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Musculoskeletal hand involvement in systemic sclerosis
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Musculoskeletal hand involvement in systemic sclerosis Robert David Sandler , Marco Matucci-Cerinic , Michael Hughes PII: DOI: Reference:
S0049-0172(19)30683-3 https://doi.org/10.1016/j.semarthrit.2019.11.003 YSARH 51559
To appear in:
Seminars in Arthritis & Rheumatism
Please cite this article as: Robert David Sandler , Marco Matucci-Cerinic , Michael Hughes , Musculoskeletal hand involvement in systemic sclerosis, Seminars in Arthritis & Rheumatism (2019), doi: https://doi.org/10.1016/j.semarthrit.2019.11.003
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Musculoskeletal hand involvement in systemic sclerosis
Robert David Sandler1, Marco Matucci-Cerinic2, Michael Hughes3
1. Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom. 2. Department of Experimental and Clinical Medicine, University of Florence, and Divisions of Internal Medicine and Rheumatology AOUC, Florence, Italy.
Corresponding author: Dr Michael Hughes BSc (Hons) MSc MBBS MRCP (UK) (Rheumatology) PhD ORCID ID: 0000-0003-3361-4909 Consultant Rheumatologist Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom. [email protected] Telephone: +44 (0)114 271 1900
Short title: MSK hand involvement in SSc
Key words: Systemic Sclerosis; Scleroderma; Musculoskeletal; Hand;
Word count = 3539
Abstract (n=169/250) Musculoskeletal (MSK) involvement of the hands is a significant source of morbidity, impacting on quality of life in patients with systemic sclerosis (SSc). MSK complications are common in SSc and can affect the whole of the MSK system. MSK hand involvement can occur early in the course of the disease. A wide range of articular involvement is recognised including from arthralgia to inflammatory joint and tendon disease. Mechanistic insights have been made into enthesitis, hand contractures and tendon friction rubs and could inform the development inform novel treatment approaches to MSK involvement in SSc. Bony involvement can include osteomyelitis from digital ulceration. Other important manifestations include (but are not limited to) calcinosis, acro-osteolysis and carpal tunnel syndrome.
MSK imaging is an important tool that allows insight into both disease
pathogenesis and to inform the clinical management of MSK complications. The purpose of this review is to provide an overview of the MSK hand complications in patients with SSc, highlighting the breadth and burden of pathology relevant to clinical practice.
Introduction Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterised by widespread tissue and internal organ fibrosis, immune system activation, and vasculopathy [1]. Musculoskeletal (MSK) hand involvement is common in patients with SSc and is associated with significant disability and reduced quality of life. There is a wide range of potential MSK hand complications [2,3], which can occur in patients with SSc (Table 1). For example, joint involvement can range from marked arthralgia to frank synovitis akin to rheumatoid arthritis (RA). The purpose of this review is to provide an overview of the MSK hand complications in SSc, highlighting the breadth and burden of pathology. Other important causes of MSK disability (beyond the scope of this review) include skin sclerosis, digital vascular disease (e.g. Raynaud’s phenomenon or digital ulcers) and inflammatory muscle disease/myositis (as this tends to affect the proximal MSK structures). Furthermore, we will not discuss the management/treatment of MSK complications, and therefore the
reader is directed toward recent review articles [3–5] including SSc-treatment guidelines [6,7] on this topic.
Review strategy The breadth of this comprehensive review was not amenable to a formal systematic literature review owing to the need to identify and appraise a broad range of sources including cross-sectional studies, registry analyses and clinical trials. The following standardised search criteria were applied within the National Institutes of Health's National Library of Medicine (PubMed) to facilitate the identification of relevant manuscripts (1065 citations on 4th May 2019):
((musculoskeletal) OR (arthritis) AND ((systemic sclerosis) OR (Scleroderma)) AND ((articular) OR (tendon) OR (calcinosis) OR (radiography) OR (ultrasound) OR (magnetic resonance imaging))
The titles and abstracts of journal articles identified from this search formed the mainstay of identifying relevant work, alongside grey searches of manuscripts cited within these articles. Separate searches were run for relevant literature related to acro-osteolysis, calcinosis and carpal tunnel syndrome. In general, we have focussed on recent publications within the past 5 years and important legacy papers.
Articular involvement Different patterns of joint involvement have been described in patients with SSc, although this still remains the subject of debate. Arthralgia is very common in patients with SSc throughout their disease and has been reported in between to occur in 38% to 97% of patients with SSc [8–10]. Joint symptoms can occur before or at the time of onset of the disease. In the study by Baron et al [9], which included 38 patients with progressive SSc, two-thirds (66%) of patients reported a history of joint pain during the course of their disease, and around half (55%) had symptoms at the time of evaluation. In a 12-month prospective study which included 76 patients with SSc, arthralgias were present in 38% of patients, and were more common in those with limited cutaneous SSc (lcSSc) compared to diffuse cutaneous SSc (dcSSc) (43.5% & 22.7%, respectively) [11].
Joint disease can be the first presentation of a SSc-spectrum disorder. In the study by Baron et al [9], the onset of joint symptoms preceded the diagnosis of SSc by 1 year in 20%, occurred during the first year of diagnosis in a third (32%), and developed after the diagnosis in half (50%). Joint pain was considered to be of either a moderate or significant severity in half (52%) of patients [9]. In a survey which included responses from 464 patients with SSc who responded to the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities, joint pain was considered the 4th most highest (out of 69) rated symptom in terms of frequency and moderate to severe impact on the activities of daily living (81% & 64%, respectively) [12].
Synovitis/arthritis and tenosynovitis The prevalence of inflammatory joint (synovitis) and tendon disease (tenosynovitis) in patients with SSc has varied widely in the reported literature. Possible reasons for such differences include (but are not limited to) the method/s of case ascertainment (including the definition of articular involvement) and discordance between the ability of clinical examination and MSK imaging techniques to detect inflammatory joint and tendon disease.
