early diagnosis and management of systemic sclerosis · of systemic sclerosis michael hughes...

Prescriber July 2018 ❚ 27prescriber.co.uk

PRESCRIBING IN PRACTICE ■

Systemic sclerosis (SSc) is a complex autoimmune connec-tive tissue disease characterised by microvascular altera-

tions and immune system activation, with fibrosis of the skin and other internal organs.1,2 SSc is a rare disease, with a reported prevalence in the UK of 8.2 per 100,000.3 Females are more commonly affected than males with a reported ratio of between 3:1 and 8:1,4 and a peak age of onset of disease of between 20 and 50 years.5

The purpose of this review is to describe the clinical spec-trum of disease seen in patients with SSc, the underlying mech-anisms/causes of disease, an initial approach to management and assessment (including drug treatments), and the role of the GP, including in the early diagnosis of SSc.

Causes Although great advancements have been made in understand-ing the aetiopathogenesis of SSc, the underlying causes/mech-anisms of the disease (including initiation) remain incompletely understood. Environmental factors are likely implicated in a genetically primed individual.2 Epigenetic modifications may hold the key to understanding the link between genetic and environmental factors.6

Vascular disease (eg vascular injury and dysfunction) is believed to be a central and perhaps initiating event in the pathogenesis of SSc. A progressive obliterative vasculopathy is observed, including remodelling of the vasculature (eg inti-mal and smooth muscle hypertrophy), which promotes local hypoxia and fibrosis. Widespread aberrant tissue fibrosis is the clinical hallmark of SSc. The myofibroblast is believed to be central to the fibrotic disease process, mediated by the action of a number of potent profibrotic factors (in particular, trans-forming growth factor [TGF] beta).2 Immune system activation is clearly apparent, including the production of characteristic SSc-associated autoantibodies (discussed below) and a rich perivascular inflammatory cell infiltrate observed in the skin of patients with early diffuse disease.

Early diagnosis and management of systemic sclerosisMICHAEL HUGHES

Systemic sclerosis (SSc) is a rare but potentially life-threatening rheumatological condition with a wide range of signs and symptoms. This article describes the GP’s key role in the early diagnosis of SSc and discusses the current and emerging treatment options.

SPL

Figure 1. Diffuse skin thickening (scleroderma) affecting the upper limbs causing significant contractures of the fingers in a patient with systemic sclerosis

■ PRESCRIBING IN PRACTICE l Systemic sclerosis

28 ❚ Prescriber July 2018 prescriber.co.uk

Signs and symptoms SSc is a complex and heterogeneous disease and is therefore associated with a wide range of possible signs and symptoms. Whereas scleroderma (see Figure 1) refers to isolated thicken-ing of the skin, in SSc there is also involvement of the internal organs, often in the presence of characteristic SSc-associated antibodies (discussed below). Scleroderma can be an isolated skin finding (eg morphoea or linear scleroderma). SSc is divided into limited and diffuse cutaneous disease (see Table 1). SSc may also occur in combination/overlap with other connective tissue diseases (eg lupus or myositis). The disease may also rarely occur in the absence of skin thickening with only internal organ involvement (‘SSc sine scleroderma’).

Raynaud’s phenomenon Almost all (over 95%) of patients with SSc have Raynaud’s phenomenon, and this is often the earliest feature of the dis-ease. Patients report a classical progression of triphasic colour change of white (deoxygenation), blue (cyanosis) and finally red (reactive hyperaemia) of the extremities (fingers and toes). Mono- and biphasic attacks are also recognised. Other vascular beds may be involved including the nose, lips and ears. Attacks of Raynaud’s phenomenon may be associated with significant pain and discomfort, especially when the circulation is restored. A key feature is that attacks of Raynaud’s are tran-sient, and are typically triggered by exposure to the cold and/or emotional stressors.

