Rheumatic Manifestations in Diabetes Mellitus Patients
Review Article
Rheumatic manifestations in diabetes mellitus patients
Meghnathi Bhowmik a
, Sundeep Upadhyaya b,
DNB R...
have been hitherto neglected. The data regarding the rheu-
matic and musculoskeletal manifestations are primarily
based on...
than 60
respectively. The ultrasound findings of diabetic
cheiroarthropathy are the thickening of the flexor tendon
sheaths ...
small bone fragments, fusion of joints, and sclerosis of the
bone are noticeable.
Stage 3 e (Reconstruction of the damaged...
thermal stimulus that normally does not provoke pain), or
hyperalgesia (exaggerated response to a stimulus that is
patients. The study done by of Nord Torndelag et al in Norway
showed significant increase of hip fracture among women
with ...
14. Conclusion
Rheumatic manifestations in diabetes are primarily non-
inflammatory. The identification of characteristic rh...
42. Tan PL, Teh J. MRI of the diabetic foot: differentiation of
infection from neuropathic change. Br J Radiol.
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Rheumatic Manifestations in Diabetes Mellitus Patients


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Rheumatic manifestations of DM are the commonest of all
described endocrine rheumatic manifestations. These manifestations have generally been under-recognized and poorly treated, compared to the other complications, such as neuropathy, nephropathy and retinopathy. These manifestations, involve not only the joints, but also the soft tissues and the bones. In 2004, the National Health Interview Survey in US determined that 58%of diabetic patients will develop functional disability.The percentage of diabetic patients with functional disability will increase as the number of diabetic patients increases.Recent data reveals that the prevalence of rheumatic manifestations in the hands and shoulders in patientswith type 1 or type 2 diabetes is 30%.3These manifestations are closely
linked to age,4 prolonged disease duration,5,6 and vascular
complications like retinopathy.7

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Rheumatic Manifestations in Diabetes Mellitus Patients

  1. 1. Rheumatic Manifestations in Diabetes Mellitus Patients
  2. 2. Review Article Rheumatic manifestations in diabetes mellitus patients Meghnathi Bhowmik a , Sundeep Upadhyaya b, * a DNB Rheumatology Resident, Indraprastha Apollo Hospitals, New Delhi, India b Senior Consultant, Department of Rheumatology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi, India a r t i c l e i n f o Article history: Received 10 May 2013 Accepted 15 May 2013 Available online 6 June 2013 Keywords: Diabetes mellitus Rheumatic manifestations Limited joint mobility a b s t r a c t The incidence of diabetes is increasing in most countries of the world and is a major public health problem. Diabetology and rheumatology are two medical specialties that have much in common, including the immuno-pathogenesis (Auto-immune for example) and share many features. Diabetes affects the connective tissues in many ways and causes alter- ations in the peri-articular and the musculo-skeletal systems. Patho-genetic mechanisms for some of these conditions have not been studied and understood completely. Some of them are considered intrinsic complications of diabetes; while in others, diabetes seems to be a mere predisposition. In most cases, these manifestations are associated with func- tional disability and pain, affecting the quality of life of the diabetic patient. The man- agement of such clinical conditions requires multidisciplinary team effort to diagnose them, since early diagnosis leads to a better outcome. This article reviews some clinical, diagnostic, therapeutic and epidemiological aspects of these conditions. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction Diabetes mellitus (DM) is a chronic metabolic condition char- acterized by persistent hyperglycemia with resultant morbidity and mortality related primarily to its associated micro vascular and macro-vascular complications, which share the phenotype of hyperglycemia.1 Factors contributing to hyperglycemia include reduced insulin secretion, decreased glucose utilization, and increased glucose production. The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple-organ systems. The two broad categories of DM are designated as type 1 and type 2. Type 1 DM is the result of complete or near-total insulin defi- ciency. Type 2 DM is a heterogenous group of disorders char- acterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production.1 Rheumatic manifestations of DM are the commonest of all described endocrine rheumatic manifestations. These mani festations