In a prospective, cross-sectional study of 120 patients with SSc, arthritis was found in one fifth (18%) of patients and was defined by concomitant erosion and joint space narrowing [13]. Whereas, in the previously described study by La Montagna et al [11], ‘clinical’ arthritis was found in 13.1% of patients. In their study, articular involvement was assessed by measuring the minimal distance between the middle finger bilaterally and the transverse palmar crease [11]. Similarly, in a study which included 41 unselected patients with SSc, only 3 patients had evidence of a SSc-RA overlap clinical picture [14]. Another key aspect relates to study design. Many previous studies have adopted a prospective, cross-sectional approach, whereas, others have examined an enriched cohort of those patients at ‘risk’ of arthritis (e.g. in the presence of inflammatory joint pain). For example, in a cross-sectional study which examined 300 consecutive patients with a current or past history of articular symptoms, clinical synovitis was found in the majority (88%) of patients [15].
In a recent meta-analysis, the probability (95% CI) for clinically manifest arthritis (5 studies) was 23% (0.149 - 0.309] and radiologically detectable arthritis (5 studies) in SSc was 26% (0.167 – 0.361) [16]. However, the authors highlight that funnel plot analysis revealed that smaller studies tended to observe larger effects [16].
Important insights can be learned from large registry data. For example, in an analysis from the German Network for Systemic Scleroderma which included 1483 patients, MSK involvement (defined as articular involvement as synovitis with swelling, with or without tenderness to palpation, in one or more joints) was found in half (47.5%) of patients [17]. Whereas, in an analysis from the European Scleroderma Trials and Research Group (EUSTAR) database which included 7286 patients with SSc, the frequency of synovitis was 15% [18].
MSK imaging can play an important role in identifying articular pathologies in patients with SSc, including in the absence of clinical signs of arthritis. In a cross-sectional observational study, which included 52 patients with SSc, synovitis and tenosynovitis was significantly underestimated by clinical examination (15% vs 6%, respectively) compared to US (46% and 27% of patients, respectively) [19]. Similarly, in a study which included 45 patients with SSc, the prevalence (n) of synovitis by US (i.e. effusion and/or synovial proliferation) was significantly higher compared than clinically involved alone (58% vs 33%) [20]. Whereas, in a prospective study which included 46 patients with SSc and 15 healthy controls, synovial hypertrophy was seen in half in 3% of hand joints and in in 46% wrist joints (and not in controls) [21]. MRI appears to be more sensitive compared to US at detecting inflammatory joint and tendon disease [22,23]. For example, Chitale et al [22] investigated US and MRI in 17 SSc patients with arthralgia and no overt inflammatory arthritis. Baseline US was performed in 13 unselected patients and 6 months later, and with an additional MRI scan (with gadolinium contrast) of the most symptomatic hand in 8 patients. At baseline and 6 months, synovitis was seen in 46% and 47% of patients, respectively, and tenosynovitis was seen in 6% and 23%. In addition, synovitis was observed in 100% and tenosynovitis in 88% of those patients who underwent MRI. In the study by Allanore et al [24] which utilised magnetic resonance arteriography to study hand vascular involvement in SSc (n=38), 50% had at least one site of synovitis, and 11% at least one site of tenosynovitis. Similarly, in a
study which included 17 patients with SSc, around half (59%) of patients had inflammatory hand findings on MRI including synovitis (n=8) and tenosynovitis (n=8) [25]. Other imaging techniques which have been examined to assess articular involvement in SSc include (but are not limited to) thermography, radioisotope bone and PET FDG imaging [15,26].
Patterns of joint involvement in SSc A key question is whether joint involvement is a SSc-disease-related manifestation (e.g. ‘SScarthropathy’),
an
overlap
(e.g.
RA)
or
the
coexistence/concomitant
unrelated
rheumatological condition (e.g. osteoarthritis ((OA)). Polyarticular and other patterns of joint involvement have been described. In the study by Baron et al [9], the most common pattern of joint distribution was symmetrical and polyarticular (61%), followed by oligoarticular (22%) and monoarticular (17%). In their study, there was a fairly similar proportion between an acute (40%) and insidious (60%) onset. Almost half (44%) had an intermittent course, 16% had a ‘chronic remittent course (persistent symptoms but having periods of distinct remissions), 36% had a slowly progressive course, and 4% had a rapidly progressive course.
Synovitis/RA-like arthritis has been described and typically affects (but is not limited to) the small joints of the hands (MCPJs and PIPJs) as well as the wrists [9,19,27] as well as the MTPJs, knees and shoulders [9]. Involvement of the distal interphalangeal joints can resemble erosive osteoarthritis (e.g. showing central erosions and collapse of the subchondral
bone
plate)
[3],
and
can
also
resemble
psoriatic
arthritis.
Degenerative/osteoarthritic features (discussed later) are common including joint space narrowing including of the carpometacarpal joints [3]. As could be expected, US is more sensitive than plain radiography to detect features of osteoarthritis (e.g. osteophytes) [28].
La Montagna [11] proposed three radiological patterns for the hands and feet:
Inflammatory joint pattern - occurrence of juxta-articular osteoporosis, space narrowing of the PIP and/or carpal joints, and/or erosive changes, either with or without digital flexion.
Degenerative joint pattern – occurrence of space narrowing of the PIPJs and or DIPJs, and/or tarsal joints, subchondral sclerosis and/or osteophytes.
Periarticular fibrotic pattern - occurrence of digital flexion, space narrowing, particularly of the DIP joints, with or without subchondral sclerosis.