Digital vascular disease A spectrum of digital vascular disease is observed in SSc. Digital (finger) ulcers are common in patients with SSc and are associ-ated with significant pain and disability.7 Around half of patients report a history of digital ulcers and these often occur early in the course of the disease.7 Patients should be educated to seek medical advice early if they develop new ulcers. Analgesia should be optimised as ulcerations may be exquisitely painful. Meticulous attention should be paid to appropriate wound care.7,8 Ulcers are often infected, in particular by Staphylococcus aureus, and therefore clinicians should have a low threshold for treatment with antibiotic therapy.7,8 Critical digital ischaemia (see Figure 2) is a medical emergency, as this may rapidly pro-gress to irreversible gangrene, with possible loss of the digit.8

Respiratory involvement Lung fibrosis (interstitial lung disease) and pulmonary arterial hypertension (PAH) are now the two leading causes of mortal-ity in SSc. Up to 80% of patients with SSc may develop lung fibrosis, and this is clinically significant in around one-third.9 Around 10% of patients with SSc may develop PAH,10 and this has a significant impact on survival. Three-year survival in SSc patients with PAH has been reported to be 56% compared to 94% in those without PAH.11 Patients with SSc undergo regular screening using pulmo-nary function tests, with or without transthoracic echocardio-gram. In a study from France, survival was much higher in those patients who were enrolled in a systematic PAH ‘detection’ programme compared to ‘routine practice’ (eight-year survival of 64% vs 17% respectively).12

Cardiovascular involvementPrimary cardiac (conduction system, myocardial and/or peri-cardial) involvement is increasingly recognised, and is often subclinical.13,14 Cardiac involvement can occur as part of the SSc disease process or due to other causes (eg secondary to PAH). Akin to many other rheumatological conditions, an

Limited cutaneous systemic sclerosis

Diffuse cutaneous systemic sclerosis

Raynaud’s phenomenon for many years (even decades) before the onset of skin change

Recent onset of Raynaud’s phenomenon around (before or after) the onset of skin change

Distal skin involvement (hands, forearms, feet and below the level of the knees), can involve the face and neck

As for limited disease, but can affect the proximal upper and lower limbs, with possible truncal involvement

Late onset of pulmonary arterial hypertension

Early onset of major internal organ involvement: cardiac, lung fibrosis, myocardial and gastrointestinal disease

Telangiectases Tendon friction rubs: associated with scleroderma renal crisis

Most are anticentromere positive: associated with the development of pulmonary arterial hypertension

Many are anti-Scl-70 (anti-topoisomerase) positive: associated with lung fibrosisAnti-RNA polymerase III positive: associated with scleroderma renal crisis

Table 1. Characteristics of limited cutaneous and diffuse cutaneous systemic sclerosis. Adapted from: LeRoy, et al. J Rheumatol 1988;15(2):202–532

Figure 2. Critical digital ischaemia in a patient with systemic sclerosis


Systemic sclerosis l PRESCRIBING IN PRACTICE ■

increased risk of cardiovascular disease has been reported by some authors,15,16 although this remains a controversial issue. An increased prevalence of large (proximal) vessel disease is also observed in patients with SSc.17

Gastrointestinal involvementThe majority (up to 90%)18 of patients have gut involvement, which can affect the whole of the gastrointestinal tract from the mouth to the anus. Patients often have significant reflux disease including from oesophageal dysmotility. Patients may also develop symptoms related to gastroparesis. Gastric antral vascular ectasia, often referred to as a ‘watermelon stomach’, is an important and potentially treatable cause of blood loss. Patients may develop malnutrition and this is often multifac-torial, including secondary to poor oral intake (eg due to a lim-ited oral aperture). Motility issues of the small and large bowel may result in pseudo-obstruction and promote the development of small-bowel bacterial overgrowth. Anorectal involvement may occur in around 40% of patients18 and this can result in poten-tially devastating faecal incontinence.

