Table 3 Management of organ-specific affection of systemic sclerosis

Raynaud’s phenomenon (RP) and digital vasculopathy/digital ulcers

(more details are represented in supplement 1)

Recommendations for RP in SSc

• The aim of RP treatment is to decrease its severity, at least a moderate reduction in the intensity of attacks, and prevent RP complications as prevention of tissue loss and digital ulceration

• Patient education and lifestyle modification to maintain body warmth and avoid other triggers for RP, discontinuing all tobacco products, and avoiding the precipitating factors and drugs which exacerbate RP are essential in RP management

• First-line treatments are calcium channel blockers (1,A) and angiotensin II receptor antagonists (2,C)

• Calcium channel blockers (CCB) (with gradually increasing dose) are the first line of treatment for RP to decrease the severity and frequency of incidence of RP.(2,C)

• In cases that do not respond adequately to a CCB alone, add or substitute either a phosphodiesterase 5 (PDE 5) inhibitor or a topical nitrate. (The combination of PDE type 5 inhibitors and topical nitrates should be avoided due to the increased risk of hypotension). (3, C)

• In severe/resisted or complicated cases, Selective serotonin reuptake inhibitors (SSRIs) (fluoxetine at 20 mg/day), and prostacyclin analogs may be used. (3,C)

• Oral antiplatelet and anticoagulant agents, pentoxifylline, and statins may be used in certain conditions as supplementary treatment. (4,D)

Recommendations for digital ulcers in SSc

• DUs require integrated management by a multidisciplinary team; management includes local and systemic treatment (3, C)

• Digital ulcers must be cleaned, and mechanical debridement of hyperkeratotic covering should be done (3, C)

• Oral vasodilator treatment should be optimized, analgesia optimized and any infection promptly treated (3, C)

• Sildenafil should now be used before considering i.v. prostanoids and bosentan (1, A)

• In severe active digital ulceration, patients should receive i.v. prostanoid (1, B). In patients with recurrent, refractory DUs, a phosphodiesterase type 5 inhibitor (1, B) or i.v. prostanoid (1, B) and an endothelin receptor antagonist (including bosentan; 1, B) should be considered

• In severe and/or refractory digital ulcers: Digital (palmar) sympathectomy (with or without botulinum toxin injection/ hyperbaric oxygen therapy) may also be considered (3, D)

8.38 ± 0.7

100%

High

Skin affection

• Treatment of skin thickening, assessed by modified Rodnan skin score, is central to the management of dcSSc treatment, and pruritus is common and troublesome in early-stage disease. (3, B)

• Patients with early dcSSc should be offered an immunosuppressive agent (3, C)

• Using low-dose corticosteroids at edematous cutaneous SSc should be individualized and evaluated case by case due to fear of SSc renal crisis (SRC) precipitation. (3, B)

• Local softening and moisturizing cream or lotion should be applied to the patient’s skin (3, C)

• Methotrexate is the first line of treatment of cutaneous manifestations of SSc with moderate effect, MMF or CYC could be used as alternative therapy (2, C)

• Rituximab may be an option in refractory severe cutaneous affection in SSc.(4, C)

• Tocilizumab, IVIG, and HSCT may be alternative options in refractory severe cutaneous SSc.(3, C)

• Pruritus could be treated with anti-histaminics or low-dose corticosteroids for a short period.(1, C)

• Current treatment options for telangiectasia include skin camouflage and laser or intense pulsed light therapy (3, C)

Calcinosis in SSc: (3, C)

• There is no effective treatment for calcinosis, colchicine may be tried with mild effect in inflammatory lesions

• Surgical excision can be proposed to promote healing and avoidance of secondary infection

• Calcinosis complicated by infection should be recognized early and treated with appropriate antibiotic therapy

• Surgical intervention should be considered for severe, refractory calcinosis, which is severely impacting upon functional ability and quality of life

8.92 ± 0.3

100%

High

Musculoskeletal disease

• Musculoskeletal involvement includes tendinopathy, joint contractures and, in some cases, overlap arthritis. (3, C)

• NSAIDs and short period of low-dose corticosteroids may be enough for mild arthralgia and early tenosynovitis.(3, D)

• Methotrexate is used for the treatment of inflammatory arthritis

• Rituximab and tocilizumab might be an alternative option in the failure of methotrexate and low-dose corticosteroids(3, C)

• TNFi should be avoided in SSc due to fear of fatal exacerbation of fibrosing alveolitis.(2, C)