have generally been under-recognized and poorly treated, compared to the other complications, such as neurop- athy, nephropathy and retinopathy. These manifestations, involve not only the joints, but also the soft tissues and the bones. In 2004, the National Health Interview Survey in US determined that 58% of diabetic patients will develop functional disability.2 The percentage of diabetic patients with functional disability will increase as the number of diabetic patients in- creases. Recent data reveals that the prevalence of rheumatic manifestations in the hands and shoulders in patients with type 1 or type 2 diabetes is 30%.3 These manifestations are closely linked to age,4 prolonged disease duration,5,6 and vascular complications like retinopathy.7 In contrast to various vascular complications of diabetes mellitus (DM) that are life threatening, rheumatic manifesta- tions lead to considerable morbidity. The micro vascular and macro-vascular complications of DM have been studied extensively, as opposed to the rheumatic complications which * Corresponding author. Tel.: þ91 9818359408. E-mail address: sundeepupadhyaya@hotmail.com (S. Upadhyaya). Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 2 6 e1 3 3 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.05.007
  3. 3. have been hitherto neglected. The data regarding the rheu- matic and musculoskeletal manifestations are primarily based on observational studies. Many authors have made an attempt to classify rheumatic manifestations of DM in various ways.3,8,9 The only proven association that has been reported to occur exclusively among DM patients is diabetic muscle infarction (DMI). The other rheumatic manifestations of DM are also commonly found in various other diseases and are not unique to DM. These manifestations are as follows: Syn- dromes of limited joint mobility e limited joint mobility, dia- betic hand syndrome (diabetic cheiroarthropathy/stiff hand syndrome), adhesive capsulitis (frozen shoulder), trigger finger (flexor tenosynovitis), dupuytren’s contractures, calcific periarthritis, osteoarthritis; diffuse idiopathic skeletal hyper- ostosis (DISH); neuropathic arthropathy (Charcot joints, dia- betic osteoarthropathy), carpal tunnel syndrome, gout, diabetic amyotrophy, reflex sympathetic dystrophy.10 The table below denotes the potential pathophysiologic relationships that might be linked to these conditions (modi- fied from “Rheumatic manifestations of diabetes mellitus. Dorota Lebiedz-Odrebina, Jonathan Kay. Rheum Dis Clin N Am. 36(2010):681e699”). 2. Diabetic muscle infarction (DMI) DMI is rare complication of DM, Angerwall et al first described it as “Tumoriform focal muscular degeneration” in two dia- betic patients way back in 1965.11 Since then many cases have been reported and more than half of these patients had type 1 DM with a mean duration of 15 years.12,13 It presents with acute onset of muscle pain and swelling. 80% of cases have thigh muscle involvement, however isolated calf muscle, simultaneous thigh and calf muscle and upper extremity muscle involvement have also been described. A palpable mass has also been reported. Recurrence in the same or different group of muscle has been observed. The mean mortality rate is 10% with DMI within 2 years of the initial diagnosis, wherein mortality were predominantly due to the macro-vascular complications.14 The typical clinical presentation and characteristic find- ings on radiology, suggests the diagnosis of DMI. There is no specific laboratory marker for DMI. Serum creatine kinase (CK) levels were elevated in slightly fewer than half of those pa- tients for whom a level was reported. MRI shows typically isointense swelling on T1 weighted images and diffuse heterogenous hyper intensity on T2 weighted images of the affected muscle with surrounding subfascial and subcutane- ous edema. Gadolinium contrast is not essential but if used will show non-enhancing areas surrounded by peripheral enhancement.15 Muscle biopsy is reserved for patients in whom diagnosis is uncertain, with atypical presentation and for those who do not improve with anti platelet or anti- inflammatory therapy.16 Typical biopsy findings will reveal muscle fiber necrosis, edema, phagocytosis of necrotic fibers, granulation tissue and collagen deposition. Patho-physiologically it has been suggested that reperfu- sion injury after muscle ischemia resulted in muscle infarc- tion, as almost all patients with DMI had microangiopathic complications of DM. Also the theory of endothelial dysfunc- tion in DM and the hypercoagulability resulting from alter- nation of the coagulation- fibrinolytic system has been proposed.17 But, due to the rarity of the condition, the asso- ciation between antiphospholipid antibody syndrome and DMI has not been proven.18 Differential diagnosis is made with myositis, venous thrombosis, tumor and diabetic amyotrophy, adverse effect of simvastatin, ruptured Baker’s cyst. The recommended man- agement of this condition is symptomatic, with pain relief and short-term immobilization as necessary. This condition tends to resolve in most cases over a period of a few weeks. Opti- mizing diabetic control is of paramount importance.19 Medical therapy with antiplatelets and/or anti-inflammatory drugs is recommended, but due to infrequent occurrence of this dis- ease, there has not been any randomized controlled trial. 