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Vasculitis: Professor Paul Bacon

Dinesh Khanna
MBBS, MSc
Associate Professor, Marvin and Betty Danto Research Professor
Director, Scleroderma Program
Department of Internal Medicine, University of Michigan Health System
khannad@med.umich.edu

1. What minimum investigations will you advise in a patient with recent-onset Raynaud’s, puffy fingers, polyarthralgias and high-titer speckled pattern ANA positivity?
2. What are differential diagnoses with this kind of presentation?

Such presentations are common in connective tissue diseases. Although systemic sclerosis (SSc) is most common, other CTDs include inflammatory myositis, SLE and MCTD. Work up should include nail-fold capillaroscopy, CTD-specific autoantibodies pertinent to the disorders mentioned above, CBC with differential, comprehensive panel, and muscle enzymes. In addition, I order complete pulmonary function test (PFT), high-resolution computer tomography (HRCT), and transthoracic echocardiography, if suspicion for SSc is high. One may question utility of HRCT at baseline without documentation of restrictive lung disease, but according to my experience, 10–20% of patients have interstitial lung disease despite ‘normal’ PFT. Also, lung fibrosis is generally irreversible.

Based on the 2013 ACR/EULAR reclassification of SSc, this patient will not be classified as SSc. There are two comments regarding this. First, classification criteria are developed for studies and trials and may not be accurate to make a diagnosis of SSc. Second, if this patient had abnormal nail-fold capillaroscopy and one of the SSc autoantibodies, then this patient will be classified under SSc. Using the 1980 criteria, this patient would not have been classified as SSc.


3. Imaging of a recently diagnosed young female diffuse systemic sclerosis patient shows NSIP pattern interstitial inflammation on HRCT of chest and mild reduction in FVC (64% predicted), but the patient is not symptomatic. How to treat this patient?

Pulmonary disease in SSc [interstitial lung disease (ILD)and pulmonary hypertension] is the leading cause of death in patients with SSc. HRCT of the lungs reveals features of ILD in 70–90% of patients with SSc. Restrictive lung disease (FVC <75%) develops in approximately 40% of SSc patients. Severe restrictive lung disease (defined as FVC <50%) is found in about 10–15% of SSc patients. Therefore, not every patient requires immunosuppressive therapy.

The decision on the timing of immunosuppression can be quite challenging. It is important to identify these SSc-ILD patients and predict their disease course, as the treatment needs to be individualized. ILD is usually irreversible in SSc. Severe and progressive ILD, as demonstrated by rapid decline in the FVC (>10% of the FVC%), usually occurs in the first 3–4 years of disease onset. The rate of decline in FVC is greater in patients with early-onset disease, FVC <70% at presentation, worse extent of lung fibrosis on HRCT (>25% involvement of lung zones or >20% total lung involvement). Thus, immunosuppressive therapy is largely indicated for SSc patients with early disease who have: (A) >10% decline in FVC% percentage in the previous 3–12 months; (B) moderate-to-severe lung involvement on HRCT; and/or (C) FVC <70% at presentation.

This patient has early disease and moderate restrictive lung disease. Therefore, this patient should be treated aggressively with an immunosuppressive therapy after infectious etiology is ruled out. I would also probe whether she is truly asymptomatic or she has changed her day-to-day activities to accommodate her limitations. Without the knowledge of baseline PFT, it is unclear how much she has declined. She may have started at 80% and had an absolute decline of 16% or started at 120% with an absolute decline of 56%! Both are clinically meaningful. Also, in USA, I do not rule out TB or other chronic infections as risk is very low, but this may be necessary in India.


4. How long to continue immunosuppressants for systemic sclerosis-associated ILD?

As stated above, SSc-ILD usually occurs early in the disease. We also know that 1 year of CYC is not effective in preventing progression of restrictive lung disease, after CYC is stopped (Scleroderma Lung Disease I). There are no evidence-based data to answer this question. My approach is 3–4 years of immunosuppressive treatment. I prefer monthly pulse CYC at doses of 500–750 mg/m2 for 6–12 months with every 3–4 month PFT to assess for stabilization. The response to therapy is measured by PFTs every 3–4 months and the patient reported improvement in dyspnea. The therapeutic response tends to be slow. Stabilization of the FVC as opposed to improvement is the norm and considered as a favorable response. Therefore, early identification and treatment are needed. The optimal duration of therapy is not known. At the end of 6–12 months of CYC therapy, if there is improvement or stabilization of lung function, the practice is to transition to either MMF or azathioprine for 2–3 more years, although some patients may require treatment for a longer duration.