• In cases of overlap between SSc and inflammatory myositis; corticosteroids (dose not exceed 0.5 mg/kg/d for fear of SRC) and MTX may be added to the conventional treatment of SSc, with MMF, and rituximab may be considered as alternative options.(2, B)

• Osteoporosis should be expected in patients with SSc and should be properly assessed and managed

8.77 ± 0.4

100%

High

Cardiopulmonary complications

(PAH) (3, C)

• Early diagnosis and management are essential for improving the outcome of SSc-PAH

• Diagnostic evaluation:

 - Clinical assessment: risk factors, history/symptoms, physical examination

 - Lab: auto-antibodies, BNP/NT, proBNP

 - Functional assessment: O2 saturation, cardiopulmonary exercise test (CPET)

 - Cardiac: Echo, ECG

 - Pulmonary functions: Pulmonary function tests/DLCo

• When to suspect:

 - Asymptomatic phase

 - Early symptoms: Shortness of breath with activity, palpitation

 - Late symptoms: Feeling tired (fatigue), signs of right heart failure (legs and ankles edema), arrhythmia, exertional chest pain/pressure, dizziness/syncope)

• An expert cardiologist should be involved with the rheumatologist in the management of SSc-PAH

• The best predictor for PAH development in SSc is declining DLCo, and Echocardiography should be done annually on all the patients. Rt heart catheterization is the gold standard test for the diagnosis of PH

• Pulmonary hypertension definition:

 - Mean pulmonary artery pressure (PAP: ≥ 20 mmHg

 - Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg

 - Pulmonary vascular resistance (PVR) > 2 wood units

• Risk factors and predictors:

 - Late age onset of scleroderma

 - Longer disease duration (> 8 years)

 - Limited scleroderma

 - Severe Raynaud’s phenomenon

 - Numerous and prominent telangiectasia

 - Low diffusion capacity (DLCo < 55%, FVC/DLC0 > 1.6)

 - NT-pro BNP elevation (together with low DLCo)

 - Auto-antibody association: anti-centromere, U1-RNP, Th/To

• Staging and risk stratification: Treatment of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) is guided by risk stratification, which uses information from clinical assessments and imaging

• Risk is graded using the REVEAL 2.0 calculator (involving 14 variables): a REVEAL score ≤ 6 corresponds with a low risk, a score of 7 or 8 corresponds to an intermediate risk and a score ≥ 9 indicates a high risk

 • Risk factors and predictors

 ▪ Late age onset of scleroderma

 ▪ Longer disease duration (> 8 years)

 ▪ Limited scleroderma

 ▪ Severe Raynaud’s phenomenon

 ▪ Numerous and prominent telangiectasia

 ▪ Low Diffusing Capacity (DLCO < 55%, FVC%/DLCO% > 1.6)

 ▪ NT-pro BNP elevation (together with low DLCO, HR = 47.2)

 ▪ Autoantibody associations:

 - Anti-Centromere, U1-RNP, U3 RNP, Th/To

• Four groups of pulmonary hypertension-specific therapies can be considered in the treatment of SSc-PAH: endothelin receptor (ETR) antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase (sGC) stimulators, and prostacyclin analogs and receptor agonists

• Low or intermediate risk:

Oral combination therapy with ETR antagonist and PDE5 inhibitor

Monotherapy with either an ETR antagonist or PDE5 inhibitor if:

  − Very mild PAH (e.g., WHO functional class I, (Pulmonary vascular resistance) PVR 3–4 WU, mPAP < 30 mmHg, normal right

  − ventricle at echocardiography)

  − PAH with suspicion or high probability of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis

  − Long-term-treated historical PAH in patients on stable monotherapy (> 5–10 years) with a low-risk profile

  − Combination therapy is unavailable or contraindicated (e.g., because of severe liver disease)

• High risk:

Combination therapy including

 - Intravenous prostacyclin analogue

 - Consider referral for lung transplantation

• Refractory cases:

 - Sequential combination therapy between two or three (endothelin-receptor antagonists, phosphodiesterase 5 inhibitors, and prostacyclin) is recommended

 - Lung-heart transplantation is the last option in the management of SSc-PAH

Monitoring: serial PFT and repeat HRCP to determine progression and need for treatment

Risk assessment after 3–6 months:

  − Low risk: structured follow-up

  − Intermediate or high risk: triple combination therapy with an ETR antagonist, PDE5 inhibitor, and prostacyclin analog

–––––––––––––––––––

(Pericarditis) (1, B)

• NSAIDs and colchicine are the first line of treatment of pericarditis

• High-dose corticosteroids and/or pericardial drainage should be considered in severe cases