3. Upper limb manifestations It mainly involves upper limb musculoskeletal structures and it appears to be associated with the duration of diabetes, poor metabolic control and presence of micro vascular complica- tions.20 Each one of the following is explained as under: “Stiff-hand syndrome” or Diabetic cheiroarthropathy (derived from greek word “cheiros”, which means hand) is characterized by hardened and stiff skin of the fingers and palm and painless limitation of mobility of the small joints of the hands. The prevalence is 8%e50% among patients with diabetes, while only 4%e20% among individuals without DM.21,22 Diabetic cheiroarthropathy is primarily a clinical diagnosis and the imaging findings are nonspecific.23 There two clinical signs which are indicative of the diagnosis are 1) The prayer sign, in which, the patient is unable to approxi- mate the palmar surface of the fingers when raising the hands as if in prayer and 2) The tabletop sign, in which, when the patient is asked to lay the palms flat on the tabletop, he is unable to touch the palmar surface of the fingers to the table. Limited mobility should be confirmed by demonstration of loss of passive extension of the proximal interphalangeal and metacarpophalangeal joints, which are less than 180 and less Conditions unique to DM Conditions more frequent in DM Conditions sharing risk factors of DM and metabolic syndrome Diabetic muscle Infarction Limited joint mobility Diffuse Idiopathic Skeletal Hyperostosis (DISH) Neuropathic arthropathy Gout Stiff/Diabetic hand syndrome Osteoarthritis Dupuytren’s contracture Stenosing flexor tenosynovitis/Trigger finger Frozen shoulder/Shoulder adhesive capsulitis Calcific shoulder periarthritis Carpal tunnel syndrome a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 2 6 e1 3 3 127
  4. 4. than 60 respectively. The ultrasound findings of diabetic cheiroarthropathy are the thickening of the flexor tendon sheaths and subcutaneous tissues,23 and MRI shows the thickening and enhancement of the flexor tendon sheaths.24 The early recognition of this disease is important since it can be reversed by treatment and is a marker of other diabetic micro-vascular complications. Rosenbloom et al25 showed in his study that the prevalence of proteinuria and retinopathy was of 11% in diabetic patients without diabetic cheiroarthr- opathy versus 50% in diabetic patients with diabetic cheir- oarthropathy. Therapeutic measures include non-steroidal ant inflammatory drugs, physiotherapy and better glycemic control. Surgery might be necessary to reduce pressure on trapped nerves and improve sensation and discomfort, although some residual problems may persist despite surgery. Sorbinil, which was once used for treating cheiroarthropathy, is no longer used due to side effects. Trigger finger alsoknown asStenosingFlexor Tenosynovitis is caused by the inflammation, fibrosis and thickening of tendon sheaths, usually over a bony prominence or where it crossed over as a pulley. It causes finger blocking in flexion with the active extension failure. The middle and index fingers are the most commonly involved. The classic presentation of popping and locking of a trigger finger is usually sufficient for making the diagnosis. Imaging for diagnostic purpose is not recommended, with X-rays considered unnecessary in patients without a history of inflammatory disease or trauma.26 The prevalence of trigger finger ranges from 5% to 36% among pa- tients with type 1 and 2 DM as compared with 2% in the general population.27,28 The incidence of these disorders in diabetic subjects has a stronger association with actual duration of the diseaseand not with the glycemiccontrol.29 Treatment consists in the modification of the routine activities of daily living in order to avoid the triggering of the digits, non-steroidal anti- inflammatory drugs, splinting, corticosteroid injection into the tendon sheath and surgical release.30 Steroid use can again disturb the glycemic control and multiple digits involvement