5. A patient with limited systemic sclerosis having dyspnea on exertion and work up revealed PASP 40 mmHg. How to treat and prognosticate this patient?

This patient is at risk for pulmonary arterial hypertension (PAH). New guidelines [Khanna D. Arthritis Rheum. 2013;65(12):3194–3201] suggest that this patient should undergo right heart catheterization (RHC). Based on the description above, this patient has pulmonary hypertension (PH) and there are three large categories for PH applicable in this patient—PAH, PH due to left heart disease, and PH associated with ILD. ILD is defined by moderate-to-severe ILD on HRCT, although studies have used an FVC% cutoff of 60–70%. The only reliable way to differentiate left heart disease (most common cause of PH in SSc) vs. PAH is RHC. Also, in 30% of patients, echocardiogram may be normal and patients may still have PAH. Dyspnea is usually a late symptom and screening is encouraged. The DETECT study (www.detect-pah.com) has provided a user-friendly algorithm that clinicians can use for early detection of PAH and refer patients for RHC.


6. How to manage non-healing ulcers over sole in diffuse systemic sclerosis?

Non-healing ulcers are uncommon in SSc and may reflect large vessel vasculopathy vs. atherosclerotic vascular disease. Work up should include arterial Doppler and if negative (i.e. no significant atherosclerotic disease), then generally treatment is anti-platelet therapy and PDE-5 inhibitors. Hyperbaric oxygen has been tried, but is very expensive and generally has modest effects.


7. When to suspect systemic sclerosis renal crisis and how to manage that?

Scleroderma renal crisis generally occurs early in the disease (first 2–3 years) and in patients with active and progressive skin fibrosis. The classic presentation is a patient with early diffuse SSc with tendon friction rubs and presence of anti-RNA polymerase III antibody. However, it has been reported in limited cutaneous SSc and sine SSc. Therefore, we recommend blood pressure measurement at home two-to-three times a week in early disease (especially in early diffuse SSc or those with anti-RNA polymerase III antibody) and provide parameters that should alert urgent discussion with their physician. Worsening blood pressure with or without hypertensive emergency and evidence of worsening renal function and microangiopathic hemolysis is defined as SRC. Prophylactic ACEi has not shown to improve outcomes and may worsen the outcomes. Treatment remains institution of ACE inhibitors.


8. Is there any window of opportunity in systemic sclerosis? Any promising drug that can revert or stop skin-thickening progression?

Window of therapeutic opportunity is usually a time period during which a treatment may prevent internal organ involvement/regress established fibrosis in SSc. We do not have any approved therapies that can be used.  However, the skin thickening in early disease usually responds to methotrexate (supported by EULAR recommendations and two RCTs). For fibrotic complications (such as lung fibrosis), early screening and treatment are the key. For vascular complications (especially PAH), careful screening during the course of the disease continues to provide an effective way to diagnose the disease early. Autologous stem cell transplant has shown encouraging results; but is also associated with treatment-related mortality and is performed in the research setting. RCTs are ongoing or just completed for tocilizumab, LPA-antagonist, and abatacept and results are eagerly awaited. At this moment, early screening and diagnosis of internal organ involvement are the best to prevent progressive disease.


9. What minimum information about this disease should be told to the patient at first visit?

Patients are very scared when they hear about a diagnosis of scleroderma. Majority of them go to the Internet and hear stories on poor outcomes. I personally spend 30–45 min educating each new patient.

  1. I discuss the available resources for up-to-date knowledge on management of SSc (e.g., www.scleroderma.org).
  2. During the first visit, I provide assurance that it is the internal organ involvement rather than the skin fibrosis that is associated with poor outcomes.
  3. Patients and family need to be supportive and understand that it is a chronic disease.
  4. Different manifestations are discussed in detail and are available in our website (http://www.med.umich.edu/scleroderma/patients/index.htm).
  5. I order SSc autoantibodies, PFT, HRCT, and ECHO as they provide prognostic information.

10. What is the place of D-Penicillamine in the treatment of SSc today?

None, as the RCT of low-dose vs. high-dose D-Penicillamine in early diffuse SSc was negative.