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Autoimmune connective tissue diseases 

Autoimmune connective tissue diseases
Chapter:
Autoimmune connective tissue diseases
Author(s):

Begonya Alcacer-Pitarch

, Edward Vital

, and Maya Buch

DOI:
10.1093/med/9780198734451.003.0008
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date: 11 April 2021

Epidemiology

Systemic sclerosis

Systemic sclerosis (SSc) is a heterogeneous connective tissue disease characterized by vasculopathy, immune activation, and fibrosis (1, 2, 3). The prevalence of SSc varies enormously, from 30 to 2280 per 1,000,000 population (4), with geographical variation recorded (5, 6, 7). In the UK the prevalence ranges from 31 per million in the West Midlands to 150 per million in South and West London (8, 9, 10).

The female-to-male ratio in SSc is approximately 3:1 (ranging from 1 to 14:1) (4, 6, 11, 12). The onset of the disease varies according to ethnic background and sex but usually its peak of incidence is reached at the fifth decade. However, SSc can occur at any age, albeit rare in children and in the very elderly (5, 6, 9, 13, 14).

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that most commonly affects skin and musculoskeletal systems but can also cause inflammation and damage in any of the major organs. Involvement of the brain, lungs, and kidneys may be fatal, but its greatest impact on mortality is via the long-term effects of disease and glucocorticoid therapy, leading to a 50-fold increase in cardiovascular disease. It usually affects women (9:1 female:male ratio) with onset from the teens to the mid-forties and a relapsing remitting course thereafter. The most severely affected patients are of Afro-Caribbean and East Asian descent and those with paediatric or adolescent onset (15).

Pathophysiology

Systemic sclerosis

SSc is characterized by three pathological features: vasculopathy, immune activation, and fibrosis. These three factors interact in a complex manner, leading to obliterative fibrointimal proliferation of small vessels with vasospastic episodes, resulting in ischaemia; immunological disruption; and activation of resident connective tissue cells with increased deposition of extracellular matrix constituents causing fibrosis (3, 16, 17, 18).

Vasculopathy is considered one of the earliest and is a key event in the pathological process of SSc (16, 17, 19), one to which much of the morbidity and mortality in SSc is related. Early on, the disease microvasculopathy can be observed clinically in the form of Raynaud’s phenomenon (RP), indicating peripheral vasculopathy. In addition, an uncontrolled fibrosis replaces the normal (controlled) wound healing-associated repair (2), and as the disease progresses the skin lesions become relatively avascular. About 12–18 months after this, there is usually little or no inflammation present but the skin lesions are left sclerotic, i.e., fibrosed, contracted, and scarred (16, 20).

Systemic lupus erythematosus

SLE is predominantly driven by activation of the immune system, affecting the vascular, neurological, renal, musculoskeletal, and integumentary systems. The occurrence of antibodies to DNA in the blood of people many years before the appearance of the disease suggests a link between such antibodies and the disease manifestations. Levels of antibody against DNA are still used as a measure of disease activity. The pathological processes in the end organs are partly driven by antibody/antigen deposition in blood vessels (e.g., glomerulus of kidney), but there are many other nuclear protein targets for antibodies in this disease and some of these lead to disease-specific targets, such as the heart. Other mechanisms of disease pathogenesis include T cellular-driven autoimmunity and cytokine abnormalities.

Lower limb pathology

Scleroderma

SSc is a multi-system disease affecting multiple major organs with distinct and important manifestations in the foot and ankle.

SSc is defined by the presence of skin tightening, and the extent of involvement determines the classification into limited (distal to elbows/knees) or diffuse (proximal to elbows/knees ± chest/trunk) disease (21). Skin changes often start with an oedematous phase (in the papillary and reticular dermis), followed by a firm induration and fibrosis (16). Clinically the oedematous phase can be observed in the form of oedematous feet. Subsequently, the skin becomes thicker and tighter on palpation as it progresses to become sclerotic, contracted, and scarred (Figure 8.1) (16, 18, 22, 23). In the feet, damage to the sebaceous glands can cause hypohidrosis, and substitution of the fat cells with collagen can lead to subcutaneous plantar fat-pad atrophy, which is thought to contribute to the increased plantar foot pressures reported in SSc (24). Initial clinical studies (24) suggest that increased plantar foot pressures and prolonged duration of loading through discrete areas of the foot (Figure 8.2) are associated with pain and functional impairment during walking; this is similar to findings reported in people with rheumatoid arthritis (RA) (25, 26).