In their study, the fibrotic pattern was the most common in the hands (inflammatory and degenerative patterns both 13.1%). whereas, in the feet the degenerative pattern was commonest (inflammatory and fibrotic = 6.6% and 7.9%, respectively) [11]. This was subsequently modified by Erre et al [14] to include a ‘normal/minimal changes pattern’ which was defined as the ‘absence of radiographic changes or occurrence of minimal radiographic abnormalities (i.e. isolated narrowing of a distal interphalangeal joint space)’. Likewise, in a study which included 41 unselected Sardinian patients with SSc, the periarticular pattern (on plain radiographs) was the most frequently observed (normal/minimal = 19.5%, inflammatory pattern = 19.5% and degenerative pattern (22.0%) [14].
Clinical associations with arthritis Disease subset is an important predictor of arthritis. For example, in the study from the German Network for Systemic Scleroderma, MSK involvement (which was defined as articular involvement as synovitis with swelling, with or without tenderness to palpation, in one or more joints) was found in around half (47.5%) of patients, in particular, in patients with SSc overlap (67.6%) and dcSSc compared to lcSSc (56.6% & 44.9%) [17]. In the previously described meta-analysis, no significant difference was observed in either radiographic or detectable peripheral arthritis between lcSSc and dcSSc [16]. Several studies have demonstrated an associated between the presence of arthritis and C-reactive peptide (CRP) [13,14,19,27], in particular, when it is greater than 10 mg/L [13,19]. Furthermore, Cuomo et al [28] reported than US-detected synovitis was only related to the level of the CRP. In general, synovial fluid analysis reveals evidence of a modest inflammatory (predominantly mononuclear) cell infiltrate (<1000mm3) [29]. In the US study by Elhai et al [19], shorter disease duration (<3 years) was associated with more synovitis and higher grade, however, this did not reach statistical significance (which the authors postulated was potentially due to the small numbers included in their study). Rheumatoid factor positivity can occur in approximately 30% of patients with SSc including in patients with secondary Sjogren’s syndrome [10]. In general, data from the literature supports that anti-CCP
antibodies but not rheumatoid factor can potentially help to distinguish between patients with SSc and the presence of arthritis (RA-like) including erosive disease [30–33] .
Joint effusions and erosions Joint effusions are common and have been observed in around half of patients with SSc as assessed by US (~50%) [20][21] and MRI (~40%) [25]. Cuomo et al [20] found no difference in the presence of joint effusion (as assessed by US) between patients with SSc and RA (49% vs 53%).
Joint erosions have been reported to occur in approximately 5 to 40% of patients with SSc [9] [11][13][24], and is often progressive [34]. The wide variation in reported erosive disease is likely to be largely driven by the ability of the imaging technique to detect erosions. For example, in the study by Low et al [18], of 7 patients with evidence of MRI erosions, only 2 had radiographic erosions. This could account for the relatively low prevalence of erosions in both the hands and the feet (4% & 1%, respectively) as reported in the study by La Montagana [11], which used plain radiography only. There are conflicting data about the relationship between rheumatoid antibodies and erosive disease in SSc. In general, rheumatoid factor does not appear to be associated with erosive disease [9,34]. However, as previously described, several authors have reported that anti- cyclic citrullinated peptide (CCP) antibodies are predictive of erosive disease. Whereas, Avouac et al [34] did not find any association between rheumatoid antibody status including anti-CCP2 antibodies and the development of new erosions. However, In a recent prospective cohort study from New Zealand which included 132 patients with SSc, double antibody positivity (rheumatoid factor and anti-CCP) was significantly associated with arthralgias and erosions, including anti-CCP antibodies and erosions alone [33]. Disease duration, elevated acute phase reactants, antinuclear antibody, the extent of scleroderma skin changes or distal tuft resorption have all been reported not to be associated with erosive disease [9,34].
Enthesitis Enthesitis and involvement of the synovial-entheseal complex has been reported in SSc. In an ultrasound pilot study, which included 100 patients with SSc and 25 healthy subjects, enthesitis (including as assessed by the Glasgow Ultrasound Enthesis Scoring System) was
significantly greater in SSc, including greater inflammatory signal and the presence of calcification and enthesophytes [35]. Common extensor tendon enthesitis was correlated with synovial-entheseal complex inflammation, which could suggest that entheseal inflammation in SSc could share the same micro-anatomical targets as spondylarthritis [35].
Hand contractures Hand (finger) flexion contractures are an important cause of disability and have been reported to occur in in approximately one quarter to one third of patients with SSc [13][17][18]. Contractures are often progressive. For example, in the study by Avouac et al [34], over a median study interval of 5 years, radiographic progression of contractures was observed in around a fifth (17%) of patients. A higher prevalence of finger flexion contractures has been reported in patients with dcSSc compared to lcSSc [11][13][17][18]. In a study from the German Network for Systemic Scleroderma, joint contractures were identified in around a quarter (26.1%) of patients, and was higher in patients with dcSSc compared to lcSSc (39.7% & 22.6%, respectively) [17]. Other reported associations have included (but are not limited to) the level of anti-topoisomerase-1 antibodies (MCPJ and PIPJ finger contractures) [36], high functional impairment (as assessed by the HAQ) [13], the radiological ‘fibrotic’ pattern [11], and internal organ involvement (e.g. ILD and oesophagus) [14]. Thickening of the A1 pulley has been described in patients with SSc [37,38], and correlates with hand disability [37]. Local/mechanical factors (e.g. soft tissue calcification) may have an important role in the development of finger contractures in SSc.
Tendon involvement Inflammatory tendon disease (tenosynovitis) has been previously described. Compared to patients with RA, tendon involvement is less inflammatory and more fibrotic (sclerosing tenosynovitis) [19]. US tenosynovitis often (~50%) occurs with concomitant synovitis [19]. There appears to be a predilection for involvement of the extensor compared to the flexor tendons [19]. In a ultrasound study which included 33 patients with SSc, ‘sclerosing’ tenosynovitis was defined ‘was defined as an iso- or hyperechoic hypertrophy of the tendon sheath with concentric alternating iso- and/or hyperechoic layers on transverse view’ was more common in patients with diffuse SSc and anti-RNA polymerase III antibody positive [27].