–––––––––––––––––––

Arrhythmia (2, B)

• Use anti-arrhythmic drugs should be used (beta blockers usually are contraindicated due to their negative effects on RP and digital ulcers)

• Anti-coagulants should be considered in certain conditions of supraventricular tachycardia

• Pacemaker may be considered for severe conduction disorders

––––––––––––––––-

Cardiac affection

• Evaluation of heart involvement in systemic sclerosis:

  All SSc patients should be assessed annually for new symptoms/abnormal findings:

  - Unexplained dyspnea

  - Palpitation

  - Syncope or pre-syncope

  - Chest pain

  - Dependent edema

  - Troponin elevation

  - BNP elevation

  - Left ventricular dysfunction (low LVEF)

  - Ischemic changes

  - Arrhythmia, conduction defects

• Cardiology referral:

  - Cardiac MRI

  - Stress Test

  - Coronary angiogram

  - Right heart catheterization

  - Holter/even recorder

  - Cardiac electrophysiology

Heart failure

  - Systolic heart failure

  i. Consider immunosuppression with or without a pacemaker (4, D)

  ii. Consider the potential benefit of an implantable cardioverter defibrillator (3, D)

  iii. Angiotensin-converting enzyme inhibitors and carvedilol. Selective β-blockers may be considered, but consider aggravation of RP (4, D)

Diastolic heart failure with preserved left ventricular ejection fraction

  i. Diuretics, including spironolactone and furosemide (4, D)

  ii. Calcium channel blockers have been shown to reduce the frequency of systolic heart failure in SSc with investigational evidence of cardiac abnormalities (3, D)

8.61 ± 0.5

100%

High

Pulmonary complications (interstitial lung disease (ILD))

• All SSc cases should be assessed for lung fibrosis. Up to 80% of SSc will develop ILD, but this might be mild and stable

Early diagnosis and management are essential for improving the outcome of SSc-ILD

• When to suspect:

  - It can be silent: no symptoms

  - Shortness of breath (also consider anemia, deconditioning, muscle weakness, aspiration, cardiac disease)

  - Chronic cough: Also acid reflux, post-nasal discharge

  - Fatigue: also deconditioning, anemia, depression

  - Weight loss: also GI disease, malabsorption

• Diagnostic Evaluation:

  - Clinical assessment

  - Lab: Auto-antibodies (ENA). Comorbidities: FBC, CK/ Aldolase, NT-proBNP, Troponin

- Cardiac studies: ECHO, ECG

- Pulmonary function tests (not screening tool, establish baseline [ILD severity, prediction], assess progression [change over time], suspect comorbidities [Myopathy: low FVC, normal DLCo/ Pulmonary hypertension: isolated DLCo, high FVC/DLCo]

- Imaging: Gold standard. It shows the anatomical distribution, severity, prediction, subsets [NSIP/UIP]

• Risk factors for SSc-ILD onset and progression:

  − Diffuse SSc (70–80%) > Limited SSc (15–25%)

  − Early disease: the majority of lung function declines in first 2–4 years

  − Severe gastro-esophageal reflux

  − Advanced age

  − Racial/Ethnic background (African American)

  − Elevated acute phase reactants-ESR, CRP

  − Autoantibodies: Increased risk: [anti-SCL70 (70%), Pm/Scl (70%), Th/To (50%), U1-RNP (40%), U3-RNP]. Decreased risk: (anti-Centromere)

• All patients with SSc should be screened for SSc-associated ILD using HRCT, particularly if they are showing respiratory symptoms or have one or more risk factors

• Diffusion lung capacity (DLCo): sensitive but not specific. Decreases in obstructive, restrictive, anemia, and pulmonary vascular disease

• An expert pulmonologist should be involved with the rheumatologist in the management of SSc-ILD

• The decision to initiate ILD-directed therapy must be made on a case-by-case based on the extent and severity of ILD

• Initial therapy: cyclophosphamide (CYC) or mycophenolate mofetil (MMF) are the drugs of choice for patients with progressive SSc-ILD, (MMF is safer and better tolerated). (3, C)

• Tocilizumab and rituximab could be used as initial therapy for SSc-ILD in patients who are not able to take MMF or CYC.(4, C)

• Maintenance treatment is continued for at least 2 years and often several years, according to the disease course (the treatment should continue till sustained disease stability.(4, C)

• MMF or azathioprine are recommended as maintenance therapy for SSc-ILD. (3, C). Tocilizumab also might be considered for maintenance therapy. (4, C)

• In refractory cases, the addition of rituximab or antifibrotic agents such as nintedanib to the ongoing therapy is recommended.(4, C)

