Hit hard and early. The effect of high dose methylprednisolon on nailfold capillary changes and biomarkers in early SSc: a 12-week randomised double-blind placebo-controlled trial.

Systemic sclerosis (SSc) is a systemic autoimmune disease with unknown
etiology, characterized by a triad of inflammation, vasculopathy and fibrosis.
The major characteristic pathogenic features of SSc consist of dysfunction of
the vasculature, activation of fibroblasts and other resident cells as well as
dysregulation of the immune system. Accumulating genetic, serological and
translational evidence indicates that SSc shares an autoimmune basis with other
systemic autoimmune diseases and that inflammatory mechanisms drive SSc
vasculopathy and fibrosis, especially early in the disease. These processes
result in fibrosis and thus organ dysfunction.

To date, no treatment is available to cure SSc. The poor clinical response to
anti-inflammatory treatment in SSc is probably the result of the fact that it
is seldom initiated very early in the disease and often when organ involvement
has already occurred. To treat patients early, we have to diagnose them early.
To date, no diagnostic criteria are available for SSc. However, to classify
patients with very early SSc, the European League Against Rheumatism
Scleroderma Trials and Research Group has identified preliminary criteria for
Very Early Diagnosis Of Systemic Sclerosis, the VEDOSS criteria. The VEDOSS
criteria consist of the combination of Raynaud*s phenomenon (RP), disease
specific auto-antibodies, typical nail fold capillaroscopic findings and *puffy
fingers*, hallmarks of very early SSc.

We hypothesize that by inhibition of the inflammatory process driving the
disease, treatment with glucocorticoids will induce remission in patients with
very early systemic sclerosis.

Objective 1: analyze the effect of short-term treatment with high dose
glucocorticoids on vasculopathic abnormalities as measured by NCM in patients
with very early SSc.

Objective 2: investigate the effects of glucocorticoids on signs and symptoms
of disease progression.

Objective 3: analyze the effect of glucocorticoids on inflammatory biomarkers
that have been implicated in SSc pathogenesis and in the response of systemic
autoimmune diseases to glucocorticoids. These biomarkers are the interferon
signature in peripheral blood cells and the soluble inflammatory mediators
platelet factor 4 (CXCL4), interleukin-1β, interleukin-6, tumor necrosis
factor-α, endothelin-1, intercellular adhesion molecule-1 and vascular
endothelial growth factor (2, 15-19).
*

This is a 12 week double-blind randomized placebo controlled trial in which 30
patients with very early SSc, fulfilling the VEDOSS criteria (9) will be
randomized in a 2:1 fashion to receive intravenous methylprednisolone or
placebo. Three-day treatment courses are given at week 0, week 4 and week 8.
The final assessment is at week 12, and patients will be followed up to one
year after baseline.

Investigational product/treatment:
Methylprednisolone 1000 mg is prepared and administered following guidelines,
in short: the methylprednisolone is dissolved in 100 cc of NaCl 0.9% by the
hospital pharmacy and administered by intravenous infusion in 30 minutes on
three consecutive days. Patients are observed at the day care facilities of the
rheumatology department. The placebo intervention with physiologic salt
solution is identical in appearance and administration to methylprednisolone.

All patients will receive prophylactic therapy with an ACE-inhibitor (enalapril
5 mg od) and proton pump inhibition (pantoprazol 40 mg od) for the duration of
the study. Treatment with other systemic therapy for SSc symptoms during the
study will be avoided whenever possible and will be regarded as a protocol
violation

other study procedures in totaly 12 months:
8 times bloodsampeling
8 times nailfold capillairy scopy
3 times pulmonary funtion test
2 times HRCT scan
2 times echocardiography
3 times questionaires
3 times optional skin bipioty

Generally there is concern of an increased risk of scleroderma renal crisis
especially in high dose glucocorticoids, but in a recent study study no
difference in kidney involvement was found between dosages of > 15 mg vs <= 15
mg per day. We assume that ACE inhibition is preventive for the development of
SRC in high risk patients, so the usual care in our hospital is to start ACE
inhibition in patients assumed to have high disease activity and in patients
treated with glucocorticoids > 7,5 mg of prednisolone. To reduce the risk of
SRC we now have included anti-RNA polymerase III positivity as an exclusion
criterion.

Daily measurements of blood pressure will be performed by the patient using an
automated device at home. A new onset of blood pressure > 150/85 mmHg obtained
at least twice over a consecutive 24 h period is considered to be abnormal, and
patients are asked to contact the trial physician if this occurs and evaluated
for the presence of scleroderma renal crisis the same day. Blood pressure
values are evaluated at the study visits. Blood glucose will be assessed weekly
by the general practitioner using fingertip blood glucose measurement.