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Systemic Sclerosis

  • dcSSc
  • lcSSc

Note: Scleroderma,  characterized by thick and indurated skin is a distinguishing hallmark of Six

Genetic factors: Loci similar to SLE, RA, Psoriasis suggest common pathogenic pathways shared among these phenotypically dissimilar conditions.  
  • First-degree relative: RR of 13 (strongest  known risk factor)
  • Twin study: 4.7 % concordance rate is only seen, although monozygotic twins had ANA positivity in 90% instances, and dizygotic twins had ANA positive in 40 % instances 
  • 36% of the family of SSc have AI conditions: Hypothyroidism, Hyperthyroidism, SLE, RA
  • Gene signatures in GWAS : HLA like in SLE, IFN signature like in SLE 
    • Non-HLA susceptibility loci associated with SSc include: 
      •  the protein tyrosine phosphatase nonreceptor 22 (PTPN22), which has been associated with SLE, myasthenia gravis, vitiligo, and Addison’s disease; 
      • IL-1β and NLRP1, an inflammasome scaffold that promotes pro-IL-1β maturation and processing; and 
Epigenetic changes: Three key forms of epigenetic modifications are 
  • DNA methylation, 
  • histone modifications, and 
  • expression of noncoding (long and micro) RNAs. MicroRNAs (miRNAs) are a large family of 18 to 23 nucleotide noncoding RNAs that function as intra-cellular regulators of gene expression.
Envioronmental and occupational risk factors:  (Harrison's)
  • Viral infections: Parvo Virus B19, CMV, EBV
  • Similar skin induration but varying biopsy findings. Conditions include. 
    • Toxic oil syndrome (contamination  rapeseed oil for cooking)
    • Eosinophilia Myalgia Syndrome (l-tryptophan supplementation)
    • Nephrogenic Systemic Fibrosis linked to gadolinium 
  • Cigarette: Not linked (unlike RA)

Healthy women may harbor circulating, and occasionally tissue-resident, stem cells of fetal origin that persist for many years after pregnancy, a condition called microchimerism.

Pathogenesis:  (Harrison's)
  • Sustained Fibroblast activation (Amplifying and Maintenance mechanisms B and C below)  is the key often initiated by transient generation of ROS and immune damage to the endothelial cells (triggering : A )

As noted above, sustained activation of Fibroblast is the key. The picture below highlights the mechanism of activation of fibroblasts. 
3 main pathways
  • SMAD signaling 
  • Non-smad signaling 
  • RAS-ERK1 signaling 

  • 3 cardinal pathophysiological mechanisms include (Harrisons)
    • (1) diffuse microangiopathy, 
    Paradoxically, the process of revascularization that normally reestablishes blood flow to ischemic tissue is defective in SSc despite elevated levels of other angiogenic factors. Moreover, bone marrow–derived circulating endothelial progenitor cells are reduced in number and impaired in function. Widespread capillary loss, obliterative vasculopathy of small and medium-sized arteries, and impaired ability to repair and replace damaged vessels are hallmarks of SSc.
    • (2) inflammation and autoimmunity, and 
    • (3) visceral and vascular fibrosis in multiple organs


