Limitation of Finger Joint
`Mobility in Diabetes Mellitus
`
`Arlan L. Rosenbloom, MD
`
`Division of Endocrinology,
`Department of Pediatrics,
`University of Florida,
`College of Medicine
`
`Reprints requests: Arlan L. Rosenbloom ,
`MD, J-296, JHMHC, Gainesville, FL
`32610.
`
`ABSTRACT
`Diabetes mellltus, both Insulin dependent and non-Insulin dependent, Is
`associated with llmllallon of Joint moblllty of the fingers, which can be
`due to connective tissue changes, neuropathy, vasculopathy, or
`combinations of these problems. Distinct clinical problems Include
`Dupuytren disease, flexor tenosynovltls, carpal tunnel syndrome (dia(cid:173)
`betic hand), stiff hand syndrome, shoulder-hand syndrome (reflex
`dystrophy) and limited joint mobility (LJM). Stiff hand and LJM
`syndromes are only seen with diabetes; the others have distinct clinical
`characteristics In those with diabetes compared to the nondlabetic
`presentation. LJM is of particular Interest because It is common in young
`patients and associated with an
`Increased risk for the serious
`complications of nephropathy and retinopathy. Journal of Diabetic
`Complications 3;2:77-87, 1989.)
`
`INTRODUCTION
`Dupuytren contraction was known for nearly 100 years 1 before an
`association with diabetes was suggested
`in 1932.2 Twenty-three
`years later, Lundbaek described the stiff hand syndrome uniquely
`found in middle-aged patients with long-standing diabetes.3 The
`associations of diabetes with the carpal tunnel syndrome, 4-5 with
`flexor tenosynovitis,6.7 and with periarthritis of the shoulder and
`shoulder-hand syndrome8 were described in the years between 1970
`and 1972.
`A syndrome of painless limitation of the finger joints, with involve(cid:173)
`ment of large joints and thick, tight, waxy skin, occurring in young pa(cid:173)
`tients with insulin-dependent diabetes, initially was described in 1974.9
`This review will concentrate on this condition because it is frequent,
`does not occur in the nondiabetic young population , and is an im(cid:173)
`portant risk factor for other complications, and because a number of
`biochemical studies have been carried out on biopsy specimens of the
`associated thick, tight, waxy skin .1° Furthermore, there is a need for
`clinicians to recognize the characteristics of the limited joint mobility
`syndrome (LJM) as distinct from other conditions affecting the finger
`joints in persons with diabetes. Th is is particularly important in view of
`the epidemiologic significance of LJM as a risk marker for microvascu(cid:173)
`lar disease, setting it apart from the less common conditions or those
`that are not uniquely associated with diabetes.
`Discussion will focus on the characteristics of each hand lesion, on
`distinctions between the disease in persons with diabetes as opposed
`to those without diabetes in conditions which are not unique to dia(cid:173)
`betes, and on pathogenic hypotheses that may bear on the vascular
`complications of diabetes.
`
`DUPUYTREN DISEASE (DD)
`DD is due to subcutaneous fibrosis of the palmar fascia . In persons
`who do not have diabetes, there is a 6:1 predominance in men , and DD
`is only seen in white Europeans The argument whether or not DD is
`
`77
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`78
`
`ROSENBLOOM
`
`more prevalent in those with diabetes than in those
`without appears related to the failure to recognize milder
`expression of DD in those with diabetes. Careful examina(cid:173)
`tion demonstrates a 40%
`incidence in middle-aged
`patients with diabetes and the absence of a gender
`difference, reminiscent of the circumstance with cardio(cid:173)
`vascular risk in women with diabetes. Women with
`diabetes tend to have knuckle pads, nodules, and skin
`tethering, without finger joint contracture. Contractures
`are more radial in the hands of those with diabetes,
`involving the third and fourth digits predominantly, than
`in those without diabetes. who typically have involvement
`of the 4th and 5th fingers. Characteristic lesions may
`precede the development of diabetes and are present in
`160/o of newly diagnosed older patients. 11
`Advanced DD lesions requiring surgery have the fol(cid:173)
`lowing characteristics: increased water, type Ill collagen.