Tendon friction rubs Tendon friction rubs (TFR)s are characterised by a palpable leathery crepitus on palpation of the joints [3,10]. TFRs have been described to be ‘related to fibrinous deposits on the surface of tendon sheaths and overlying fascia’ [10]. TFRs may occur in approximately 10% of patients with SSc [17][18], and are more common in patients with dcSSc [17]. Common sites for TLRs include the hands and wrists, ankles, knees and elbows [10,39], and can occur at multiple sites [39]. TFRs often occur early in the course of the disease. It has been observed that TFRs are common in Caucasians [39]. TFRs are associated with a more severe disease course, in particular, in patients with early dcSSc [18,40]. Change in TFRs (i.e. worsening/improvement) are predictive of changes in skin disease and functional impairment [39]. Elhai et al [19] reported that TFRs were only observed in those patients with evidence of US tenosynovitis [19]. Tendon rupture is a rare potential complication. Rosenbaum [19] reported complete rupture of the wrist extensor tendon mechanism. Histopathology demonstrated mild chronic synovitis and fibrin deposits on the surface of the synovium. There was non-specific degradation of the tendons with fibrous tissue proliferation and replacement with granulation-like fibroblastic tissue. Stoenoiu et al [41] postulated that TFRs may originate through deep connective tissue infiltrates surrounding tendons which impairs the smooth gliding during active motion, as opposed to fibrinous deposits on the surface of the tendons or tendon sheaths.
Osteomyelitis Digital ulcers (DUs) are common in patients with SSc and can be complicated by osteomyelitis [42], in particular, if there is infection of the DU [43]. Osteomyelitis may be detected at an earlier stage by MRI compared to plain radiography [44].
Acro-osteolysis Acro-osteolysis involves shortening of the phalanges due to bone resorption. It occurs most commonly in the hands but can also affect the feet. Estimates of prevalence in SSc ranges between 20 to 40% [9,11,13,14,45], although in one study it was identified as high as 70% [46]. The aetiopathogenesis of A-O is incompletely understood; however, hypoxia [47] is considered to play a major role, which can promote osteoclastogenesis [48]. A-O is
associated with the severity of digital vascular manifestations, such as digital ischaemia/ulceration
and
calcinosis
[49].
Vitamin
D
deficiency
and
secondary
hyperparathyroidism has been reported to be associated with acro-osteolysis [46]. It has been postulated that low levels of vitamin D may represent silent malabsorption and could be a risk factor for secondary hyperparathyroidism and bone resorption [46].
Calcinosis Calcinosis is seen in up to 20% to 40% of patients with SSc [13,50–54]. Calcinosis is more common in the limited cutaneous subset with positive anti-centromere antibodies [14,53,55,56]. However, in one prospective study of 120 patients with SSc, calcinosis occurred with equal frequency in both lcSSc and dcSSc [13]. Calcinosis affects the hands most commonly, with a specific preference for the thumb [57]. Calcinosis is associated with erosion, telangiectases, nailfold capillary abnormalities and digital ulceration [9,13]. Calcinosis is often subclinical and can be assessed by different imaging techniques. CT (including multi-detector) and MRI have been used to objectively assess calcinosis. In a recent study which included 15 patients with SSc, calcinosis could be successfully measured and with comparable results (e.g. number and area/volume of calcinotic lesions) by plain radiography, CT and MRI [58]. Calcinosis needs to be carefully monitored as it can become infected [59] and/or ulcerate [60]. A classification system for patients with calcinosis and SSc has been proposed, taking into account clinical and radiographic features [60]. These include classifying calcinosis as “visible and palpable” or “non-visible and palpable” with further sub-classification of the “visible and palpable” subset following palpation and radiography as “mousse” (soft consistency, with white cream-like material), net (diffuse thin network), plate (large, uniform and flat agglomerate) or stone (single stone or multiple hard agglomerates) [60]. The majority of fingertip calcinoses were mousse or stone and seemed to be less painful than those occurring around the knees or elbows.
Peripheral nervous system Although carpal tunnel syndrome (CTS) is the most recognised peripheral nervous system involvement in SSc, other forms are recognised including ulnar nerve entrapment [61,62].
Carpal Tunnel Syndrome
CTS or median neuropathy at the wrist (MNW) is an important potentially early or even presenting feature of SSc [63]. However, this may be an underestimate of true prevalence as US and electrophysiological evidence of MNW has been demonstrated in up to 88% of patients with SSc and with no clinical features of CTS [64,65]. Possible aetiology for MNW in SSc includes a reduction in median nerve elasticity and density [66,67]. Chronic ischaemia from progressive microangiopathy leading to axonal loss has also been postulated to be implicated in peripheral nerve dysfunction in SSc [68]. In addition, in patients with SScRaynaud’s
phenomenon
(compared
to
primary
Raynaud’s
phenomenon)
the
neuroanatomical lesion is postulated to include both the median and ulnar nerves (suggesting a possible polyneuropathy) compared to only at the level of the carpal tunnel [69].
Conclusion The MSK effects of SSc on the hand are wide-ranging and a significant cause of morbidity. An awareness of the heterogeneous nature of hand involvement in patients with SSc, including inflammatory joint/tendon disease with associated arthropathy, calcinosis, bone resorption/infection and neuropathy alongside use of modern imaging techniques can allow the Rheumatologist to screen for and initiate early appropriate management of these complications. Greater understanding of the pathogenesis of MSK hand complications will hopefully drive the development of novel approaches to treatment.