Figure 8.1 Fibrosis affecting the feet, causing capillary compression during normal movement such as ankle plantar flexion.

Figure 8.1 Fibrosis affecting the feet, causing capillary compression during normal movement such as ankle plantar flexion.

Figure 8.2 Highly elevated plantar foot pressures in the metatarsophalangeal joints of a patient with systemic sclerosis.

Figure 8.2 Highly elevated plantar foot pressures in the metatarsophalangeal joints of a patient with systemic sclerosis.

Reproduced with kind permission from B. Alcacer-Pitarch.

As a result of the structural changes within the integumentary system, the foot’s normal biological and biomechanical properties are lost. This compromises skin integrity, tissue viability, healing, and the foot’s ability to adapt to the increased pressures: for example, the extensibility of the skin is reduced because of fibrosis of the hypodermis (27). The loss of skin extensibility together with the fibrosis of periarticular soft-tissue structures (21, 28) limits range of motion (ROM) at joints, with a subsequent impact on function (24).

The structural and biomechanical changes of the skin, together with tendon and joint pathologies, can lead to the development of flexion contractures. When this happens in the toes, the toes are left in a fixed-flexed position which has a major impact on gait and shoe fit. These deformities not only impair the movement of the affected joints but also contribute to the risk of developing ulcers over the flexed joints and areas of skin tension. Indeed, ulcer aetiology is multifactorial. The skin is exposed to constant stress and shear as a result of external factors such as footwear, and internal factors such as fixed deformities and the skin’s inability to adapt to pressure because of the presence of fibrosis. Combined with vasculopathy this causes the deformed and fibrosed areas to be at high risk of ulceration (29, 30).

Ulceration also occurs in areas without deformity, and particularly on the apex of the toe. The aetiology of ulcers in people with SSc is commonly associated with vasculopathy, presence of calcium deposits, skin fibrosis, and/or hyperkeratosis (31). Once ulcers are present they are extremely painful and have a very slow healing rate, the latter being negatively affected by the amount of skin pathology. The ulcers can become chronic, increasing the risk of amputation (31). Lower limb amputation as a result of refractory ulcers has an incidence of 0.67% (32) in patients with SSc. Even in cases where healing is achieved, the ulcerated area experiences tissue loss and scar tissue formation. Skin scarring, together with the presence of vasculopathy, adds to the impairment of the biomechanical properties of the local skin, leaving the area even more prone to re-ulceration.

Systemic lupus erythematosus

There is very little work on the foot and ankle in SLE. Two patient surveys, one in the UK and one in New Zealand (NZ), have reported a high prevalence of foot complaints in this group—87% in the UK and 77% in NZ (33, 34). The NZ group found that rearfoot and ankle joint pain predominated, but there was a high prevalence of forefoot, especially metatarsophalangeal joint pain, in both groups.

Fifty per cent of both groups of respondents reported significant RP, with about one-fifth reporting foot ulceration at some point. These figures represent a high burden of foot symptoms in SLE, but it must be remembered that these were voluntary respondents and may have self-selected because of their symptoms. In addition, there was no control group with which to compare the frequency of symptoms. One other study has looked at musculoskeletal involvement by performing ultrasound examination of the joints in a small sample—80% of the examined group were found to have grey-scale synovial hypertrophy, although only a minority of these had vascular inflammation (35).

Vascular-related foot pathology in both diseases

One of the first microvascular clinical presentations is RP. It affects between 90% and 98% of patients with SLE and SSc.