`and chondroiton sulfate; increased proportions of sol(cid:173)
`uble collagen and reducible crosslinks (indicating syn(cid:173)
`thesis of new collagen); and increased glycosylation of
`reduced crosslinks. The accumulation of type Ill colla(cid:173)
`gen and increased hydroxylation and glycosylation of re(cid:173)
`ducible crosslinks are characteristic of granulation and
`scar tissue. 12
`
`STIFF HAND SYNDROME
`Stiff hand syndrome is an unusual and incapacitating
`condition that appears to be due to vascular insuffi(cid:173)
`ciency. It was initially described in five patients with
`long-standing IDDM.3 Complaints of tingling or a burn(cid:173)
`ing sensation in the hand preceded the advent of pain,
`which was aggravated by movement and led to inva(cid:173)
`lidism in two patients. Subcutaneous tissue of the fingers
`and palms was stiff and hard, with dystrophic changes of
`the fingernails in two patients. There was no muscle atro(cid:173)
`phy. The most characteristic feature was a radiographic
`appearance of calcification of the arteries of the hand
`in all five patients. There was a paucity of elastic fibers
`seen on skin biopsy examination, but no other changes.
`
`CARPAL TUNNEL SYNDROME
`Compression of the median nerve within the carpal tun(cid:173)
`nel is a common entrapment neuropathy and results in
`paresthesias of the thumb, index, and little fingers, with
`pain that is often worse at night. Diabetes accounts for
`5-16% of instances.4 Jung and others5 described a "dia(cid:173)
`betic hand syndrome" that appeared to involve both the
`median and ulnar nerve distribution and was bilateral
`and symmetrical, affecting all distal and proximal inter(cid:173)
`phalangeal and metacarpal-phalangeal joints. Their 23
`patients included 6 who were not taking insulin, with
`an average age of 43 years and an average diabetes du(cid:173)
`ration of 17 years. In addition to the typical thenar mus(cid:173)
`cle atrophy seen in those without diabetes, there is at(cid:173)
`rophy of the intrinsic and hypothenar muscles, as well
`as decreased nerve conduction velocity for both me(cid:173)
`dian and ulnar nerves. Thus, in diabetes, this condition
`appears to be more a neuropathic than an entrapment
`problem, although connective tissue stiffening and over(cid:173)
`growth could contribute to compression.
`
`FLEXOR TENOSYNOVJTIS
`The congenital form of "trigger finger" almost exclu(cid:173)
`sively involves the thumb and is not associated with
`diabetes.6 It is estimated that one-third of multiple pal(cid:173)
`mar flexor tenosynovitis in adults is related to diabetes,
`with a marked predominance in women , a predeliction
`for the right hand, and preferential involvement of the
`thumb, middle, and ring fingers. This appears to be
`a connective tissue proliferative problem, with fibrous
`tissue accumulating in the tendon sheath, particularly
`where the tendon is constricted as it passes through a
`fibrous ring or pulley, or over a bony prominence, with
`swelling occurring distal to the constriction and pain
`with movement of the swollen segment through the nar(cid:173)
`rowed ring. Crepitus may be palpable or audible with
`movement and locking can occur in flexion or extension
`when a nodule becomes impacted. 13
`
`PERIARTHRITIS OF THE SHOULDER AND SHOULDER-HAND
`SYNDROME
`Periarthritis, also referred to as adhesive capsulitis, can
`result from trauma, inflammation, or myocardial infarc(cid:173)
`tion and is often associated in these cases with the
`shoulder-hand syndrome. This has also been referred
`to as reflex sympathetic dystrophy, causalgia, post(cid:173)
`traumatic osteoporosis, or Sudeck atrophy.14 Diffuse
`swelling, coldness, erythema, tenderness, and hyperhy(cid:173)
`drosis of the hand may precede, accompany, or follow
`the development of thickening of the joint capsule, with
`adherance to the head of the humerus and marked re(cid:173)
`duction in the volume of the glenohumeral joint. Swelling
`and vasomotor instability resolve, with the development
`of trophic skin changes and contractures. After weeks or
`months. the tenderness, swelling, and vasomotor dys(cid:173)
`function completely resolve with residual atrophic or
`dystrophic changes, finger contractures, and occasion(cid:173)
`ally frozen shoulder with atrophy of the shoulder girdle
`muscles and osteoporosis of the bones of the hand and
`shoulder.