    Immunopathogenesis: https://doi.org/10.1080/1744666X.2019.1614915

    Microvascular endothelial cell injury and apoptosis is a key first step in the SSc that drives immunopathogenesis. 
    • highlighted in purple are processes involved in the pathogenesis of SSc; added information in black is to show the comparison of SSc pathogenesis to the rest of the clinical immunology)
      • Innate and Adaptive Immune mechanisms are involved in pathogenesis. 
        • Innate Immune System
          • Physical Mucosal Barrier
          • Proteins
          • Cells like Granulocytes, NK Cells, Macrophages, Dendritic Cells
            • Plasmacytoid dendritic cells infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-. (IFN-.alpha) and small chemokine PF4, also known as CXCL4) which are both hallmarks of the disease.
          • Phagocytic defects
          • Cell Signalling including IFN Gamma: TLR activation from IFN produced by plasmacytoid dendritic cells 
            • Type 1 IFN INTERFERON SIGNATURE is noted in SSc
          • Complement (Alternate and Lectin Pathways)
        • Adaptive Immune System
          • T-Cell
            • T-Cell Development
            • T-Cell Maturation
            • T-Cell Activation and antigen presentation or Functioning 
                • T cells are also involved in SSc
              • Th1:
              • Th2 : SSc has TH2 cell activation 
                • CD4+ Interestingly, among T cells (T cells), the type 2 T helper (TH2) cells – characterized by secretion of IL-4 and IL-13 – are more expressed in SSc than TH1 cells, which primarily secreteanti-fibrotic IFN.
              • Th17: Also, implicated in SSC. T reg cells have been noted to transform into Th17 cells
          • B-Cell
            • Impaired Development
            • Impaired Functioning 
              • T-cell mediated
              • T-cel independent DATA LATA 
                • In diffuse cutaneous SSc (dcSSc) anti-topoisomerase AAbs

                  (ATA), formerly known as anti-Scl70 AAbs, are more prevalent,

                  whereas anticentromere AAbs (ACA) are more frequent

                  in limited cutaneous SSc (lcSSc).

                  A possible pathogenic role of ATA in SSc has been suggested

                  following its binding to fibroblasts and induced adhesion and

                  activation of cocultured monocytes [48]. This observation might

                  provide an explanation for the amplification of the fibrogenic

                  cascade in ATA-positive SSc patients.

        • Regulatory Immune System
          • Innate System Regulation
            • Regulatory cell dysfunction is noted in SSc. Decreased regulatory T cells in circulation is noted. Also, these regulatory Tcells can transform into pathogenic effector T Cell 
          • Adaptive System Regulation
    • Clinical features
      • Early-stage: s/sx reflect inflammation and vascular INJURY
      • Late-stage: s/sx reflect fibrosis and vascular INSUFFICIENCY 

      • Early stage: Related to vascular injury 
        • Raynauds 
        • mucocutaneous telangiectasia; 
        • nailfold capillary changes (giant capillaries, hemorrhages, and avascular areas); 
        • PAH; 
        • digital tip pitting and ischemic ulcers; 
        • gastric antral vascular ectasia (also called watermelon stomach); and 
        • scleroderma renal crisis.
      • Late stage: 
        • Intimal proliferation is noted in various organs leading to insufficiency 
        • Vascular changes are most prominent in the Heart, Lungs, Skin, GI tract 
    • Pathology: 
      • Early stage: Only in this stage inflammatory cells infiltrate around the blood vessels are prominent
      • Long standing: Non-inflammatory, proliferative/obliterative vasculopathy of small arteries / arterioles , loss of capillaries, and fibrosis  

      • Skin: marked expansion of dermis with obliteration of sweat glands, sebaceous glands, hair follicles ; loss of dermal-epidermal ridges ; reduction of capillaries, and lymphatics 
      • Lung: Most common: NSIP; Less common: UIP 
      • GI: Replacement of the normal intestinal architecture results in 
        • disordered peristaltic activity, 
        • gastroesophageal reflux, 
        • gastroparesis and small bowel dysmotility, 
        • pseudo-obstruction, and 
        • bacterial overgrowth
        • Chronic gastroesophageal reflux - esophageal inflammation, ulcerations, stricture formation, and recurrent microaspiration. 
        • In up to one-third of patients with SSc who have severe gastroesophageal reflux, Barrett’s esophagus develops
      • Renal: Vascular lesion predominate, GN only in Overlap syndromes


