. Pal SK 1 , Biswas S, Sinharay K, Banerjee A Rheumatological problems in diabetes mellitus. J Indian Med Assoc. 2002 Jul;100(7):458-60.

  4. Larkin ME, Barnie, Barnie, Braffet BH, Cleary PA, Diminick L, Harth J, Gatcomb P, Golden E, Lipps J, Lorenzi G, Mahony C, Nathan DM. Musculoskeletal complications in type 1 diabetes. Diabetes Care 2014 Jul;37(7):1863-9. doi: 10.2337/dc13-2361. Epub 2014 Apr 10.

  5. Cherian A, Kuruvilla A. Electrodiagnostic approach to carpal tunnel syndrome. Ann Indian Acad Neurol 2006;9:177-82.

  6. Pillai S, Littlejohn G
    Metabolic factors in diffuse idiopathic skeletal hyperostosis - a review of clinical data. Open Rheumatol J. 2014 Dec 19;8:116-28. doi: 10.2174/1874312901408010116. eCollection 2014.

  7. Kannikar Wongdee and Narattaphol Charoenphandhu Update on type 2 diabetes-related osteoporosis Osteoarthritis Cartilage. 2015 May 15. pii: S1063- 4584(15)01147-4. doi: 10.1016/j.joca.2015.04.026. [Epub ahead of print]

  8. Laiguillon MC, Courties A, Houard X, Auclair M, Sautet A, Capeau J, Feve B Berenbaum F, Sellam J Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis. Surg Neurol Int. 2014; 5(Suppl 3): S122-S125. Published online 2014 Apr 16. doi: 10.4103/2152- 7806. 130675.

  9. Fabio A. Nascimento, Luana Antunes Maranha Gatto, Roberto Oliver Lages, Heraldo Mello Neto, Zeferino Demartini, Junior, and Gelson Luis Koppe. Diffuse idiopathic skeletal hyperostosis: A review World J Diabetes. 2015 Jun 10; 6(5): 673-678. Published online 2015 Jun 10. doi:10.4239/wjd.v6.i5.673

  10. Wasko MC, McClure CK, Kelsey SF, Huber K, Orchard T, Toledo FG. Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial. Diabetologia. 2015 Jul 22. [Epub ahead of print]

  11. RP Agrawal, Sunil Gothwal, Pankaj Tantia, Ritvik Agrawal, Puneet Rijhwani, P Sirohi, Jai Kumar Meel Prevalence of Rheumatological Manifestations in Diabetic Population from North-West India. J Assoc Phys India 2014 . 62: 788-792.

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