`The clinical picture and natural history is quite differ(cid:173)
`ent in those with diabetes. Bridgeman 8 found that 11 %
`of 800 patients with diabetes had frozen shoulders com(cid:173)
`pared to 2.3% of 600 age- and sex-matched controls
`without diabetes. Minimal functional disability was noted
`among 15 of these patients who had a clinical history of
`pain for greater than 3 months and had greater than 50%
`loss of range of motion at the shoulder; their pain was
`limited to relatively mild discomfort around the shoulder
`joint.
`When patients were selected on the basis of finger
`joint stiffness. 29 individuals aged 23-65 years, with
`a diabetes duration of 14-48 years, had a nearly 50%
`prevalence of frozen shoulder; Dupuytren disease and
`flexor tenosynovitis were also common, each present in
`one-third of patients but not thought sufficient to ac(cid:173)
`count for the finger joint limitation. Controls who were of
`the same age and duration of diabetes but were without
`finger contracture had only a 7% prevalence of frozen
`shoulder. Bilateralality was present in 10 of the 13, an
`uncommon circumstance in the spontaneous disease,
`
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`JO!NT MOBILITY IN DIABETES
`
`79
`
`where only 5% of cases are bilateral. Half of those with
`finger joint contraction may have had a form of the stiff
`hand syndrome, 3 as digitai or radiai artery calcification
`was seen in 50% of those with finger contracture ver(cid:173)
`sus 14% of controls; there also was a fourfold increase
`in peripheral neuropathy in those with joint contracture,
`suggesting a neuropathic component as well. 15 Histo(cid:173)
`logic findings in this study emphasize the difference
`from shoulder periarthritis in those without diabetes. In
`contrast to the inflammatory reaction with synovial cell
`proliferation, collagen degeneration, and inflammatory
`ceii iniiitraiion seen in those without diabetes, these
`patients had histologic findings identical to those de(cid:173)
`scribed above in Dupuytren disease. 12
`Using less stringent criteria than in the previous study,
`Pal and others 16 found that 20% of 49 IDDM and 18.3% of
`60 NIDDM had shoulder capsulitis in contrast to 5.3%
`of controls. Half the patients with diabetes of both types
`had finger joint contracture in contrast to 20% of con(cid:173)
`trols, and the contractures were more severe in those
`with diabetes; there was no correlation between shoul(cid:173)
`der and finger joint limitation. The major difference
`between this study and that of Fisher and colleagues15
`was that the latter eliminated half of their initial pa(cid:173)
`tient population because of the joint contractures be(cid:173)
`ing obviously due to Dupuytren disease, osteoarthritis,
`or flexor tenosynovitis. Thus, the lack of correlation be(cid:173)
`tween shoulder and finger limitation in the Pal studyi 6
`may be the result of inclusion of numerous patients with
`, ___ 4"1 , . , : .... : ..... 1:- :.,..,: .........
`- ·~ - ..
`Ulll'C'I IUIIII;) VI JVllll IIIIIILQ\IUII .
`Among 60 diabetic patients with painful shoulders
`seen in a rehabilitative population , 25% were found to
`have decreased working capacity, 42% had restricted hip
`joint mobility, and recovery was found to be compara(cid:173)
`ble to that of nondiabetic patients with shoulder cap(cid:173)
`sulitis. Thirty-five percent of the shoulders regained nor-
`
`TABLE 1 Poputatlon-based Studies of LJM In IDDM
`
`mal mobility, half had clinical limitation, and the rest had
`functional limitation over a median observation time of
`29 months. iODM was associated with worae prognosis,
`and nearly two-thirds of these patients had the associ(cid:173)
`ated hand syndrome.17
`
`LIMITED JOINT MOBILITY (LJMI
`Initially described as a striking limitation of the fin(cid:173)
`gers and large joints, in association with short stature,
`thick, tight, waxy skin, delayed sexual maturation, and
`early miciovascul&i complications in 3 older teenagers
`with long-standing diabetes,9 LJM was found to oc(cid:173)
`cur as a milder manifestation in 8-50% of IODM stud(cid:173)
`ied in the United States, 1a-2s Japan,30 ltaly,31 lrefand,32
`England, 15.33- 35 Mexico, 35 Ethiopia, 37 and Hungary.38
`Prevalence depends on the age of the population and
`the duration of diabetes, as well as on examination tech(cid:173)
`nique. The studies are summarized in Table 1.