warrants surgical release for better relief of symptoms. Dupuytren’s contracture (DC) is characterized by the thickening and shortening of the palmar fascia, palmer or digital nodules, causing a contracture in flexion of the affected finger. In nondiabetic patients, the most affected fingers are the ring and the little finger, but in individuals with DM, DC mainly affect middle and ring fingers and the hand involve- ment is frequently bilateral.31 The prevalence of DC in dia- betes ranges between 20% and 63%, which is higher than among subjects without diabetes by about 13%.6,21 DC is associated with disease duration, long-term poor metabolic and glycemic control and presence of micro vascular com- plications.32 Diabetic cheiroarthropathy and DC may coexist in the same patient.21 Treatment of DC includes topical intralesional steroid injection, a good glycemic control, physiotherapy, and for the refractory cases, surgery. Collage- nase injection in the palmar fascia has been used recently, and there was significant reduction in fixed flexion contrac- tures as well as a marked improvement in range of motion. Generalized hand stiffness has been observed after surgical intervention.33 Therefore, collagenase injection, sourced from clostridium histolyticum, is a good alternative to the surgical treatment even though it is expensive. 4. Adhesive capsulitis of the shoulder (Frozen shoulder syndrome, shoulder periarthritis) It is a condition characterized by an insidious and progressive loss of active and passive mobility of glenohumeral joint, presumably due to the capsular contraction,34 resulting in pain and progressive restriction on abduction and external rotation. In 1934, Codman first coined the term Frozen Shoulder; later on Naviaser framed the term Adhesive Capsulitis to describe the same condition. Natural course of the disease can be divided into 3 phases: Pain, Stiffness and Recovery. This condition is found in around 11e30% in diabetic patients, which is considerably greater than in nondiabetics.21 Longer duration of the disease and treatment with insulin was associated with a larger percentage of shoulder calcification.35 The diagnosis of adhesive capsulitis is often one of exclusion. Early in the disease process, adhesive capsulitis may clinically appear similar to other shoulder conditions such as major trauma, rotator cuff tear, rotator cuff contusion, labral tear, bone contusion, subacromial bursitis, cervical or peripheral neuropathy. If a history of these other conditions is negative and if radiographs do not demonstrate osteoarthritis, then it could be adhesive capsulitis.36 In idiopathic adhesive capsu- litis, the joint capsule is thickened and adheres to the head of the humerus, thereby reducing the glenohumeral joint vol- ume. The treatment includes analgesics, physical therapy, intra-articular corticosteroid injection into the glenohumeral joint and subacromial bursa37 and kineto-therapy. Arthro- scopic capsular release is used for refractory adhesive shoul- der capsulitis and is preferred to open surgical release due to shorter length of postoperative recovery. 5. Neuropathic osteoarthropathy (Charcot osteoarthropathy, diabetic osteoarthropathy) It is characterized in its early stages by acute inflammation leading to bone and joint fractures, dislocation, instability and gross deformities.38 It is a progressive and degenerative arthropathy, which is associated with variety of diseases involving neuropathy. In patients with diabetes, Charcot osteoarthropathy is associated with a longstanding duration of diabetes and peripheral neuropathy. The estimated preva- lence among diabetic patients varies in the range of 0.08e13%.39 It most commonly involves the ankle, tarsome- tatarsal, metatarsophalangeal and toe interphalangeal joints. The disease is staged as below: Stage 0 e (Inflammation), is characterized by erythema, edema and heat but there are no structural changes visible on plain X-ray.40 Stage 1 (Development) is characterized by bone resorption, bone fragmentation, and joint dislocation. The swelling, warmth, and redness persist, but there are also radiographic changes such as evidence of debris formation at the articular margins, osseous fragmentation, and joint disruption. Stage 2 (Coalescence) involves bony consolidation, osteo- sclerosis, and fusion after bony destruction. Absorption of a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 2 6 e1 3 3128