    American College of Rheumatology/European League against Rheumatism Classification Criteria for the Classification of Systemic SclerosisModified from van den Hoogen F, Khanna D, Fransen J, et al: 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65:2737–2747, 2013.
    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 fingers2
    Sclerodactyly of the fingers (distal to the MCPs but proximal to the proximal interphalangeal joints)4
    Fingertip lesions (only count the higher score)Digital tip ulcers2
    Fingertip pitting scars3
    Abnormal nailfold capillaries2
    Pulmonary arterial hypertension and/or interstitial lung disease (maximum score 2)Pulmonary arterial hypertension2
    Interstitial lung disease2
    Raynaud’s phenomenon3
    SSc-related autoantibodies (maximum score is 3)ACA
    RNA Pol

    ACA, Anticentromere; MCPs, metacarpophalangeal joints; RNA Pol, anti-RNA polymerase III; Scl-70, antitopoisomerase 1; SSc, systemic sclerosis.

    Ms. B

    2 for diffuse: SCL70; RNA Pol III
    2 for both: U3RNP, B23, 
    3 for limited : Anticentromere, Th/TO, APLA
    3 for OverlaP: PM/SCL; U1RNP (MCTD- PM, SCL, SLE); ANti-KU (muslce and joint); 

    The speckled nuclear staining pattern (left) can be detected in 30% of patients with diffuse scleroderma and suggests the presence of anti–topoisomerase I antibodies.

    The homogeneous nucleolar staining pattern (center) is detected in 25 to 50% of patients with the myositis–scleroderma overlap syndrome

    A pattern characterized by the clumping of the nucleoli  is highly specific for diffuse scleroderma (in 5% of patients).

    Nucleolar antigens are RNA polymerases, fibrillarin, Th/To, or PM-Scl. 

    The anticentromere-antibody staining pattern (right) can be detected in 70 to 80% of patients with limited cutaneous scleroderma 

    The antigens for anticentromere-ab is kinetochore proteins of the centromere regions of chromosomes.

    Up to 11% of patients with scleroderma can test negative for anti-nuclear antibodies (ANAs).
    AntigenSubtypeClinical Phenotype
    Topoisomerase 1 (Scl-70) ABSENT as no evidence of diffuse diseaseDiffusePulmonary fibrosis, cardiac involvement
    Centromere (protein B, C)
    ABSENT as no evidence of digital ischemia or PAH or calcinosis
    LimitedSevere digital ischemia, PAH, sicca syndrome, calcinosis
    RNA polymerase III
    Not checked but no evidence of severe skin disease, renal crisis
    DiffuseSevere skin disease, tendon rubs, cancer, GAVE, renal crisis (±sine scleroderma)
    U3-RNP (fibrillarin) - predictor of internal organ involvementDiffuse or limitedPrimary PAH; esophageal, cardiac, and renal involvement; muscular disease
    Good chance this may come positive
    LimitedPulmonary fibrosis, rare renal crisis, lower GI dysfunction
    Good chance this may come positive
    Diffuse or limitedPAH, lung disease
    Cardiolipin, β2GPILimitedPAH, digital loss
    PM/SclOverlapMyositis, pulmonary fibrosis, acro-osteolysis
    U1-RNPOverlapSLE, inflammatory arthritis, pulmonary fibrosis

    How to measure sclerodactaly? 


    SKIN Ds
    • MTX (arthritis, myositis if present): 2 RCTfor skin disease, no data for visceral disease, 
    • MMF (ILD) (small prospective studies)
    • CYC( refractory to MTX or MMF or severe rapidly progressive disease)
    • Target doses for MTX are 15 mg to 25 mg weekly and for MMF 1.5 g to 3 g daily - goal in at least 3 month and evaluate for at least another three to six months 
    Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol. 1996;35(4):364.
    A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351. 