`Several reports have described LJM in non-insulin-
`"'•'""""""'1!11.,;.._,.,..,
`""'---- ~--• .-.1:-1,,.. ... ♦"""'""
`~ ...
`ir1 Te
`... ,..11
`""'"
`,a=
`Ut:t,Jt:flU~IIL UIOU'C'U;;.:, a.:,,
`ff'ICill,
`Cl.:,O
`.;)U111111Qt1£.'1Ci'U
`Ill
`ble 2, with frequencies ranging from 25 to 76%, with
`the exception of a single study that involved only
`non-insulin-taking patients. 39
`Gender and race do not influence prevalence. In con(cid:173)
`trol pediatric populations, fewer than 2% had stiffness
`of the 5th fingers only (Table 1), while older popula(cid:173)
`tions may have as much as 20% invoivement, presum(cid:173)
`ably related to occupation and arthritic changes associ(cid:173)
`ated with aging (Table 2).
`Changes typically begin in the metacarpal-phalangeal
`and proximal interphalangeal joints of the 5th finger and
`extend medially. The distal interphalangeal joint may
`also be involved, as may larger joints, most commonly
`wrist and elbow, but also the ankles and the cervical
`and thoracolumbar spine. Limitation is painless, nonre-
`
`Reference
`
`Age Group
`
`Number
`
`9/t LJM
`
`18
`70
`19
`30
`20
`31
`32
`21
`17
`22
`36
`23
`34
`24
`25
`26
`37
`35
`27
`38
`28
`16
`29
`
`7-18
`6-26
`1-18
`3-~8
`1-28
`?
`5-57
`3-22
`2-16
`5-24
`15-32
`7-23
`?
`?
`6-27
`3-24
`14-62
`6-39
`11 -83
`5-18
`7-25
`18-82
`9-30
`
`229
`196
`310
`58
`309
`210
`115
`100
`112
`137
`34
`204
`215
`104
`311
`95
`110
`254
`238
`55
`375
`49
`211
`
`28
`40
`8
`30
`30
`9
`36
`32
`42
`19
`41
`21
`46
`19
`36
`40
`44
`15
`55
`44
`33
`49
`19
`
`Controls
`
`'lo LJM
`
`1
`0
`2
`
`3
`
`21
`0
`3
`1
`
`3
`2
`4
`4
`
`20
`0
`
`No.
`
`201
`124
`,,,,
`199
`'"
`
`90
`
`50
`52
`34
`90
`
`39
`300
`110
`45
`
`75
`239
`
`Location
`
`Florida
`Florida
`Chicago
`IA __ ..,
`._,,Clt,JGII
`Florida
`Italy
`Belfast
`Boston
`Nottingham
`New Jersey
`Mexico City
`Florida
`London, UK
`California
`F!cride
`New York
`Ethiopia
`Bath
`Boston
`Hungary
`California
`Newcastle
`Florida
`
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`80
`
`TABLE 2 Populatlon-baaed Studies of LJM In NIDO
`
`Referenc:e
`
`Age Group
`
`Number
`
`0/o LJM
`
`34
`58
`37
`39
`27
`59
`32
`
`?
`?
`28-79
`?
`?
`mean 55
`34-85
`
`241
`80
`190
`165
`41
`168
`60
`
`34
`45
`25
`4
`76
`47
`52
`
`Centre!:
`
`0/oLJM
`
`15
`2
`
`9
`26M/9F
`20
`
`No.
`
`47
`300
`
`45
`100
`75
`
`ROSENBLOOM
`
`Loc:atlon
`
`London, UK
`Montreal
`Ethiopia
`Italy
`Boston
`Scotland
`Newcastle
`
`sponsive to physical therapy, and nondisabling. Unrec(cid:173)
`ognized cervical spine involvement has been described
`as complicating endotrachial intubation.40
`
`Examination and Classlflcallon The original method for
`demonstrating milder LJM was to have the patient place
`the hand on a flat surface, palm down, with the fin(cid:173)
`gers fanned. The examiner would then determine con(cid:173)
`tact with the plane surface by viewing at table level. The
`normal hand makes contact with the entire palmar sur(cid:173)
`face of the fingers.41 A somewhat simpler initial exami(cid:173)
`nation technique has been to have the patient attempt to
`approximate the palmar surfaces of the intraphalangeal
`joints in a praying position; w!th the fingers fanned
`and the wrists maximally flexed (Figure 1). Regardless
`of findings, the examiner should extend the proximal
`and distal interphalangeal and metacarpal-phalangeal
`joints. These should extend 180° and 60° respectively,
`but there may be resistance to the permitted movement.