The clinical presentation of RP can be divided into three phases. The initial phase is the ischaemic phase, where the digits present with a pallor discoloration (white), reflecting vasospasm; this phase is followed by the deoxygenation phase, where the digits become cyanotic (blue discoloration); in the final phase, the reperfusion phase, the digits become red, expressing the compensatory vasodilation (36, 37, 38). These clinical signs are accompanied by symptoms such as cold, paraesthesia, and pain during the duration of the RP attacks (Figure 8.3).

Figure 8.3 The deoxygenation phase in Raynaud’s phenomenon.

Figure 8.3 The deoxygenation phase in Raynaud’s phenomenon.

In a study of 100 patients with SSc, 90% were affected by RP in their feet and 31% had necrotizing RP, which is characterized by digital ulcers (9). The reported proportion of patients affected by foot ulcers ranges from 20% to 26% (9, 39).

In SSc, the presence of RP in combination with the microvasculopathy and skin fibrosis can lead to ulcers on the apices of the digits, over the extensor surfaces of the joints, and on the lower leg/malleolus (Figure 8.4) (31, 40, 41). Macrovasculopathy can lead to larger lower limb ulceration and amputation (42). Other risk factors for the development of ulcers in SSc include the presence of calcinosis (Figure 8.4), impaired skin biomechanics due to fibroses or hyperkeratosis (31), and/or neuropathy. The latter, though, lacks a formal body of evidence as it has only been reported in a case study of peripheral sensory neuropathy (43).

Figure 8.4 (Left) Digital ulcer on the apex of the second toe caused by microvasculopathy. (Middle) Malleolus ulcer caused by skin fibrosis and vasculopathy. (Right) Leg ulcer caused by calcinosis.

Figure 8.4 (Left) Digital ulcer on the apex of the second toe caused by microvasculopathy. (Middle) Malleolus ulcer caused by skin fibrosis and vasculopathy. (Right) Leg ulcer caused by calcinosis.

Ulcers in people with SSc are often extremely painful and can take many months to heal. The mean time-to-heal varies depending on the type of ulcer, ranging from 25 to 281 days, but in some cases it has been reported to be as long as 810 days (31). These lesions are accompanied with pain and functional impairment, and can lead to tissue loss and amputation of fingers and/or toes. All of these factors contribute to a highly negative effect on the patient’s quality of life (44, 45).

The development and healing of ulcers in patients with SSc and SLE can be further aggravated by the presence of vasculitis (Figure 8.5). Vasculitis in SSc can lead to severe ischaemia, ulcers, necrosis, and amputations, the latter more commonly seen when the vessels of the digits are involved (46). In some cases, vasculitis can contribute to the pathogenesis of neurological lesions (47, 48) by affecting the arteriae nervorum, causing necrosis of the nerve bundles. Depending on the nerve affected, this can cause peripheral neuropathy (49). Which, clinically, presents as an asymmetric neuropathy or multiple mononeuropathies (49), with diffuse degeneration distal to the lesion area (50). This pattern is characteristic of necrotizing vasculitis (51).

Figure 8.5 (Left) Vasculitis on right leg in an antineutrophil cytoplasmic antibody (ANCA)-positive systemic sclerosis patient, potential precursor for ulceration. (Right) Left leg ulcer with signs of vasculitis in the perilesional skin.

Figure 8.5 (Left) Vasculitis on right leg in an antineutrophil cytoplasmic antibody (ANCA)-positive systemic sclerosis patient, potential precursor for ulceration. (Right) Left leg ulcer with signs of vasculitis in the perilesional skin.

Neurologically related foot pathology

The affected nerve fibres from the autonomic nervous system cause parasympathetic underactivity and sympathetic overdrive (52, 53), which are reflected in the feet as abnormal sympathetic skin responses, RP, and hypohidrosis (52, 54, 55, 56, 57). The prevalence of peripheral nervous system abnormalities in SSc varies, but has been reported to be as high as 50% in a small sample (n=14) (54) and as low as 5.6% in a larger cohort (n=125) (58, 59). Patient self-report sensory neuropathy occurred in 16% of a sample of SLE patients in the UK (33). Mononeuritis multiplex, sensorimotor neuropathy, and compression neuropathies are all observed in SLE and SSc. The clinical presentation of peripheral neuropathy is typically distal but with a non-length-dependent pattern to the sensory symptoms, more sensory than motor, and mostly multiple mononeuropathy or asymmetric in involvement (suggesting multifocal pathology) (49, 54). It has also been described to be present with early neurological signs of sensory–motor mononeuropathy, which progresses to a typical distal polyneuropathy in the rest of the body with greater involvement of the lower limbs (60). When sensory symptoms are present they can vary from allodynia, lancinating pains, burning, paraesthesia, and pruritus through to loss of sensation, and these symptoms have been reported to be more prominent in the extremities (54).