Articular
Arthralgia Inflammatory arthritis Osteoarthritis/degeneration Psoriatic arthritis-like Erosion
Tendon
Tenosynovitis Tendon friction rub Tendon Rupture
Bone
Acro-osteolysis Osteomyelitis
Soft Tissue
Calcinosis Hand/finger contracture
Peripheral nervous
Median neuropathy at the wrist/carpal tunnel syndrome
system
Other neuropathies (e.g. ulnar neuropathy)
Table 1: MSK hand complications in patients with SSc,
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Musculoskeletal hand involvement in systemic sclerosis Robert David Sandler , Marco Matucci-Cerinic , Michael Hughes PII: DOI: Reference:
S0049-0172(19)30683-3 https://doi.org/10.1016/j.semarthrit.2019.11.003 YSARH 51559
To appear in:
Seminars in Arthritis & Rheumatism
Please cite this article as: Robert David Sandler , Marco Matucci-Cerinic , Michael Hughes , Musculoskeletal hand involvement in systemic sclerosis, Seminars in Arthritis & Rheumatism (2019), doi: https://doi.org/10.1016/j.semarthrit.2019.11.003
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Musculoskeletal hand involvement in systemic sclerosis
Robert David Sandler1, Marco Matucci-Cerinic2, Michael Hughes3
1. Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom. 2. Department of Experimental and Clinical Medicine, University of Florence, and Divisions of Internal Medicine and Rheumatology AOUC, Florence, Italy.
Corresponding author: Dr Michael Hughes BSc (Hons) MSc MBBS MRCP (UK) (Rheumatology) PhD ORCID ID: 0000-0003-3361-4909 Consultant Rheumatologist Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom. [email protected] Telephone: +44 (0)114 271 1900
Short title: MSK hand involvement in SSc
Key words: Systemic Sclerosis; Scleroderma; Musculoskeletal; Hand;
Word count = 3539
Abstract (n=169/250) Musculoskeletal (MSK) involvement of the hands is a significant source of morbidity, impacting on quality of life in patients with systemic sclerosis (SSc). MSK complications are common in SSc and can affect the whole of the MSK system. MSK hand involvement can occur early in the course of the disease. A wide range of articular involvement is recognised including from arthralgia to inflammatory joint and tendon disease. Mechanistic insights have been made into enthesitis, hand contractures and tendon friction rubs and could inform the development inform novel treatment approaches to MSK involvement in SSc. Bony involvement can include osteomyelitis from digital ulceration. Other important manifestations include (but are not limited to) calcinosis, acro-osteolysis and carpal tunnel syndrome.
MSK imaging is an important tool that allows insight into both disease
pathogenesis and to inform the clinical management of MSK complications. The purpose of this review is to provide an overview of the MSK hand complications in patients with SSc, highlighting the breadth and burden of pathology relevant to clinical practice.
Introduction Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterised by widespread tissue and internal organ fibrosis, immune system activation, and vasculopathy [1]. Musculoskeletal (MSK) hand involvement is common in patients with SSc and is associated with significant disability and reduced quality of life. There is a wide range of potential MSK hand complications [2,3], which can occur in patients with SSc (Table 1). For example, joint involvement can range from marked arthralgia to frank synovitis akin to rheumatoid arthritis (RA). The purpose of this review is to provide an overview of the MSK hand complications in SSc, highlighting the breadth and burden of pathology. Other important causes of MSK disability (beyond the scope of this review) include skin sclerosis, digital vascular disease (e.g. Raynaud’s phenomenon or digital ulcers) and inflammatory muscle disease/myositis (as this tends to affect the proximal MSK structures). Furthermore, we will not discuss the management/treatment of MSK complications, and therefore the
reader is directed toward recent review articles [3–5] including SSc-treatment guidelines [6,7] on this topic.
Review strategy The breadth of this comprehensive review was not amenable to a formal systematic literature review owing to the need to identify and appraise a broad range of sources including cross-sectional studies, registry analyses and clinical trials. The following standardised search criteria were applied within the National Institutes of Health's National Library of Medicine (PubMed) to facilitate the identification of relevant manuscripts (1065 citations on 4th May 2019):
((musculoskeletal) OR (arthritis) AND ((systemic sclerosis) OR (Scleroderma)) AND ((articular) OR (tendon) OR (calcinosis) OR (radiography) OR (ultrasound) OR (magnetic resonance imaging))
The titles and abstracts of journal articles identified from this search formed the mainstay of identifying relevant work, alongside grey searches of manuscripts cited within these articles. Separate searches were run for relevant literature related to acro-osteolysis, calcinosis and carpal tunnel syndrome. In general, we have focussed on recent publications within the past 5 years and important legacy papers.
Articular involvement Different patterns of joint involvement have been described in patients with SSc, although this still remains the subject of debate. Arthralgia is very common in patients with SSc throughout their disease and has been reported in between to occur in 38% to 97% of patients with SSc [8–10]. Joint symptoms can occur before or at the time of onset of the disease. In the study by Baron et al [9], which included 38 patients with progressive SSc, two-thirds (66%) of patients reported a history of joint pain during the course of their disease, and around half (55%) had symptoms at the time of evaluation. In a 12-month prospective study which included 76 patients with SSc, arthralgias were present in 38% of patients, and were more common in those with limited cutaneous SSc (lcSSc) compared to diffuse cutaneous SSc (dcSSc) (43.5% & 22.7%, respectively) [11].
Joint disease can be the first presentation of a SSc-spectrum disorder. In the study by Baron et al [9], the onset of joint symptoms preceded the diagnosis of SSc by 1 year in 20%, occurred during the first year of diagnosis in a third (32%), and developed after the diagnosis in half (50%). Joint pain was considered to be of either a moderate or significant severity in half (52%) of patients [9]. In a survey which included responses from 464 patients with SSc who responded to the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities, joint pain was considered the 4th most highest (out of 69) rated symptom in terms of frequency and moderate to severe impact on the activities of daily living (81% & 64%, respectively) [12].
Synovitis/arthritis and tenosynovitis The prevalence of inflammatory joint (synovitis) and tendon disease (tenosynovitis) in patients with SSc has varied widely in the reported literature. Possible reasons for such differences include (but are not limited to) the method/s of case ascertainment (including the definition of articular involvement) and discordance between the ability of clinical examination and MSK imaging techniques to detect inflammatory joint and tendon disease.