    • Antihistamines 
    • Maintaining adequate lubrication of the skin is essential, and patients should use lubricating creams, especially those that are lanolin-based. 
    • Counter-irritants such as capsaicin or menthol may also be used for symptomatic relief. 
    • Simple measures such as avoiding repeated exposure to environmental factors associated with itch such as heat or excessive drying after water exposure can also be helpful. 
    • Low-dose oral glucocorticoids (less than 10 mg daily dose of prednisone or equivalent) can be effective for severe pruritus, but topical corticosteroids are rarely helpful.
    • There are anecdotal reports that montelukast or ondansetron may be effective, as they have been in refractory itching in other diseases such as cholestasis or opiate-induced pruritus, although formal trials have not been performed with these agents. In addition, one case series found that low-dose naltrexone may also be helpful
    Calcinosis cutis with infection
    • Treatment of Raynaud phenomenon is generally the same in patients with and without SSc
    • Nonpharmacologic measures 
      • Avoidance of cold exposure 
      • Strategies to maintain whole body and digital warmth 
      • Other general measures:
        • Avoidance of repeated traum
        • We do not routinely counsel patients with RP to stop consuming caffeine-containing drinks, although some experts have recommended doing so
        • In patients with RP undergoing surgery, the risk of attacks from increased cold exposure in the operating room can be reduced by keeping patients warm
        • Control or limitation of emotional stress because the thermoregulatory vessels are constricted by increased sympathetic tone
      • Avoidance of vasoconstricting drugs
      • Smoking cessation
    • Pharmacologic measures 
      • Initial pharmacologic therapy
        • Dihydropyridine CCB: Amlodipine vs some prefer nifedipine (RCT) 
        • Other Dihydropyridine CCB:  nicardipinefelodipine, lacidipine, nisoldipinenimodipine, and isradipine
        • The nondihydropyridine CCBs are generally avoided because they have not been shown to be consistently effective
      • Unable to tolerate or receive preferred initial therapy — Alternative therapies may be required in patients in whom CCBs are contraindicated or poorly tolerated (eg, patients with severe gastrointestinal dysmotility, severe pulmonary artery hypertension, significant cardiac disease with edema, and/or low BP).
          • The decision to use one agent over another depends largely on the side effect profile and whether there are additional benefits for other comorbidities. As an example, a PDE type 5 inhibitor may be preferable to a CCB in a patient with RP secondary to SSc, particularly in a patient with concomitant pulmonary hypertension
        •  We use a low-dose PDE type 5 inhibitor in patients with uncomplicated RP in whom CCBs are contraindicated or not tolerated. We typically start with sildenafil 20 mg once or twice daily and increase the dose to 20 mg three times daily if no benefit is achieved. The dose may be further increased to 40 mg three times daily in patients who do not respond and can tolerate the higher dosing. This dose is similar to that used in patients with pulmonary hypertension. Sildenafil is also available as 25 mg and may be titrated up to 50 mg twice or three times daily as tolerated in a similar manner to that of the 20 mg formulation. As with CCBs, we advise that patients obtain a BP cuff to monitor their BP serially while titrating the dose.
        • Topical nitrate — In our experience, the topical nitrates are more useful for patients with a single or small number of severely affected digits and for short-term (days to weeks) use, compared with patients with more diffuse involvement and with the need for chronic use (months to years). 
        • Angiotensin II receptor blocker — Angiotensin II receptor blockers (ARBs) may be used for patients with uncomplicated RP who cannot tolerate CCBs or who may benefit from the use of an ARB for other indications (eg, hypertension, heart failure, proteinuric chronic kidney disease). 
        • Selective serotonin reuptake inhibitor — Fluoxetine may be used in patients with uncomplicated RP who cannot tolerate CCBs or the systemic vasodilatory effects of some of the other alternative agents. 
        • Other medications – Several other medications that have been used for which there are limited data to define clinical utility include the sympatholytic drugs methyldopa and reserpine (which has been given intra-arterially) . However, none of these agents is a specific inhibitor of the alpha-2C-adrenergic receptor that is thought to be the major pathway through which cold-induced digital artery vasoconstriction is triggered.