`In the absence of definite limitation, this can only be re(cid:173)
`ported as suspicious. Thickening of the tissue surround(cid:173)
`ing the limited joints and inability to tent the skin may
`
`FIG. 1 Normal approximation of pa/mar surfaces of finger
`joints of 20-year-old with diabetes of 9 years duration (A); lim(cid:173)
`ited ability to fully approximate the pa/mar surfaces of the finger
`joints because of stiffness of all proximal and distal interpha(cid:173)
`langeal joints in 16-year-old with diabetes for 11 years (B); se(cid:173)
`vere limitation in 26-year-otd with 24 year history of diabetes
`(C). (Reproduced with permission.•3 )
`
`also be noted, particularly over the dorsa of the fingers
`and metacarpals. Maximal passive extension of the wrist
`should be at least 70° and of the elbow at least 180°.
`Cervical spine lateral flexion should permit ear to shoul(cid:173)
`der, and thoracolumbar spine lateral flexion should be
`at least 35° in young patients.41
`This examination will reveal obvious limited joint mo(cid:173)
`bility but, as noted, the clinical sensation of joint limita(cid:173)
`tion without absolute reduction in maximum extension
`is highly subjective. Buithieu and associates29 compared
`metacarpal-phalangeal (MCP) and wrist maximal exten(cid:173)
`sion in 239 controls and 211 I DDM aged 9-30 years, and
`found a significant proportion of those without clinical
`L,JM by the above examination to have MCP and wrist
`limitation, defined as less than 2 standard deviations of
`the control mean. Those without LJM (n = 172) included
`25% with MCP limitation and 13% with wrist limitation.
`Thus, earlier detection of LJM may be possible through
`objective measurement.
`The staging of LJM has been useful in describing
`relationships of other findings to LJM and for patient
`follow-up. "No limitation" includes equivocal or unilat(cid:173)
`eral findings . "Mild LJM" indicates involvement of one
`or two proximal interphalangeal (PIP) joints, one large
`joint, or only the MCP joints bilaterally. "Moderate limi(cid:173)
`tation" refers to involvement of three or more PIP joints,
`or one finger joint and one large joint bilaterally. "Se(cid:173)
`vere LJM" refers to obvious hand deformity at rest or
`associated cervical spine involvement.20
`The term "juvenile diabetic cheiroarthropathy" was
`applied to 11 patients with severe LJM reported by
`Benedetti and Noacco42 in 1976. This terminology is in(cid:173)
`adequate in view of the involvement of large joints, in
`addition to the hand, and the implication that the joint
`itself is involved, which is not the case; radiographs of
`the joints fail to reveal any intrinsic abnormality, only the
`periarticular thickening.
`
`Natural History Duration of diabetes is the most impor(cid:173)
`tant variable in the expression of LJM in cross-sectional
`studies. This is important because it has led to the con(cid:173)
`clusion that the association with long-term complica(cid:173)
`tions is simply that both are related to duration. 26 How(cid:173)
`ever, when the time of development of joint changes can
`be estimated, attained age is more important than dura(cid:173)
`tion of diabetes.43 In a group of 76 patients with age of
`onset varying from infancy to adolescence, development
`of LJM occurred between ages 10 and 20 years in over
`
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`JOINT MOBILITY IN DIABETES
`
`81
`
`90%. Of 15 patients with onset of diabetes at under 4
`years of age, none developed LJM before 11 years; this
`was indistinguishable from children with later onset dia(cid:173)
`betes. When the population was evenly divided between
`those with onset under and those with onset over 7 years
`of age, there was a 2.5 year difference in the mean age
`of LJM onset despite a 6.3 year difference in the mean
`age of onset of diabetes.
`The interval between detection of mild LJM and pro(cid:173)
`gression to moderate or severe changes varies from 3
`months to 4 years, with a mean of 2 years. Following
`this period, progression , if any, appeared to be very slow.