  5. 5. small bone fragments, fusion of joints, and sclerosis of the bone are noticeable. Stage 3 e (Reconstruction of the damaged joints and bone) Healing and new bone formation occurs. Decrease in the sclerosis and bony remodeling signify that the deformity (subluxation, incongruity and dislocation) is permanent.41 It is important that the patient is put on early immobili- zation and hence imaging studies should be obtained in the early disease course itself. Radiological imaging aspects are important in diagnosing Charcot neuroarthropathy, however, they are not present in patients with stage 0 disease, for which, magnetic resonance imaging and 111 ln-WBC scans are used. However, the use of MRI offers the highest diagnostic accuracy.42 It typically reveals ligamentous disruption, joint deformity, center of signal enhancement within joints and the subchondral bone.43 The goal of the treatment for acute or quiescent Charcot neuroarthropathy should be to maintain structural stability of the foot and ankle, to prevent skin ul- ceration, and to preserve the plantigrade shape of the foot so that prescription footwear can be used. Bisphosphonates can significantly reduce the levels of the bone turnover, temper- ature and pain, but the clinical benefit such as an earlier re- turn to ambulation or radiographic improvement is weak at best. Surgery is reserved for severe ankle and midfoot de- formities that are susceptible to skin ulceration and that make braces and orthotic devices difficult to use.44 6. Carpal tunnel syndrome (CTS) It is a painful neuropathic disorder caused by the compression of the median nerve between the carpal ligament and other surrounding structures within the carpal tunnel. It is a form of entrapmentneuropathy.Ithasbeenreportedinupto20percent of diabetic patients, but the incidence rises to 75 percent in those with limited joint mobility.45 CTS may be more common in those with prediabetes.46 The presentation typically includes pain and paresthesias of the thumb, index, and middle finger and along the medial aspect of the ring finger. This also occa- sionally is characterized by proximal irradiation, the O´ shaking signO´ in which, there is disappearance of the symptoms after vigorous flapping of the hands, the Tinel sign, wherein, per- cussion ofthemedian nervetriggerspainresemblinganelectric sensation along the course of the median nerve and the Phalen test (wrist dorsiflexion) e the patient has to hold the hands against each other in full palmar flexion, paresthesias begin- ning between 30 and 120 s in this static position. One essential parameter of the motor or sensory deficit is a pathological change in motor or sensory conduction velocity evaluated with the aid of electromyography. Treatment is either conservative or surgical. The conservative therapy includes splinting, ste- roids, activity modification, non-steroidal anti-inflammatory drugs and vitamin B6 supplementation. Of the conservative approaches, only splinting47 and steroids are supported with evidence.48 Surgicalreleaseofthe carpaltunnelistypicallyused in patients who fail to achieve an adequate relief with conser- vative managements and for those with moderate to severe symptoms.49 However, in diabetic patient the recuperation after the surgical intervention is slower and less important.50 7. Diabetic amyotrophy It is a condition occurring in type I and II DM, in which patients develop severe aching or burning and lancinating pain in the hip and thigh, followed by a weakness and wasting of the thigh muscle and significant weight loss. It is associated with poor glycemic control.51 The results of the electro-diagnostic studies, which are often met, are consistent with the pres- ence of a neurogenic lesion that involves lumbo-sacral roots, plexus and peripheral nerves.52 This condition is most likely caused by inflammatory, immune-mediated vascular radi- culoplexopathy.53,54 The diagnosis is based on a clinical pre- sentation, the presence of diabetes and neural studies. Good functional recovery is expected within 2e3 years. Occasional relapses can occur. Medical therapy includes immunosup- pressive agents, such as cyclophosphamide and methyl- prednisolone. Kifoyle et al studied the therapy with pulsed methyl-prednisolone and noted a significant improvement in pain and weakness in the majority of the patients.55 Although these initial studies are encouraging, a Cochrane review concluded that no evidence from randomized clinical trials supports the use of immunotherapy treatment in lumbo- sacral plexopathy.56 The treatment also consists in a good glycemic control, physical therapy and occupational therapy. 