Renal involvementThe scleroderma renal crisis is reported to occur in between 5% to 10%19,20 of patients with SSc and was previously the leading cause of death. Patients may present with an acute hypertensive crisis including features of acute kidney injury, hypertensive retinopathy, fever, pulmonary oedema and encephalopathy.20 Early diagnosis and initiation of treatment with ACE inhibitors is crucial to maxim-ise the chance of a good outcome. Renal replacement therapy is needed in almost all patients. Although renal recovery may occur up to several years after the onset of a renal crisis, around half of patients require lifelong renal replacement therapy.19

Musculoskeletal complicationsNon-specific musculoskeletal pain (eg arthralgias) are common, including from extensive skin thickening with stiffness of the joints. Significant hand contractures may develop, especially in patients with early diffuse disease. Patients may also develop overt inflammatory joint (similar to rheumatoid arthritis) and muscle (myositis) disease.

Non-lethal morbidity SSc can be a significantly fatiguing disease. Depression is not uncommon in patients with SSc and is potentially multifactorial in origin, including from chronic pain and body image dissat-isfaction. In a systematic review, which included two studies utilising the Beck Depression Inventory, the prevalence of clin-ically significant depressive symptoms was between 51% and 65%.21 Patients may develop sexual dysfunction and there is often a high level of body image dissatisfaction, including from cutaneous telangiectases (cutaneous dilated blood vessels). Calcinosis (subcutaneous and/or intracutaneous calcium deposition) is common in patients with SSc and although this is often subclinical (eg only seen on radiographs), it can cause significant pain and ulcerate/become infected. Marked pruritus is often seen in patients with early diffuse cutaneous disease.

Which patient groups are most susceptible?This can be considered in relation to the proposed criteria for the ‘very early diagnosis of systemic sclerosis’ (VEDOSS). VEDOSS should be suspected in patients with one of three red flags: Raynaud’s phenomenon, puffy fingers or the presence of antinuclear antibodies (ANA). The diagnosis is then made by either the presence of SSc-associated autoantibodies and/or abnormal nailfold capillaries. ANA are present in the majority (over 95%) of patients with SSc.22 Common SSc-associated autoantibodies are anti- topoisomerase I (Scl-70), anticentromere and anti-RNA polymer-ase III.23 The key importance of these antibodies is reflected through their inclusion in recent classification criteria for SSc (see Table 2).24

Nailfold capillaroscopy is a non-invasive imaging method that allows the microcirculation to be examined in situ. The nailfold capillaries run parallel to the skin at the base of the nail and this allows them to be examined in their entirety. Normal nailfold cap-illaries are reassuring and have a regular and uniform (‘hairpin’

Item Sub-item(s) Weight/score

Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (sufficient criterion)

9

Skin thickening of the fingers (only count the higher score)

Puffy fingersSclerodactyly of the fingers

24

Fingertip lesions (only count the higher score)

Digital tip ulcersFingertip pitting scars

23

Telangiectasia 2

Abnormal nailfold capillaries 2

Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2)

Pulmonary arterial hypertension Interstitial lung disease

2

2

Raynaud’s phenomenon 2

Systemic sclerosis-related autoantibodies (maximum score is 3)

AnticentromereAnti-topoisomerase IAnti-RNA polymerase III

3

Table 2. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for systemic sclerosis.24 Although these are intended for use as classification and not diagnostic criteria, they are a useful reference aid for clinicians in routine clinical practice. Patients with a total score of ≥9 are classified as having definite scleroderma. A key exclusion is that the criteria should not be applied to those patients who have a scleroderma-like disorder that better explains their manifestations (eg eosinophilic fasciitis and scleromyxedema)



like) appearance. For those clinicians who do not have access to a stereomicroscope or videocapillaroscopy (the latter of which is considered to be the ‘gold standard’), capillaroscopy can also be performed using lower magnification techniques including an ophthalmoscope, dermatoscope or USB microscope.25,26 In a study that included 586 patients who were followed up for 3197 person-years, the presence of SSc-specific autoanti-bodies and SSc-type capillaroscopic abnormalities were inde-pendent predictors of the development of SSc (hazard ratios of 4.7 and 4.5 respectively).27 Patients with both abnormalities were 60 times more likely to develop SSc.