`Many do not progress beyond the mild changes. In adult
`populations. two-th irds of affected patients will have at
`least 2 fingers involved.32,34 One-half of young patients
`with greater than 5 years duration of diabetes who have
`LJM will have moderate or severe changes, and approx(cid:173)
`imately one-third of the affected group will have severe
`limitation.20
`
`Relationship to Diabetes Control Among the controlled stud(cid:173)
`ies. no relationship of LJM to metabolic control of di(cid:173)
`abetes has been demonstrated, using either glycosy(cid:173)
`lated hemoglobin levels or clinical criteria. However,
`longitudinal data from the time of diabetes onset have
`not been studied in relationsh ip to the development
`of LJM . The more severely affected patients have had
`hepatomegaly. 31 ·4 1
`
`Effects on Growth Growth failure and delayed sexual mat(cid:173)
`uration were striking features in the initial patients de(cid:173)
`scri bed with severe LJM .9 ,42 Subsequent study in a larger
`population confirmed the association of severe LJM with
`growth limitation, but this was not seen with mild LJM. 41
`In individuals who had greater than 3 years duration
`
`O < 25 Per centile
`~ 25 - 50
`bill 50-75
`■ > 75
`
`100
`
`C 80
`0
`~ ,.
`Q. 60
`0
`Cl..
`.....
`0
`c 40
`.,
`~ .,
`
`Cl..
`
`2 0
`
`None
`68
`
`Mi ld
`31
`
`Moder ate/Severe
`19/24
`
`FIG. 2 Distribution of height percentiles in 142 children with
`diabetes onset before puberty and of 3 or more years dura(cid:173)
`tion according to severity of LJM. Reference data is from the
`National Center for Health Statistics growth charts; distribu(cid:173)
`tion should be equal for each of the bars. ( Reproduced with
`permission. •3)
`
`of diabetes and onset preceding adolescence, thereby
`permitting sufficient time for growth failure to occur, all
`stages of LJM were seen to be associated with growth
`impairment. 43 Of 142 youngsters studied, 31 had mild
`LJM and 43 more severe changes. Without LJM, 68%
`were below the 50th percentile, rather than the expected
`50%, and most of this discrepancy was in the group be(cid:173)
`low the 25th percentile (38% versus the expected 25%).
`Mild LJM resulted in four times the excess below the
`25th percentile (72%) and moderate to severe limitation
`did not significantly worsen this picture (Figure 2). It
`is interesting that the small proportion above the 75th
`percentile was similar without, with mild, or with severe
`LJM .
`
`Differential Diagnosis The characteristic features of LJM,
`particularly as it appears in the young patient, should re(cid:173)
`su It in little or no diagnostic confusion. There is no other
`condition that results in painless, non-inflammatory lim(cid:173)
`itation of the hand and larger joints in young persons.
`Rheumatoid arthritis (RA) is not more frequent in dia(cid:173)
`betes, and patients with LJM do not meet the pain or
`inflammatory criteria for RA 41 LJM is easily distinguish(cid:173)
`able from DD, the only other condition associated with
`diabetes and involving the hand that is not associated
`with pain , by the absence of palmar fascial thickening
`and nodules, as well as by the fingers involved. DD is
`not seen in young patients. In older patients, DD and
`LJM may be seen together. All the other conditions af(cid:173)
`fecting the hand in diabetes are associated with pain and
`other characteristic findings, as noted in Table 3. Despite
`the ease of differential diagnosis, some have lumped to(cid:173)
`gether these various conditions as LJM , or considered
`them to be varying manifestations of the same process,
`which could be true only in such a broad sense as to be
`meaningless.