Musculoskeletal involvement

Ninety per cent of patients with SLE and SSc report musculoskeletal complaints. These range from intermittent small and large joint arthralgia to chronic polyarthritis (33, 61, 62) and muscle involvement (63, 64). Joint symptoms have been reported to be present in 66% of patients with SSc (65), with muscular symptoms in half of the patients, the latter with a predominance of muscle weakness and myalgia (59). Clinically they may present as a painful, stiff, symmetrical arthropathy, which is clinically indistinguishable from that of RA (61, 65). The arthropathy and joint symptoms are not exclusive to early disease; they can also emerge as the disease progresses, and approximately half of patients with SSc develop arthralgia after diagnosis (65, 66). In the feet the arthropathy presents with a significant degenerative pattern in 18% of patients, fibrotic pattern in 8%, and inflammatory pattern in 7%. In the feet, the toe flexor tendons are affected by tendon contractures (Figure 8.6) and tenosynovitis, while the extensor tendons and the anterior and posterior tibial muscle tendons have been reported to be affected by tendinitis (67) (21, 64). Tendon friction rubs (associated with fibrinous deposits on the tendon sheath) affect the anterior and posterior tibial muscle tendons, toe flexors and extensor tendons, the Achilles’ tendon, and the tendons on the dorsum of the foot, but detailed epidemiology data are lacking (21, 64, 68). These three clinical features contribute to the functional impairment of the joints and arthralgia.

Figure 8.6 Flexion contractures in a patient with systemic sclerosis and acroosteolysis of the hallux’s phalanx.

Figure 8.6 Flexion contractures in a patient with systemic sclerosis and acroosteolysis of the hallux’s phalanx.

Management

Conservative management

There is a lack of evidence regarding the management of disease-specific foot pathologies in patients with SSc and SLE. Instead, clinical management is based on evidence of treating similar pathologies in other diseases.

Careful consideration needs to be taken when clinically assessing and treating foot and ankle problems in patients with SSc and SLE. In relation to foot pathology these patients are considered high-risk patients owing to the severity of the disease, which affects multiple systems, all of which potentially have a direct or indirect effect on foot pathology. For example, impaired lung and heart function in SSc (69, 70, 71) will have an effect on the efficacy of soft-tissue oxygenation, therefore contributing to the severe effect that the vasculopathy already has on soft-tissue oxygenation of the limbs. In patients with SLE, renal involvement has been found to be associated with carotid atherosclerosis (72), possibly affecting the vascular tree from the lower limbs, causing peripheral arterial disease (73).

Provision of patient education as a preventative measure to avoid/reduce foot pathology in patients with SSc and SLE is crucial. A recent qualitative study in SLE patients has demonstrated that patients self-report a wide range of foot symptoms but usually self-treat rather than seek medical advice that is often indicated (74). Advice should be given on how to avoid situations that decrease blood flow, such as to minimize RP attacks by avoiding exposure to cold and stress, and smoking cessation. In addition, information should be provided on ulcer care, skin care, nail care, how to avoid increased harmful friction and shear from ill-fitted hosiery and footwear, and on when and how to access foot health services (75, 76, 77).

Patients need to be screened on a regular basis for the presence of peripheral neuropathy, as tactile sensitivity has been reported to be impaired in half of patients with SSc (78), and pure sensory and sensory–motor polyneuropathy has been found to be present in 40% of patients with SLE (79). Regular screening is important, as patients are often unaware of the loss of sensitivity, and present with subclinical neuropathy, thus putting them at risk of injury in the presence of harmful stimuli.