In a prospective, cross-sectional study of 120 patients with SSc, arthritis was found in one fifth (18%) of patients and was defined by concomitant erosion and joint space narrowing [13]. Whereas, in the previously described study by La Montagna et al [11], ‘clinical’ arthritis was found in 13.1% of patients. In their study, articular involvement was assessed by measuring the minimal distance between the middle finger bilaterally and the transverse palmar crease [11]. Similarly, in a study which included 41 unselected patients with SSc, only 3 patients had evidence of a SSc-RA overlap clinical picture [14]. Another key aspect relates to study design. Many previous studies have adopted a prospective, cross-sectional approach, whereas, others have examined an enriched cohort of those patients at ‘risk’ of arthritis (e.g. in the presence of inflammatory joint pain). For example, in a cross-sectional study which examined 300 consecutive patients with a current or past history of articular symptoms, clinical synovitis was found in the majority (88%) of patients [15].
In a recent meta-analysis, the probability (95% CI) for clinically manifest arthritis (5 studies) was 23% (0.149 - 0.309] and radiologically detectable arthritis (5 studies) in SSc was 26% (0.167 – 0.361) [16]. However, the authors highlight that funnel plot analysis revealed that smaller studies tended to observe larger effects [16].
Important insights can be learned from large registry data. For example, in an analysis from the German Network for Systemic Scleroderma which included 1483 patients, MSK involvement (defined as articular involvement as synovitis with swelling, with or without tenderness to palpation, in one or more joints) was found in half (47.5%) of patients [17]. Whereas, in an analysis from the European Scleroderma Trials and Research Group (EUSTAR) database which included 7286 patients with SSc, the frequency of synovitis was 15% [18].
MSK imaging can play an important role in identifying articular pathologies in patients with SSc, including in the absence of clinical signs of arthritis. In a cross-sectional observational study, which included 52 patients with SSc, synovitis and tenosynovitis was significantly underestimated by clinical examination (15% vs 6%, respectively) compared to US (46% and 27% of patients, respectively) [19]. Similarly, in a study which included 45 patients with SSc, the prevalence (n) of synovitis by US (i.e. effusion and/or synovial proliferation) was significantly higher compared than clinically involved alone (58% vs 33%) [20]. Whereas, in a prospective study which included 46 patients with SSc and 15 healthy controls, synovial hypertrophy was seen in half in 3% of hand joints and in in 46% wrist joints (and not in controls) [21]. MRI appears to be more sensitive compared to US at detecting inflammatory joint and tendon disease [22,23]. For example, Chitale et al [22] investigated US and MRI in 17 SSc patients with arthralgia and no overt inflammatory arthritis. Baseline US was performed in 13 unselected patients and 6 months later, and with an additional MRI scan (with gadolinium contrast) of the most symptomatic hand in 8 patients. At baseline and 6 months, synovitis was seen in 46% and 47% of patients, respectively, and tenosynovitis was seen in 6% and 23%. In addition, synovitis was observed in 100% and tenosynovitis in 88% of those patients who underwent MRI. In the study by Allanore et al [24] which utilised magnetic resonance arteriography to study hand vascular involvement in SSc (n=38), 50% had at least one site of synovitis, and 11% at least one site of tenosynovitis. Similarly, in a
study which included 17 patients with SSc, around half (59%) of patients had inflammatory hand findings on MRI including synovitis (n=8) and tenosynovitis (n=8) [25]. Other imaging techniques which have been examined to assess articular involvement in SSc include (but are not limited to) thermography, radioisotope bone and PET FDG imaging [15,26].
Patterns of joint involvement in SSc A key question is whether joint involvement is a SSc-disease-related manifestation (e.g. ‘SScarthropathy’),
an
overlap
(e.g.
RA)
or
the
coexistence/concomitant
unrelated
rheumatological condition (e.g. osteoarthritis ((OA)). Polyarticular and other patterns of joint involvement have been described. In the study by Baron et al [9], the most common pattern of joint distribution was symmetrical and polyarticular (61%), followed by oligoarticular (22%) and monoarticular (17%). In their study, there was a fairly similar proportion between an acute (40%) and insidious (60%) onset. Almost half (44%) had an intermittent course, 16% had a ‘chronic remittent course (persistent symptoms but having periods of distinct remissions), 36% had a slowly progressive course, and 4% had a rapidly progressive course.
Synovitis/RA-like arthritis has been described and typically affects (but is not limited to) the small joints of the hands (MCPJs and PIPJs) as well as the wrists [9,19,27] as well as the MTPJs, knees and shoulders [9]. Involvement of the distal interphalangeal joints can resemble erosive osteoarthritis (e.g. showing central erosions and collapse of the subchondral
bone
plate)
[3],
and
can
also
resemble
psoriatic
arthritis.
Degenerative/osteoarthritic features (discussed later) are common including joint space narrowing including of the carpometacarpal joints [3]. As could be expected, US is more sensitive than plain radiography to detect features of osteoarthritis (e.g. osteophytes) [28].
La Montagna [11] proposed three radiological patterns for the hands and feet:
Inflammatory joint pattern - occurrence of juxta-articular osteoporosis, space narrowing of the PIP and/or carpal joints, and/or erosive changes, either with or without digital flexion.
Degenerative joint pattern – occurrence of space narrowing of the PIPJs and or DIPJs, and/or tarsal joints, subchondral sclerosis and/or osteophytes.
Periarticular fibrotic pattern - occurrence of digital flexion, space narrowing, particularly of the DIP joints, with or without subchondral sclerosis.
In their study, the fibrotic pattern was the most common in the hands (inflammatory and degenerative patterns both 13.1%). whereas, in the feet the degenerative pattern was commonest (inflammatory and fibrotic = 6.6% and 7.9%, respectively) [11]. This was subsequently modified by Erre et al [14] to include a ‘normal/minimal changes pattern’ which was defined as the ‘absence of radiographic changes or occurrence of minimal radiographic abnormalities (i.e. isolated narrowing of a distal interphalangeal joint space)’. Likewise, in a study which included 41 unselected Sardinian patients with SSc, the periarticular pattern (on plain radiographs) was the most frequently observed (normal/minimal = 19.5%, inflammatory pattern = 19.5% and degenerative pattern (22.0%) [14].