8. Reflex sympathetic dystrophy and complex regional pain syndrome (CRPS) Reflex sympathetic dystrophy is a component of CRPS, which is a neuropathic pain disorder with significant autonomic features. CRPS is divided into CRPSeI (reflex sympathetic dystrophy) and CRPS II (causalgia), which represent the absence or the presence of documented nerve injury respec- tively. CPRS I typically develops after a minor tissue trauma or bone fracture and is associated with a predisposing condi- tion.57 Predisposing conditions include DM and other endo- crine disorders like hyperthyroidism, hyperparathyroidism and metabolic disease such as type IV hyperlipidemia.58 It presents with classic neuropathic pain characteristics that includes allodynia, intense burning pain and hyperalgesia. There is also local edema and changes suggestive of auto- nomic involvement like altered sweating, skin color and skin temperature in the affected region. The International Association for Study of Pain (IASP)59 listed the diagnostic criteria for CRPS I. IASP defines CRSP 1 as I¨A variety of painful conditions following injury which ap- pears regionally having a distal predominance of abnormal findings, exceeding in both magnitude and duration the ex- pected clinical course of the inciting event and often resulting in significant impairment of motor function, and showing variable progression over timeO´ . (Other 2 criteria sets described below also use this definition.) IASP 1994 consensus criteria includes the following: 1. Type 1 is a syndrome that develops after an initiating noxious event. 2. Spontaneous occurrence of pain in the absence of an external stimulus, allodynia (pain due to a mechanical or a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 2 6 e1 3 3 129
  6. 6. thermal stimulus that normally does not provoke pain), or hyperalgesia (exaggerated response to a stimulus that is normally painful) that is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event. 3. There is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor (sweating) activity in the region of the pain since the inciting event. 4. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. Criteria 2, 3 and 4 are necessary for a diagnosis of CRPS type 1. Bruehl60 and Veldman61 improved upon these criteria. Bruehl criteria are as follows: 1. Continuing pain disproportionate to any inciting event. 2. Patient must report at least 1 symptom in each of the 4 following categories: a) Sensory: reports of hyperesthesia b) Vasomotor: reports of temperature asymmetry or skin color changes or skin color asymmetry c) Sudomotor/edema: reports of edema or sweating changes or sweating asymmetry d) Motor/trophic: reports of decreased range of motion or motor dysfunction (weakness, tremor, dystonia) or trophic changes (hair, nail, skin) 3. Must display at least 1 sign in 2 or more of the following categories: e) Sensory: evidence of hyperalgesia (to pinprick) or allodynia (to light touch) f) Vasomotor: evidence of temperature asymmetry or skin color changes or asymmetry g) Sudomotor/edema: evidence of edema or sweating changes or sweating asymmetry h) Motor/trophic: evidence of decreased range of motion or motor dysfunction (weakness, tremor, dystonia) or trophic changes (hair, nail, skin) Veldman criteria are as follows: 1. Presence of 4 out of 5 symptoms: a) Diffuse pain during exercise b) Temperature differences between affected and unaf- fected extremity c) Color differences between affected and unaffected extremity d) Volume differences between affected and unaffected extremity e) Limitations in active range of movement of the affected extremity 2. Occurrence or increase of symptoms during or after use 3. Symptoms in an area larger than the area of the primary injury While IASP criteria are non-specified, possibly not as reproducible as Bruehl’s or Veldman’s criteria, they are cited more widely in the literature, including treatment trials.62 The treatment includes medical therapy, invasive procedures and paramedical therapy. The medical therapy consists in analge- sics, corticosteroids, oral muscle relaxants, bisphosphonates, and calcium-channel blockers. Invasive treatment consists in intravenous sympathetic blockade percutaneous sympathetic blockade, surgical sympathectomy, spinal cord stimulation, and amputation. Other paramedical interventions include physiotherapy, occupational therapy, and psychological treat- ment.63 Sympathetic nerve block seems to be unhelpful. 