• Hematopoietic Stem Cell Transplantation (HSCT) should be reserved for patients who failed all previous therapies. (5, D)

• Lung transplantation may be considered in severe respiratory failure if the patient is fit for operation.(3, B)

• Adjuvant corticosteroids are reserved for patients with extrapulmonary affection.(4, D)

• Adding prophylactic vaccination for pneumococcal, influenza, and COVID-19 infections is recommended before starting ILD treatment with immunosuppressants.(3, B)

8.31 ± 0.9

100%

High

Gastrointestinal tract disease

Oropharyngeal disease (3, B)

• Regular dental hygiene is necessary for preventing dental caries

Gastro-esophageal disease (3, C)

• Avoidance of eating 2 h before sleep and dietary modification is recommended

• It is better to confirm eradication of H. Pylori before starting long-standing anti-inflammatory drugs or corticosteroids as its presence increases peptic ulcer complications

• GERDs are treated with proton pump inhibitors, histamine H2 receptor antagonists, and HCL antisecretory drugs

• Prokinetic dopamine antagonists may be used for dysphagia and reflux

• Injectable octreotide may be considered, and endoscopic injection of botox into the pyloric sphincter has been used for resistant cases of GERD

• iron replacement therapy and red blood cells transfusion may be used for gastric antral vascular ectasis (GAVE) treatment

• argon plasma coagulation or laser therapy are effective for GAVE treatment

Intestinal (3, C)

• Intermittent broad-spectrum oral antibiotics (e.g. ciprofloxacin) are recommended for intestinal overgrowth, and rotational regimes may be helpful

• Parenteral nutrition should be considered in severe malabsorption and deteriorated general condition refractory to enteral supplementation

• Anti-diarrhoeal agents (e.g., loperamide) or laxatives may be used for symptomatic management of diarrhea or constipation that often alternate as clinical problems

• Rifaximine is a locally acting anti-microbial and recommended in cases of small intestinal bacterial overgrowth as it works locally with no systemic complications

8.69 ± 0.5

100%

High

Renal complications

• Patients at risk of scleroderma renal crisis (SRC), should be followed closely and their blood pressure monitored at least weekly (3, C)

• Risk Factors:

▪ Early diffuse skin disease: 2–3 years from SSc onset, median 8 months

▪ Anti-RNA polymerase III (60%)

▪ Use of corticosteroids > 15 mg/day or low doses for longer time

• Avoidance of corticosteroids ( dose > 20 mg/day) is important to avoid scleroderma renal crisis (SRC), as this might precipitate its incidence(2, B)

• The onset of SRC usually occurs in early diffuse scleroderma (the first 1–4 years after diagnosis) (2, C)

• SRC can mark SSc onset or precede SSc diagnosis (20% no skin involvement)

• SRC is a medical emergency in which the patient should be hospitalized

• SRC typical clinical presentation

 - Very high blood pressure (> 20 mmHg over usual blood pressure)

 - Sudden renal failure (rising creatinine, proteinuria)

 - Malignant hypertension (flash pulmonary edema, headache, retinopathy, encephalopathy)

 - Hemolytic anemia and/or thrombocytopenia (thrombotic microangiopathy, schistocytes)

• The aim of treatment is to decrease systolic blood pressure by 20 mmHg within the first 24 h

• The first line of treatment is ACE inhibitor (3, C), a long-acting ACEi is most used but short-acting agents might be recommended in cases with hemodynamic compromise

• Calcium channel blockers may be considered as a second line of treatment for the management of refractory hypertension in conjunction with an angiotensin-converting enzyme inhibitor in SRC (3, C)

• There is no evidence about using ACE inhibitors in SRC prophylaxis, using ACE inhibitors may prevent early diagnosis of SRC in some patients by modulating hypertension

• Renal dialysis and renal transplantation may be required in resisted SRC patients.(4, C)

• ACE inhibitors should be continued even in patients who have progressed to dialysis, as renal dialysis may be temporary if renal functions improve

8.62 ± 0.5

100%

High

Neurological complications

• Neuropathy is common in the first 10 years after SSc onset

• Compression neuropathies can be treated with decompression surgery.(4, C)

• Non-compression peripheral neuropathy in SSc may occur secondary to traumatic injury, ischemia, metabolic sequelae, or adverse effects of medication. (3, C)

• Treatment of non-compressive peripheral neuropathies included corticosteroids, CYC, amitriptyline, gabapentin, methotrexate, and anticonvulsants.(3, D)

8.15 ± 1.6

92.3%

High