This week in Morning Report we discussed classification of different subtypes of systemic sclerosis, manifestations of each subtype, investigations, and a brief overview of management. The summary is posted below.

1. An Approach to Polyarthritis

We began our discussion with a differential diagnosis for polyarthritis, which included:

• Seropositive arthritis
  • Rheumatoid arthritis
    • Subtypes of this which include RS3PE
  • Systemic lupus erythematosus
  • Scleroderma or systemic sclerosis
  • Mixed connective tissue disease
  • Sjogren’s syndrome (can get Jacoud’s arthropathy)
  • Dermatomyositis
• Osteoarthritis
• Viral polyarthritis (parvovirus B19 as an example)
• Drug-induced causes such as drug-induced lupus
• Crystal arthropathy such as polyarticular gout
• Less likely seronegative disease (psoriatic arthritis, ankylosing spondylitis, IBD-related arthritis, reactive arthritis)
• Polymyalgia rheumatica
• Infectious arthritis like Lyme arthritis
• Sarcoid arthropathy

2. Classification of Systemic Sclerosis Subtypes

There are four subtypes of systemic sclerosis outlined by the diagram. In this section we discuss the features of the subtypes.

SSc sine scleroderma:

Defined as having features of systemic sclerosis without skin induration. This includes having each of the following:

• Raynaud’s or a peripheral vascular finding such as digital tip pitting scars or ulcers, gangrene, abnormal nailfold capillaries
• Positive ANA with a speckled or nucleolar immunofluorescence pattern
• One of: interstitial fibrosis, primary pulmonary arterial hypertension without fibrosis, esophageal motility alterations that are characteristics to the disease, or renal failure in keeping with scleroderma renal crisis (SRC)

Limited Cutaneous Systemic Sclerosis (lcSSc)

• Face and limbs (distal to elbows and knees) and puffy fingers distal to MCPs
• Trunk and proximal extremities are spared
• Many patients with lcSSc have CREST syndrome
  • Calcinosis (calcium deposits in the skin)
  • Raynaud’s phenomenon (vasoconstriction in response to cold or stress)
  • Esophageal dysfunction (acid reflux, decrease in motility of the esophagus)
  • Sclerodactyly – thickening and tightening of the skin of the hands/fingers
  • Telangectasias – Dilatation of capillaries
• Prominent vascular manifestations
• Pulmonary hypertension
• Raynaud’s (can lead to digital ulceration, ischemia, or infarction)
• Antibodies:
  • ANA, anti-centromere

Diffuse Cutaneous Systemic Sclerosis (dcSSc

• Puffy hands and skin thickening that develops proximal to elbows and knees
• Associated with internal organ involvement:
  • Interstitial lung disease
  • Renal Crisis
  • Cardiac disease (pericardial, myocardial, or conduction)
  • GI (dysmotility, angiodysplasias)
• Antibodies:
  • ANA, anti-Scl70 (anti-DNA Topoimerase I)
  • Anti-RNA polymerase III antibody is generally associated with rapidly progressive skin involvement as well as an increased risk for scleroderma renal crisis (SRC)

What are cutaneous manifestations in systemic sclerosis?

• Skin thickening and hardening
• Calcinosis cutis (calcifications in the soft tissue)
• Telangiectasias
• Digital tip ulcers and/or pitting at the fingertips and ulceration over the DIP and PIP related to repetitive microtrauma over tightened skin
• Capillary nail changes
• Pruritus and edema in early stages
• Skin hyperpigmentation or depigmentation (“salt and pepper”)
• Loss of appendicular hair
• Dry skin
• Lipoatrophy

3. Diagnostic Criteria for Systemic Sclerosis

The diagnostic criteria for systemic sclerosis is listed below and a total score of 9 or more is needed to make the diagnosis.

Criterion	Score
Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints Skin thickening of the fingers (only count the highest score in this section) –> If puffy fingers: Score of 2 –> If whole finger, distal to the MCP: Score of 4	9
Fingertip lesions (only count the highest score) Digital tip ulcers: 2 Pitting scars: 3
Telengectasias	2
Abnormal nailfold capillaries	2
Pulmonary arterial hypertension and/or interstitial lung disease	2
Raynaud’s phenomenon	3
Scleroderma related antibodies (any of anti-centromere, anti-topoisomerase/anti-SCL70, anti-RNA polymerase III)	3

4. Management of Systemic Sclerosis

Before we go into management of the different complications of systemic sclerosis, one of the complications that we discussed at morning report is scleroderma renal crisis (SRC).

Scleroderma renal crisis:

This refers to the onset of malignant hypertension (though can have normotensive cases) as well as acute onset of oligo-anuric renal failure. The urinalysis reveals mild proteinuria. Microangiopathic hemolytic anemia and thrombocytopenia can occur. The mainstay of treatment is anti-hypertensives with ACE-inhibitors, specifically captopril.