Clinical associations with arthritis Disease subset is an important predictor of arthritis. For example, in the study from the German Network for Systemic Scleroderma, MSK involvement (which was defined as articular involvement as synovitis with swelling, with or without tenderness to palpation, in one or more joints) was found in around half (47.5%) of patients, in particular, in patients with SSc overlap (67.6%) and dcSSc compared to lcSSc (56.6% & 44.9%) [17]. In the previously described meta-analysis, no significant difference was observed in either radiographic or detectable peripheral arthritis between lcSSc and dcSSc [16]. Several studies have demonstrated an associated between the presence of arthritis and C-reactive peptide (CRP) [13,14,19,27], in particular, when it is greater than 10 mg/L [13,19]. Furthermore, Cuomo et al [28] reported than US-detected synovitis was only related to the level of the CRP. In general, synovial fluid analysis reveals evidence of a modest inflammatory (predominantly mononuclear) cell infiltrate (<1000mm3) [29]. In the US study by Elhai et al [19], shorter disease duration (<3 years) was associated with more synovitis and higher grade, however, this did not reach statistical significance (which the authors postulated was potentially due to the small numbers included in their study). Rheumatoid factor positivity can occur in approximately 30% of patients with SSc including in patients with secondary Sjogren’s syndrome [10]. In general, data from the literature supports that anti-CCP
antibodies but not rheumatoid factor can potentially help to distinguish between patients with SSc and the presence of arthritis (RA-like) including erosive disease [30–33] .
Joint effusions and erosions Joint effusions are common and have been observed in around half of patients with SSc as assessed by US (~50%) [20][21] and MRI (~40%) [25]. Cuomo et al [20] found no difference in the presence of joint effusion (as assessed by US) between patients with SSc and RA (49% vs 53%).
Joint erosions have been reported to occur in approximately 5 to 40% of patients with SSc [9] [11][13][24], and is often progressive [34]. The wide variation in reported erosive disease is likely to be largely driven by the ability of the imaging technique to detect erosions. For example, in the study by Low et al [18], of 7 patients with evidence of MRI erosions, only 2 had radiographic erosions. This could account for the relatively low prevalence of erosions in both the hands and the feet (4% & 1%, respectively) as reported in the study by La Montagana [11], which used plain radiography only. There are conflicting data about the relationship between rheumatoid antibodies and erosive disease in SSc. In general, rheumatoid factor does not appear to be associated with erosive disease [9,34]. However, as previously described, several authors have reported that anti- cyclic citrullinated peptide (CCP) antibodies are predictive of erosive disease. Whereas, Avouac et al [34] did not find any association between rheumatoid antibody status including anti-CCP2 antibodies and the development of new erosions. However, In a recent prospective cohort study from New Zealand which included 132 patients with SSc, double antibody positivity (rheumatoid factor and anti-CCP) was significantly associated with arthralgias and erosions, including anti-CCP antibodies and erosions alone [33]. Disease duration, elevated acute phase reactants, antinuclear antibody, the extent of scleroderma skin changes or distal tuft resorption have all been reported not to be associated with erosive disease [9,34].
Enthesitis Enthesitis and involvement of the synovial-entheseal complex has been reported in SSc. In an ultrasound pilot study, which included 100 patients with SSc and 25 healthy subjects, enthesitis (including as assessed by the Glasgow Ultrasound Enthesis Scoring System) was
significantly greater in SSc, including greater inflammatory signal and the presence of calcification and enthesophytes [35]. Common extensor tendon enthesitis was correlated with synovial-entheseal complex inflammation, which could suggest that entheseal inflammation in SSc could share the same micro-anatomical targets as spondylarthritis [35].
Hand contractures Hand (finger) flexion contractures are an important cause of disability and have been reported to occur in in approximately one quarter to one third of patients with SSc [13][17][18]. Contractures are often progressive. For example, in the study by Avouac et al [34], over a median study interval of 5 years, radiographic progression of contractures was observed in around a fifth (17%) of patients. A higher prevalence of finger flexion contractures has been reported in patients with dcSSc compared to lcSSc [11][13][17][18]. In a study from the German Network for Systemic Scleroderma, joint contractures were identified in around a quarter (26.1%) of patients, and was higher in patients with dcSSc compared to lcSSc (39.7% & 22.6%, respectively) [17]. Other reported associations have included (but are not limited to) the level of anti-topoisomerase-1 antibodies (MCPJ and PIPJ finger contractures) [36], high functional impairment (as assessed by the HAQ) [13], the radiological ‘fibrotic’ pattern [11], and internal organ involvement (e.g. ILD and oesophagus) [14]. Thickening of the A1 pulley has been described in patients with SSc [37,38], and correlates with hand disability [37]. Local/mechanical factors (e.g. soft tissue calcification) may have an important role in the development of finger contractures in SSc.
Tendon involvement Inflammatory tendon disease (tenosynovitis) has been previously described. Compared to patients with RA, tendon involvement is less inflammatory and more fibrotic (sclerosing tenosynovitis) [19]. US tenosynovitis often (~50%) occurs with concomitant synovitis [19]. There appears to be a predilection for involvement of the extensor compared to the flexor tendons [19]. In a ultrasound study which included 33 patients with SSc, ‘sclerosing’ tenosynovitis was defined ‘was defined as an iso- or hyperechoic hypertrophy of the tendon sheath with concentric alternating iso- and/or hyperechoic layers on transverse view’ was more common in patients with diffuse SSc and anti-RNA polymerase III antibody positive [27].