First- and second-line treatment optionsFigure 3 presents an overview of the British Society of Rheumatology/British Health Professionals in Rheumatology (BSR/BHPR) guideline for the treatment of SSc,9 which is a useful reference tool for clinicians in both primary and sec-ondary care alike. A key point to highlight is the importance of distinguishing between the limited and diffuse subsets of SSc, as this has an important impact on the likely disease course including prognosis, and in making treatment decisions. Table 3 presents first- and second-line treatment options for SSc. Symptomatic treatment is indicated in all patients with SSc, including for vascular manifestations (eg Raynaud’s phe-nomenon). We have recently described in detail the assessment and management of Raynaud’s phenomenon.28 An approach to treatment of the condition is summarised in Table 4. Early diffuse cutaneous SSc is a management priority and often

requires the introduction of immunosuppressive treatment (ie cyclophosphamide, methotrexate or mycophenolate mofetil). Regular follow-up is needed in all patients with SSc, including to observe for the development of organ-based complications.

Emerging treatment optionsThere has been a flurry of recent and ongoing international research into the treatment of SSc, including in patients with early diffuse disease. In a recent double-blind, placebo-con-trolled trial, treatment with tocilizumab (an interleukin 6 recep-tor-α inhibitor) was associated with a greater reduction of skin thickening at 24 weeks than placebo.29 Several studies have supported autologous stem cell trans-plantation as a viable treatment option for patients with poor prognosis SSc.30,31 Compared with the existing gold standard of cyclophosphamide, treatment may stabilise/improve skin sclerosis and internal organ involvement, and is associated with a long-term survival benefit. However, it is also associated with an increased early treatment-related mortality, and should not be considered as a ‘cure’ for the disease.

The GP’s role in management The GP’s role is two-fold. Firstly, GPs must be ever vigilant and consider the diagnosis of SSc, especially in patients presenting with Raynaud’s phenomenon. A suggested referral pathway in primary care for patients with possible SSc is presented in Figure 4. Secondly, GPs have an overall picture of SSc patients’ ongoing care, and are likely to be consulted by patients, in par-

Figure 3. Overview of the British Society for Rheumatology/British Health Professionals in Rheumatology (BSR/BHPR) treatment guideline for systemic sclerosis (SSc)9

IcSSc dcSSc Overlap SSc

Therapy: vascular

Therapy: vascular, immunosuppressive

Manage according to severity and activity of overlap features

– arthritis, myositis, lupus

Identification and treatment of severe organ-based

complicationsTherapy of major organ-based

complications

Management of common morbidityRaynaud’s, upper GI, anorectal disease, erectile

dysfunction, calcinosis, telangiectasia

Systemic sclerosis

lcSSc = limited cutaneous systemic sclerosis; dcSSc =diffuse cutaneous systemic sclerosis


Systemic sclerosis l PRESCRIBING IN PRACTICE ■

ticular between hospital attendances, about symptoms poten-tially related to disease-related complications. In addition, disease-modifying therapy is often prescribed and monitored in primary care. Strong links between primary and secondary care are needed in the care of patients with SSc.

ConclusionSSc is a serious and potentially life-threatening rheumatological condition that has a significant impact on the patient’s quality of life. There is an increasing interest in facilitating the earlier diagnosis of SSc, and GPs have a key role in identifying those patients likely to develop SSc, including those presenting with Raynaud’s phenomenon. There are now a number of available treatments to manage the different organ-based complications associated with the disease. Immunosuppressive therapies are indicated in early diffuse cutaneous SSc. Emerging therapies including stem cell transplantation are now a treatment reality, and many new treatments are now being researched. GPs have an important role in the care of patients with SSc and therefore need to be aware of the many possible manifestations of the dis-ease, and the different and emerging approaches to treatment.