`There have been a number of examples of diagnos(cid:173)
`tic confusion in the literature. A recent textbook of di(cid:173)
`abetes describes only LJM in a section entitled "Stiff
`Hand Syndrome."44 The report of LJM preceding the de(cid:173)
`velopment of diabetes by 3 years in a teenage patient45
`suggested an important constitutional component to re(cid:173)
`cent reviewers of connective tissue complications of
`diabetes.13 However, the patient described had devel(cid:173)
`oped stiffness in the MCP and PIP joints and wrists
`more or less simultaneously, had thickening and con(cid:173)
`traction of flexor tendons in the palm , and experienced
`progressive disability. Robertson and others4B described
`a patient in her late 20s with characteristic features of
`flexor tenosynovitis, but she was reported as having
`"juvenile diabetic cheiroarthropathy." Three patients re(cid:173)
`ported as having LJM appeared to have the carpal tun(cid:173)
`nel syndrome (diabetic hand syndrome), with additional
`features of shoulder-hand syndrome in one and flexor
`tenosynovitis in another.47
`Superimposition of other hand syndromes on LJM as
`patients age would not be surprising .17 Under these cir(cid:173)
`cumstances, the original LJM problem may be difficult
`to distinguish, but the presence of pain or paresthesias,
`neurologic find ings, disability, finger locking, swelling,
`muscle atrophy, palmar skin or fascial thickening, or ab(cid:173)
`sence of greater involvement of the 4th or 5th fingers,
`
`Sanofi Exhibit 2134.005
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`IPR2018-01675
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`

`

`82
`
`TABLE 3 Olfferentlal Diagnosis of Joint Syndrome, Involving the Hand In Diabetes
`----· . ····-·-
`....... s-, .......
`Involved
`
`Pe!n/
`Parfftheala
`
`Muscle
`
`Frequency
`
`Condition
`
`ROSENBLOOM
`
`Other D!t!!nct!ve
`Featurea
`
`LJM
`
`Dupuytren disease
`
`Begins fifth,
`extends radially
`3rd, 4th
`
`Flexor
`tenosynovitis
`
`Carpal tunnel
`(diabetic hand)
`
`Stiff hand
`
`Shoulder- hand
`(reflex dystrophy)
`
`1st, 3rd, 4th
`
`All
`
`All
`
`All
`
`No
`
`No
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Normal
`
`Normal
`
`Normal
`
`Intrinsic,
`palmar atrophy
`
`Normal
`
`Atrophy
`
`50+% of !DOM after 5
`yrs and puberty
`Up to 40% over age 40
`yrs; 16% at diagnosis
`
`33% assoc. with
`diabetes
`
`5-16% are due to
`diabetes
`Rare; IDDM > 20 yrs
`
`Not disabling; assoc.
`thick, tight, waxy skin
`Milder expression com-
`man in women; may
`precede diabetes
`Marked predominance
`in women: locking.
`disability
`Ulnar as well as median
`nerve involvement in
`diabetes
`Disability: calcified
`vessels; hard palmar
`skin, soft dorsal
`Shoulder limitation 20% Most bilateral; often
`older IDDM, NIDOM;
`assoc. with other
`reflex dystrophy
`hand syndromes
`unusual
`
`should be apparent indicators that other or additional
`problems are present. It is likely that people affected
`with LJM would be at higher risk for the development of
`other connective tissue proliferative problems, and pos(cid:173)
`sibly neuropathy.27
`llA11............
`'"'--·-----' ---··- ___ .., ___ ... : ___ __ , __ : .... . ~--.LL. -
`n UIUll\:ICU 111:::1 VC l.iUIIUUl.illUII VCIVl.illY IVI lllt:
`IIUUI UIIGlllJ
`ulnar and median nerves has been described in older
`patients with LJM, in comparison to those without LJM
`who had comparable durations of diabetes.48 Also noted
`was decreased vibratory sense in both upper and lower
`extremities in the presence of LJM. Studies of 361 Joslin
`patients, aged 11-83 years, demonstrated a modest but
`significantly greater frequency of symptomatic neuropa(cid:173)
`thy in those under the age of 40 with LJM; this associa(cid:173)
`tion was not significantly different with or without LJM
`in older age groups.27
`
`Cardiac Funcllon Postexercise echocardiography in a
`group of 25 otherwise healthy adolescents with IDDM
`revealed abnormalities in systolic function indicative of
`subciinical cardiomyopathy. Among the 12 patients who
`had LJM, 5 had flat interventricular septa! motion; no
`other patients had this abnormality and 1 of the 26 con(cid:173)
`trn,~ nin .49
`
`Pulmonary Changes The initial suggestion of diminished
`pulmonary capacity in diabetes was a report of 11 young
`men with IDDM who had decreased elastic recoil at
`low lung volumes and decreased pulmonary capacity.so
`Barta51 subsequently described a single patient with
`LJM and limited pulmonary capacity. This association
`was systematically studied in 12 adolescents and young
`adults with severe LJM who had significantly less to(cid:173)
`tal lung capacity, thoracic gas volume, residual volume,
`forced vital capacity, and forced expiratory volume than
`controls matched for age, gender. height, and duration
`of diabetes who did not have LJM.52
`
`Fibrous Disease of the Breast Breast lumps were found in
`12/88 women with IDDM, aged 20-40 years, and 11 of
`
`these 12 women had LJM. Diabetes duration was 8-30
`years and all but one had retinopathy. 53 Although this
`might be a significant association, no data were provided
`in this report about the prevalence of LJM in the women
`without breast lumps, and the prevalence of breast lumps
`in the entire diabetes population was similar to that in
`IIUl)Uli1Ut:11\,; ~U~Uli1IIVll;:i . ,,.u ;:iUU;:ili1lllli1llUII ur lllt:;:it: u11-
`controlled observations has been forthcoming.