9. Diffuse idiopathic skeletal hyperostosis (DISH) (Forestier’ disease) It is characteristically associated with ligamentous calcifica- tion and ossification of the ligaments and entheses. It typically has a predilection for anterolateral aspect of the spinal col- umn, sometimes leading to bony ankylosis. It has been demonstrated that DISH is associated with diabetes mellitus particularly with Type 2 DM. Hyperinsulinemia has been suggested to play the pathophysiologic role and serves as a link between DM, obesity and development of vertebral hy- perostosis. Several other metabolic disturbances and concomitant diseases have been suggested to be associated with DISH including obesity, increased waist circumference, hypertension, dyslipidemia, hyperuricaemia and the meta- bolic syndrome.64e67 In one study, patients with DISH and those with osteoarthritis had elevated levels of insulin and growth hormone; however, the level of IGF-1 was higher in patients with DISH than in those with osteoarthritis.68 Often an asymptomatic condition, DISH, however may have numerous clinical symptoms including pain, stiffness, limited range of spinal motion and an increased susceptibility to un- stable spinal fractures after trivial trauma. Cervical and lum- bar segments of the spine are also frequently affected by DISH, and clinical manifestations include dysphagia and airway obstruction at cervical levels and radiculopathy. The diagnosis of DISH is based mainly on radiologic fea- tures. Radiographic criteria for the diagnosis proposed by Resnick and Niwayama require the involvement of at least four contiguous thoracic vertebral segments, typically described as I¨flowing osteophytesO´ along the anterolateral aspects of those four vertebrae, preservation of intervertebral disc spaces and the absence of apophyseal joint degeneration or sacroiliac in- flammatory changes.69 Later, Utsinger, in 1985 proposed a revised diagnostic criterion that incorporated the involvement of peripheral entheses. He suggested that symmetric periph- eral enthesopathy and continuous ossification along with the anterolateral aspect of the 2 or more contiguous vertebral bodies support a probable diagnosis of DISH.70 Treatment is generally symptomatic including NSAIDs, heat application, analgesics,andphysiotherapy. Controlofassociatedmetabolic disorders, may reduce the morbidities associated with these disorders, may retard future cardiovascular disease and possibly slow down the progression of soft tissue ossification. Therapeutic interventions should also aim at a reduction of insulin secretion and insulin resistance. Stretching and strengthening exercises brings about an improvement in spi- nal mobility but not in the pain associated with it. Osteoporosis can either occur as a direct consequence of the disease, or it can be treatment manifestation in diabetic a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 2 6 e1 3 3130
  7. 7. patients. The study done by of Nord Torndelag et al in Norway showed significant increase of hip fracture among women with type I DM compared with non-diabetic women (relative risk ¼ 6.9, CI ¼ 2.2e21.6).71 Regarding type II diabetes, this association is not very clear. It was demonstrated that the thiazolidinediones, an oral hypoglycemic agent, causes a reduction in bone mass and increase in risk to fracture.72 10. Gout Monosodium urate crystals deposition in the joints due to hyperuricemia results in gout. Several cross sectional studies have studied and proved the co-relation between metabolic syndrome, hyperuricemia and gout. The majority of patients under excrete uric acid through the kidney, which results in hyperuricemia and a small proportion of patients over pro- duce uric acid. However the exact pathophysiological mech- anism needs to be studied further. Strict glycemic control would definitely go a long way in better control of the disease. 11. Osteoarthritis (OA) OA is characterized by chronic joint pain and swelling due to degenerative process. It usually involves the knee joint, hips, spine and the first carpometacarpal joints. OA has been said to be more common in diabetics with an earlier age of onset as compared to nondiabetic, with more severe joint destruction. There is often joint crepitus on ex- amination and effusion or both. X-ray typically shows reduced joint space, subchondral cyst and ostophytes. However further studies are warranted due to scarcity of large database studies. 12. Epidemiology of diabetes the India scenario Diabetes is pandemic in both developed and developing countries. In 2000, there were an estimated 175 million people with diabetes worldwide and by 2030; the projected estimate of diabetes is 354 million.73 The greatest relative rise is pre- dicted in the developing countries of the Middle Eastern Crescent, Sub-Saharan Africa and the Indian subcontinent. By the year 2030, over 85 percent of the world’s diabetic patients will be in developing countries. Talking about India alone, the prevalence of diabetes is expected to increase from 31.7 million in 2000e79.4 million in 2030.73 These estimates are valid if the prevalence of obesity continues to remain the same as it is at present. However, since the incidence of obesity is rising at a rapid rate in developed as well as in the developing