Tendon friction rubs Tendon friction rubs (TFR)s are characterised by a palpable leathery crepitus on palpation of the joints [3,10]. TFRs have been described to be ‘related to fibrinous deposits on the surface of tendon sheaths and overlying fascia’ [10]. TFRs may occur in approximately 10% of patients with SSc [17][18], and are more common in patients with dcSSc [17]. Common sites for TLRs include the hands and wrists, ankles, knees and elbows [10,39], and can occur at multiple sites [39]. TFRs often occur early in the course of the disease. It has been observed that TFRs are common in Caucasians [39]. TFRs are associated with a more severe disease course, in particular, in patients with early dcSSc [18,40]. Change in TFRs (i.e. worsening/improvement) are predictive of changes in skin disease and functional impairment [39]. Elhai et al [19] reported that TFRs were only observed in those patients with evidence of US tenosynovitis [19]. Tendon rupture is a rare potential complication. Rosenbaum [19] reported complete rupture of the wrist extensor tendon mechanism. Histopathology demonstrated mild chronic synovitis and fibrin deposits on the surface of the synovium. There was non-specific degradation of the tendons with fibrous tissue proliferation and replacement with granulation-like fibroblastic tissue. Stoenoiu et al [41] postulated that TFRs may originate through deep connective tissue infiltrates surrounding tendons which impairs the smooth gliding during active motion, as opposed to fibrinous deposits on the surface of the tendons or tendon sheaths.
Osteomyelitis Digital ulcers (DUs) are common in patients with SSc and can be complicated by osteomyelitis [42], in particular, if there is infection of the DU [43]. Osteomyelitis may be detected at an earlier stage by MRI compared to plain radiography [44].
Acro-osteolysis Acro-osteolysis involves shortening of the phalanges due to bone resorption. It occurs most commonly in the hands but can also affect the feet. Estimates of prevalence in SSc ranges between 20 to 40% [9,11,13,14,45], although in one study it was identified as high as 70% [46]. The aetiopathogenesis of A-O is incompletely understood; however, hypoxia [47] is considered to play a major role, which can promote osteoclastogenesis [48]. A-O is
associated with the severity of digital vascular manifestations, such as digital ischaemia/ulceration
and
calcinosis
[49].
Vitamin
D
deficiency
and
secondary
hyperparathyroidism has been reported to be associated with acro-osteolysis [46]. It has been postulated that low levels of vitamin D may represent silent malabsorption and could be a risk factor for secondary hyperparathyroidism and bone resorption [46].
Calcinosis Calcinosis is seen in up to 20% to 40% of patients with SSc [13,50–54]. Calcinosis is more common in the limited cutaneous subset with positive anti-centromere antibodies [14,53,55,56]. However, in one prospective study of 120 patients with SSc, calcinosis occurred with equal frequency in both lcSSc and dcSSc [13]. Calcinosis affects the hands most commonly, with a specific preference for the thumb [57]. Calcinosis is associated with erosion, telangiectases, nailfold capillary abnormalities and digital ulceration [9,13]. Calcinosis is often subclinical and can be assessed by different imaging techniques. CT (including multi-detector) and MRI have been used to objectively assess calcinosis. In a recent study which included 15 patients with SSc, calcinosis could be successfully measured and with comparable results (e.g. number and area/volume of calcinotic lesions) by plain radiography, CT and MRI [58]. Calcinosis needs to be carefully monitored as it can become infected [59] and/or ulcerate [60]. A classification system for patients with calcinosis and SSc has been proposed, taking into account clinical and radiographic features [60]. These include classifying calcinosis as “visible and palpable” or “non-visible and palpable” with further sub-classification of the “visible and palpable” subset following palpation and radiography as “mousse” (soft consistency, with white cream-like material), net (diffuse thin network), plate (large, uniform and flat agglomerate) or stone (single stone or multiple hard agglomerates) [60]. The majority of fingertip calcinoses were mousse or stone and seemed to be less painful than those occurring around the knees or elbows.
Peripheral nervous system Although carpal tunnel syndrome (CTS) is the most recognised peripheral nervous system involvement in SSc, other forms are recognised including ulnar nerve entrapment [61,62].
Carpal Tunnel Syndrome
CTS or median neuropathy at the wrist (MNW) is an important potentially early or even presenting feature of SSc [63]. However, this may be an underestimate of true prevalence as US and electrophysiological evidence of MNW has been demonstrated in up to 88% of patients with SSc and with no clinical features of CTS [64,65]. Possible aetiology for MNW in SSc includes a reduction in median nerve elasticity and density [66,67]. Chronic ischaemia from progressive microangiopathy leading to axonal loss has also been postulated to be implicated in peripheral nerve dysfunction in SSc [68]. In addition, in patients with SScRaynaud’s
phenomenon
(compared
to
primary
Raynaud’s
phenomenon)
the
neuroanatomical lesion is postulated to include both the median and ulnar nerves (suggesting a possible polyneuropathy) compared to only at the level of the carpal tunnel [69].
Conclusion The MSK effects of SSc on the hand are wide-ranging and a significant cause of morbidity. An awareness of the heterogeneous nature of hand involvement in patients with SSc, including inflammatory joint/tendon disease with associated arthropathy, calcinosis, bone resorption/infection and neuropathy alongside use of modern imaging techniques can allow the Rheumatologist to screen for and initiate early appropriate management of these complications. Greater understanding of the pathogenesis of MSK hand complications will hopefully drive the development of novel approaches to treatment.
Articular
Arthralgia Inflammatory arthritis Osteoarthritis/degeneration Psoriatic arthritis-like Erosion
Tendon
Tenosynovitis Tendon friction rub Tendon Rupture
Bone
Acro-osteolysis Osteomyelitis
Soft Tissue
Calcinosis Hand/finger contracture
Peripheral nervous
Median neuropathy at the wrist/carpal tunnel syndrome
system
Other neuropathies (e.g. ulnar neuropathy)
Table 1: MSK hand complications in patients with SSc,
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