Once the skin is affected by fibrosis in SSc it rarely returns to its original form; however, in patients with early diffuse SSc, systemic treatment with methotrexate has been shown to improve skin fibrosis (80). Additionally, skin hypohidrosis can be treated locally with emollients or creams containing a low concentration of urea (5–10%) (81, 82, 83). Creams with higher concentrations of urea (i.e., 40%) are recommended in the presence of hyperkeratosis because of the keratolytic effect of urea (84, 85). In addition to using creams with urea, when there is a buildup of hyperkeratosis sharp debridement is recomended. In the case of plantar callosities, the removal of the callus decreases plantar pressures (86, 87). Debridement should also be considered to address high-risk presentations such as extravasated blood or underlying ulceration. Although debridement can alleviate pain, it might be short-lived, as is reported in patients with RA (88).

The treatment of ulcers will vary depending on the aetiology. In SSc and SLE, ischaemic digital ulcers, when active, are treated systemically with calcium channel blockers, angiotensin-converting enzyme inhibitors, losartan, or fluoxetine (89). If ulcers fail to respond, or re-occur, therapy can be escalated to oral sildenafil for 6 weeks, followed by intravenous prostanoids such as iloprost (90, 91). In cases of refractory or progressive ulceration, bosentan can also be used (89). Ulcers in SSc and SLE are extremely painful, so patients should be provided with appropriate pain management, such as a short-term course of opioids (30, 92, 93).

To optimize the healing process in both diseases, systemic treatments should be combined with local ulcer care, treating the wound bed and the perilesional skin (93, 94). For example, vitamin E gel used on the perilesional skin in ulcers of patients with SSc reduces the healing time (95) and debridement of necrotic tissue is recommended to avoid infection and promote healing (93, 94). Ulcer healing can also be impaired by the presence of vasculitis—in these cases systemic treatment with immunosuppressive medication needs to be provided (96).

In ulcers caused by calcinosis, the calcium deposits present on the wound bed (Figure 8.7) should be removed when possible. This is performed either surgically (97) or, as emerging evidence suggests, using carbon dioxide (CO2) laser (98), as the removal of the calcium may reduce healing time, pain, and infection risk (93).

Figure 8.7 A plaque of calcium phosphate (hydroxyapatite) present on the ulcer wound bed of a patient with systemic sclerosis.

Figure 8.7 A plaque of calcium phosphate (hydroxyapatite) present on the ulcer wound bed of a patient with systemic sclerosis.

The presence of disabling foot pain is common in patients with SSc and SLE (76, 99). A multi-centre randomized controlled trial in people with plantar foot pain and SSc compared the effectiveness of a simple pressure-relieving insole (Figure 8.8) with an insulating sham insole. The results at 12 weeks demonstrated a systematic improvement in pain in both groups, but the between-group differences were insignificant (100). Neuropathic pain has also been reported in SSc. When lower limb painful neuropathy is present it is commonly treated in the same way as diabetic painful polyneuropathy (101).

Figure 8.8 Simple pressure-relieving insole used in randomized controlled trial.

Figure 8.8 Simple pressure-relieving insole used in randomized controlled trial.

Both diseases can present with inflammatory joint pathology and during examination of inflamed joints the clinician needs to bear in mind that, in some cases, pre-existing joint disease and/or treatment with cytotoxic drugs and/or systemic corticosteroids can operate as a predisposing factor for joint infection. This is important because sometimes the progression of symptoms of a chronically abnormal joint can be attributed to underlying inflammatory joint disease, thus delaying the diagnosis of joint infection. Therefore, a monoarticular presentation must be considered as an infection until proven otherwise (102) as the adverse consequences of sepsis increase if left untreated.