countries, these projections could well be a gross underestimation. In the past 20 years, the rates of obesity have increased by a multiple of three in developing countries the people have adopted a Western lifestyle with over consumption of cheap, energy dense food and decreased physical activity. The rela- tionship between obesity and poverty is complex: being poor in one of the world’s poorest countries is associated with underweight and malnutrition, whereas being poor in a mid- income country is associated with an increased risk of obesity. A developing country like India faces the paradox of families, in which the children are underweight and the adults are overweight. This combination has been attributed by some people to intrauterine growth retardation resulting in low birth weight, which apparently confers a predisposition to obesity later in life through the acquisition of a hefty pheno- type that, when accompanied by rapid childhood weight gain, is conducive to the development of insulin resistance and metabolic syndrome.74 A national survey of diabetes conducted in six major cities in India in the year 2000 has shown that the prevalence of diabetes in urban Indian adults was 12.1%.75 The onset of diabetes among Indians is about a decade earlier than their western counterparts and this has been noted in Asian In- dians in several studies.76 In the national survey 54.1% of diabetes developed it in the most productive years of their lives i.e. before the age of 50 years and they also had a higher risk of developing chronic complications of diabetes.76,77 The prevalence of type 2 diabetes is 4e6 times higher in the urban areas as compared to rural areas. The prevalence of impaired glucose tolerance (IGT) in the rural population is also high at 7e8%, which indicates presence of a genetic basis for type 2 diabetes in ethnic Indian population.78 This increasing prevalence will inevitably result in an increasing prevalence of the diabetes and associated condi- tions including rheumatic manifestations. 13. Pathophysiology Insulin resistance is a feature common to both type 2 DM and the metabolic syndrome. The onset of insulin resistance is heralded by postprandial hyperinsulinemia, followed by fasting hyperinsulinemia and, ultimately, hyperglycemia. The pathophysiology of these rheumatic disorders in dia- betic patients is not clear. It could be associated with con- nective tissue disorders, such as the formation of abnormally glycosylated end products or the impaired degradation of byproducts, it could be indirectly related to the vasculopathy and neuropathy commonly complicating the primary disease, or finally, it could be attributed to a combination of factors. Studies comparing the incidence of specific musculoskeletal disorders between type 1 and type 2 diabetic patients did not show significant differences between the two groups, despite the substantial difference in the mean age of the patients in the two groups. Most rheumatic complications seem to be associated with the duration of DM and appear in diabetic patients of younger age than their counterparts in the general population. Rheumatic disorders in these patients are prob- ably related to the long-term glycemic control of the diabetes. However, no direct association could be proven with the metabolic control of the disease. Keeping in mind the alarm- ing rate at which the number of diabetic patients are on the rise in a developing country like India, a low threshold for recognizing and treating such conditions early on in the dis- ease course will go a long way in changing the overall outcome and also help in reducing a lot the morbidity associated with diabetes. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 2 6 e1 3 3 131
  8. 8. 14. Conclusion Rheumatic manifestations in diabetes are primarily non- inflammatory. The identification of characteristic rheumato- logic manifestations of diabetes early may facilitate its man- agement accordingly; on the other hand, presence of rheumatic manifestations in a diabetic patient can serve as a marker for poor glycemic control and presence of micro vascular compli- cations like diabetic retinopathy. Most common are the upper limb syndromes. It has been shown that limited joint mobility and dupuytren contractures are more common than other rheumatic manifestations. Conflicts of interest All authors have none to declare. r e f e r e n c e s 1. Foster DW. Diabetes mellitus [chapter 334]. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. p. 2060–2081. 2. Egede LE. Diabetes, major depression, and functional disability among U.S. adults. Diabetes Care. 2004;27:421e428. 3. Cagliero E. 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