`
`._I_ - .. L-.6.- -
`
`.1. ! -.1.: __ -6. .LL-- - · · -
`
`- - -..J!- L -
`
`.a.!_ - - - -- 1-.a.!---
`
`Skin Changes Thick, tight, waxy skin, most prominent
`over the dorsum of the hand and the forearm, was de(cid:173)
`scribed in the initial patients9 and in one-third of those
`with LJM described later, and only in those with mod(cid:173)
`erate to severe LJM.20-41 When ascertainment is on the
`basis of skin changes, determined by resistance to tent(cid:173)
`ing, skin change has been found to be more frequent
`than LJM, but with LJM present only in those who had
`skin changes; 47 of 137 patients had skin change, among
`whom 26 also had LJM. 22 A further report reinforces the
`impression of skin changes being more frequent than
`LJM when more careful examination is done. Bucking(cid:173)
`ham and associates28 found skin changes in 34% of pa(cid:173)
`tients without LJM, 70% with mild LJM, and 100% with
`severe LJM. These impressions were further reinforced
`hy 11ltr~<>n11nn c,t11ni>P~ nf Q? tnnM ~g"'n ?n-'.<R Y""~r~ with
`a wide range of diabetes duration. Those with LJM had
`thicker skin than those without LJM, who in turn had
`thicker skin than those without diabetes. 54 Correlation
`of LJM with ultrasound measurement of skin thickness
`was also described in 80 measurements in a younger
`population by Lieberman and others. 55
`Biopsy study of the skin has shown thickening of
`the dermis and epidermis, with accumulation of colla(cid:173)
`gen and loss of skin appendages, compared to control
`biopsies.24-41 The pathologic features have been more
`carefully defined by Hannah and colleagues.56 Clinical
`evidence of skin thickening was described in 22% of
`IDDM and 4% of controls. Full thickness skin biopsy
`specimens from the forearm were compared from 9 pa(cid:173)
`tients with IDDM and thick skin, 4 patients with IDDM
`and clinically normal skin. 4 patients with progressive
`
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`

`

`JOINT MOBILITY IN DIABETES
`
`83
`
`systemic sclerosis, and 4 nondiabetic controls. Distinct
`differences from scleroderma and normal skin were
`noted in the iDDM. Those with thick skin showed ac(cid:173)
`tive fibroblasts and extensive collagen polymerization in
`the rough endoplasmic reticulum. In contrast to sclero(cid:173)
`derma, in which there is a bimodality of collagen fiber
`sizes, the thick skin of diabetes demonstrated a predom(cid:173)
`inance of large collagen fibers; this was also present in
`those with diabetes who did not have clinically thick skin .
`Thus, as suggested in some of the clinical studies, skin
`changes may be present in the absence of obviously ab(cid:173)
`normal skin, and certainly in the absence of clinical LJtv1.
`
`Association with Microvascular Disease (Nephropalhy. Retlnopa(cid:173)
`thy) Among the initial 7 patients with severe LJM, 5 had
`clinically apparent retinopathy or proteinuria before age
`18. 41 We subsequently studied our clinic population with
`diabetes duration >4.5 years. which was the shortest du(cid:173)
`ration at which microvascular complications had been
`noted, and found that 82 of 169 had LJM. Exactly 50%
`of this population with LJ~.,1 had microvascular compli(cid:173)
`cations, in contrast to only 10 of the 87 without LJM.
`Severity of LJM correlated directly with the frequency
`and severity of the microvascular disease (figure 3).
`Life table analysi