Inflammatory Arthritis

An expert consensus study (see reference #1 below) showed that for inflammatory arthritis, 79% of experts agreed that first- through fourth-line treatments were: 1) Methotrexate, 2) low-dose glucocorticoids, 3) Hydroxychloroquine, and 4) Rituximab or tocilizumab, respectively.  Also if not contraindicated, can use NSAIDs for symptomatic relief of arthralgias. Steroids were used in low doses (54% with prednisone at <7.5 mg/day and 41% at 7.5–20 mg/day) for a short period (67% would prescribe for less than three months, 8% for three to six months, and 25% for more than six months).

Raynaud’s Phenomenon	– Dihydropyridine-type calcium antagonists (nifedipine) diminished frequency and severity of attacks – (Phosphodiesterase type 5) PDE-5 inhibitors should also be considered – Prostanoids reduce the frequency and severity of attacks (intravenous iloprost in severe) – Small study indicated that fluoxetine might improve attacks
Digital ulcers	– Intravenous iloprost for healing digital ulcers – PDE-5 inhibitors promote healing of digital ulcers and can prevent further digital ulcer formation – Bosentan (two high-quality RCTs) efficacious in diminishing the number of new digital ulcerations in patients with SSc (should be considered to reduce the number of new digital ulcers especially if this occurs despite other therapies)
Pulmonary arterial hypertension	– Several endothelin receptor antagonists (ERAs) (ambrisentan, bosentan, and macitentan), PDE-5 inhibitors (tadalafil, sildenafil) and riociguat have been approved for treatment – Intravenous epoprostenol improves exercise capacity and hemodynamic measures – Other prostacyclin analogues can be used
Skin and lung disease	– Methotrexate improves skin score in early diffuse SSc in those without visceral involvement –Cyclophosphamide should be considered in patients with ILD (particularly in progressive ILD) -Two RCTs have shown that hematopoietic stem cell transplant will improve skin findings and steady lung function
Scleroderma-related GI disease	– Experts recommend PPI should be used for the treatment of SSc-related GERD and can prevent esophageal ulcers/ stricture development (lack of RCTs) – Lack of RCTs, but experts recommend prokinetic drugs should be used for the management of SSc-related symptomatic motility disturbances (dysphagia, GERD, early satiety, bloating, pseudo-obstruction, etc) – Intermittent or rotating antibiotics to treat symptomatic small intestine bacterial overgrowth in patients with SSc (despite lack of RCTs)

5. Counselling on Common Medications

Finally, a few medications that we discussed during morning report are listed here. Side effects and pearls on drug monitor are listed below! This is not a comprehensive list of all the medications that a patient

Drug	Side Effects to Counsel and Monitoring
Glucocorticoids	Side effects: HTN specifically precipitating scleroderma renal crisis Reactivation of infections (hepatitis B, TB) Infections such as pneumocystis Avascular necrosis Hyperglycemia Osteoporosis Steroid myopathy Hair/skin changes among others side effects – PJP prophylaxis: depends on dose (prednisone of 20 mg or more planned for 4 weeks or more usually requires PJP prophylaxis) – Prednisone 7.5 mg or more screen for hepatitis B – Prednisone 15 mg or more for one month or more à screen for latent TB – Strongyloides in those who have lived in or traveled to endemic area
Methotrexate	Hepatotoxicity, nausea, pancytopenia, hypersensitivity pneumonitis, fibrosis, oral ulcers, alopecia, teratogenic – Baseline CXR, HCV, HBV, CBC, liver profile, Cr – Initially CBC, liver profile, Cr q2-4 weeks for 3 months or if dose changes, then q8-12 weeks during 3 to 6 months, then q12weeks. More frequent if indicated (from UpToDate)
Hydroxychloroquine	– Complications to know of include: retinal toxicity, rash, phototoxicity, myotoxicity (rare), cardiotoxicity (rare) – Baseline and annual ophthalmologic examination

I hope that you found this helpful. Please do not hesitate to reach with any comments or questions to cmr@wchospital.ca.

Resources:

1.Fernández-Codina, A., Walker, K. M., Pope, J. E., & Scleroderma Algorithm Group (2018). Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis & rheumatology (Hoboken, N.J.), 70(11), 1820–1828. https://doi.org/10.1002/art.40560 Reference here: https://pubmed.ncbi.nlm.nih.gov/29781586/

2.ACR/EULAR Classification Criteria for Systemic Sclerosis (SSc, Scleroderma). Accessed at https://www.rheumatology.org/Portals/0/Files/SSc%20Class%20Criteria%20slides.pdf

3.Kowal-Bielecka O, Fransen J, Avouac J, et al. Ann Rheum Dis 2017;76:1327–1339. Accessed at https://ard.bmj.com/content/annrheumdis/76/8/1327.full.pdf

4. Image from webpage – Systemic Sclerosis. AOCD. Accessed at https://www.aocd.org/page/SystemicSclerosis Accessed on February 13, 2022

5. David R. Pearson, Victoria P. Werth, Lisa Pappas-Taffer. Systemic sclerosis: Current concepts of skin and systemic manifestations. Clinics in Dermatology. Volume 36, Issue 4,
2018, Pages 459-474, ISSN 0738-081X,
https://doi.org/10.1016/j.clindermatol.2018.04.004.
(https://www.sciencedirect.com/science/article/pii/S0738081X18300634)

6. Varga, John. (Nov 2021). Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults. UpToDate.