References1. Gabrielli A, et al. Scleroderma. N Engl J Med 2009;360(19):1989–2003. 2. Allanore Y, et al. Systemic sclerosis. Nat Rev Dis Prim 2015;23;1:15002.

Organ system Clinical manifestation Examples of treatments

Skin and musculoskeletal

SclerodermaInflammatory arthritis

Immunosuppressive therapy (eg cyclophosphamide, methotrexate and mycophenolate mofetil)

Cardiovascular Heart failure

Inflammatory cardiac disease

Appropriate drug therapies used in heart failure (eg ACE inhibitors and diuretics)Immunosuppressive therapy (eg steroid and/or cyclophosphamide)

Respiratory Pulmonary arterial hypertension

Interstitial lung disease

Endothelin-receptor antagonistsProstacyclin analogues Phosphodiesterase type 5 (PDE5) inhibitorsSoluble guanylate cyclase agonistsImmunosuppressive therapy (eg cyclophosphamide and mycophenolate mofetil)

Gastrointestinal Gastro-oesophageal reflux disease Proton-pump inhibitors

Peripheral vascular Raynaud’s phenomenon and digital ulcers Calcium-channel blockersPDE5 inhibitorsAngiotensin II-receptor blockersEndothelin-receptor antagonists Prostacyclin analogues (eg intravenous iloprost)

Renal Scleroderma renal crisis ACE inhibitors

Table 3. First- and second-line treatment options for systemic sclerosis.9 Some of these treatments can potentially be initiated in primary care (eg drug therapy for Raynaud’s phenomenon and proton-pump inhibitors for reflux disease). Scleroderma renal crisis is a medical emergency that requires immediate specialist input. Drugs for pulmonary arterial hypertension should be initiated under the supervision of a specialist centre

• First distinguish between primary and secondary Raynaud’s phenomenon – including consideration of referral to rheumatology, in particular, if concern about a secondary cause, including systemic sclerosis

• Patient education is essential for all patients• Scleroderma and Raynaud’s UK (SRUK) is a useful source of

information about Raynaud’s phenomenon (and systemic sclerosis) for both patients and clinicians (www.sruk.co.uk)

• Lifestyle adaption and conservative measures (eg keeping warm and cold avoidance) is indicated in all patients with Raynaud’s phenomenon.

• Efforts should be made to support smoking cessation, if relevant • Drug therapies are indicated if conservative measures are insufficient

to control symptoms• Calcium-channel blockers are often used as first-line treatment• Phosphodiesterase type 5 (PDE5) inhibitors are increasingly being

used after failure of calcium-channel blockers• Other drug therapies used in Raynaud’s phenomenon include

angiotensin II-receptor blockers and fluoxetine• Digital ulcers and critical digital ischaemia represent persistent

ischaemia/gangrene and can result in significant ischaemic tissue loss/need for amputation

• Persistent discolourisation/evolving gangrene is a medical emergency, which requires urgent evaluation

Table 4. An approach to the treatment of Raynaud’s phenomenon



3. Allcock RJ, et al. A study of the prevalence of systemic sclerosis in northeast England. Rheumatology (Oxford) 2004;43(5):596–602. 4. Valentini G, Black C. Systemic sclerosis. Best Pract Res Clin Rheumatol 2002;16(5):807–16. 5. Mayes MD, et al. Prevalence, incidence, survival, and disease charac-teristics of systemic sclerosis in a large US population. Arthritis Rheum 2003;48(8):2246–55. 6. Altorok N, et al. Epigenetics, the holy grail in the pathogenesis of systemic sclerosis. Rheumatology (Oxford) 2015;54(10):1759–70. 7. Hughes M, Herrick AL. Digital ulcers in systemic sclerosis. Rheumatology (Oxford) 2017;56(1):14–25. 8. Hughes M, et al. Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology 2015;54(11):2015–24. 9. Denton CP, et al. BSR and BHPR guideline for the treatment of sys-temic sclerosis. Rheumatology (Oxford) 2016;55(10):1906–10.10. Chaisson NF, Hassoun PM. Systemic sclerosis-associated pulmo-nary arterial hypertension. Chest 2013;144(4):1346–56. 11. Hachulla E, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinerAIR-Sclerodermie study. Rheumatology 2008;48(3):304–8. 12. Humbert M, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis

and long-term survival. Arthritis Rheum 2011;63(11):3522–30. 13. Kahan A, et al. Cardiac complications of systemic sclerosis. Rheumatology 2006;48(Suppl. 3):iii45–8. 14. Lambova S. Cardiac manifestations in systemic sclerosis. World J Cardiol 2014;6(9):993–1005. 15. Au K, et al. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum 2011;63(7):2078–90. 16. Man A, et al. The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study. Ann Rheum Dis 2013;72(7):1188–93. 17. Hasegawa M, et al. Arteriographic evaluation of vascular changes of the extremities in patients with systemic sclerosis. Br J Dermatol 2006;155(6):1159–64. 18. Forbes A, Marie I. Gastrointestinal complications: the most frequent internal complications of systemic sclerosis. Rheumatology (Oxford) 2009;48(Suppl. 3):iii36–9. 19. Penn H, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. Q J Med 2007;100(8):485–94. 20. Denton CP, et al. Renal complications and scleroderma renal crisis. Rheumatology (Oxford) 2009;48(Suppl. 3):iii32–5.21. Thombs BD, et al. Depression in patients with systemic sclerosis: a systematic review of the evidence. Arthritis Rheum 2007;57(6):1089–97.22. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005;35(1):35–42. 23. Kayser C, Fritzler MJ. Autoantibodies in systemic sclerosis: unan-swered questions. Front Immunol 2015;6:167. 24. van den Hoogen F, et al. 2013 classification criteria for systemic scle-rosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2013;65(11):2737–47. 25. Baron M, et al. Office capillaroscopy in systemic sclerosis. Clin Rheumatol 2007;26(8):1268–74.26. Hughes M, et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis–spectrum disorders. Rheumatology (Oxford) 2015;58(3):1435–42.27. Koenig M, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phe-nomenon to systemic sclerosis: A twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008;58(12):3902–12.28. Hughes M, Herrick A. Assessment and management of Raynaud’s phenomenon. Prescriber 2017;28(7):11–6. 29. Khanna D, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 2016;387(10038):2630–40. 30. van Laar JM, et al. Autologous hematopoietic stem cell transplan-tation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis. JAMA 2014;311(24):2490–8. 31. Sullivan KM, et al. Myeloablative autologous stem-cell transplanta-tion for severe scleroderma. N Engl J Med 2018;378(1):35–47. 32. LeRoy EC, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15(2):202–5. 33. Gunawardena H, McHugh N. Features and recommended treatment of systemic sclerosis. Prescriber 2008;7:59–65.

Declaration of interestsNone to declare.

Dr Michael Hughes is a Consultant Rheumatologist in the Department of Rheumatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield

Figure 4. Suggested referral pathway in primary care for patients with possible systemic sclerosis (SSc). Adapted from Gunawardena and McHugh. Prescriber 2008;7:59–6533

Other features of SSc

Investigations negative and no other

features of SSc

Monitor and observe for features of possible SSc

Develops features of SSc

Refer to rheumatology

*Minimal (or ‘basic’) investigations in patients presenting with Raynaud’s phenomenon should comprise a full blood count, erythrocyte sedimentation rate, antinuclear antibody (ANA) measurement and nailfold capillaroscopy, all of which should be normal/negative in primary Raynaud’s phenomenon28

Routine investigations* including ANA

Abnormal investigations including ANA,

especially SSc-associated

antibodies

Patient presenting with Raynaud’s phenomenon

early diagnosis and management of systemic sclerosis · of systemic sclerosis michael hughes...

Documents