Surgical management

Surgical interventions are generally performed as a last resort because of the increased risk of postoperative healing complications as a result of poor tissue viability (98). For example, surgery has been recommended when calcium deposits cause disability owing to the location of the lesion, although it is important to know that after excision further deposits can occur (103). In addition, when severe ischaemia is present, it may be possible to improve the circulation by revascularization of the digits with arterial reconstruction (mainly of large proximal vessels) or regional sympathectomies (77, 104). In cases of recalcitrant ulcers associated with severe ischaemia or widespreading gangrene, surgical amputation might be appropriate (105).

There are no reports of corrective foot and ankle surgery or joint replacement surgery in these diseases and the above considerations about healing would be apposite in this context.

Imaging strategies in systemic sclerosis

Nail fold capillaroscopy is used to aid diagnosis and identify patients at risk of digital ulcerations; ultrasound is used to assess soft-tissue pathologies; ultrasound virtual touch imaging and quantification measures absolute quantification of skin stiffness; and optical coherence tomography is used to assess skin fibrosis.

Nail fold capillaroscopy

This diagnostic imaging technique is used to discriminate primary (idiopathic) RP, affecting 10% of the general population, from secondary (to other disease/condition) RP (36, 37, 38). In primary RP normal capillary architecture can be observed, whilst in secondary RP clear abnormalities are recognized; the most well-described changes have been observed in patients with SSc. Structural changes of the skin’s capillaries such as haemorrhage, megacapillaries, and loss of capillary density can be observed through the assessment of the nail fold capillaroscopy of the fingers and toes, although the toes seem to be less affected, possibly because of the lesser severity of the RP and skin involvement (106, 107). These capillary changes imply insufficient vasodilatory capacity and also irreparable vascular damage and are associated with the development of digital ulcers (108).

Depending on the nail fold capillaroscopy patterns the presence of an early, active, or late vasculopathy can be determined. These patterns correlate with disease duration and severity and are predictive of future organ prognosis (109, 110, 111, 112). The RP and capillary changes manifest on a clinical level prior to the development of fibrosis of the skin, gut, and other internal organs such as lung and myocardial disease. Hence the results from the nail fold capillaroscopy are part of the criteria to diagnose SSc (113).

Touch imaging and quantification

A new ultrasound technology called virtual touch imaging and quantification (VTIQ) has also been applied to assess the skin involvement in SSc. VTIQ is an innovative non-invasive technique that measures the absolute quantification of skin stiffness. A pilot study showed that shear wave velocity (a measure of skin stiffness) was significantly higher in patients with SSc than in controls; it was also strongly correlated with the level of local skin pathology (measured by the modified Rodnan Skin Score) in some anatomical sites and could differentiate between clinically unaffected skin and healthy skin (114). This early study demonstrates the potential of this technology to measure skin involvement in SSc. However, further studies of VTIQ with larger sample size are required to validate this technique.

Optical coherence tomography

Although not yet widely used as a skin assessment tool in SSc, optical coherence tomography is a reliable quantitative outcome measure utilized to assess skin fibrosis in SSc (115, 116). This technology allows the visualization of the loss of the dermal–epidermal junction present in skin fibrosis and a decrease in optical density of the papillary dermis; these are changes associated with a worse modified Rodnan Skin Score. It can also distinguish between affected and healthy skin by a decrease in the optical density pattern on the reticular dermis (116).

Musculoskeletal ultrasound

Ultrasound is widely used in inflammatory musculoskeletal diseases and may be particularly valuable in SLE. Although musculoskeletal disease is one of the most common manifestations of SLE, it may be more difficult to diagnose and treat than other inflammatory arthritis. Recent work has shown that the majority of symptomatic patients do not have clinical synovitis. Of patients with inflammatory symptoms but no clinical synovitis, approximately 40% have ultrasound-detected synovitis, which may indicate the need for more immunosuppressive therapy (117).

Research agenda and future directions

The relative infrequency of these disorders provides a challenge to clinical research. There is a need for studies with large cohorts to evaluate the pathological mechanism of lower limb neurological- and musculoskeletal-related foot pathologies and on the development of tailored clinical interventions for foot pathologies. Since any one centre is unlikely to have a large enough cohort to perform these studies, large multi-centre trials are required, in particular to focus on the development of clinical pathways for the treatment of lower limb pathologies.

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