Table 4.

Application of CRISS in a clinical trial

CRISS is a 2-step process.
Step 1: Subjects who develop new or worsening of cardiopulmonary and/or renal involvement due to systemic sclerosis are considered as not improved (irrespective of improvement in other core items) and assigned a probability of improving equal to 0.0. Specifically if a subject develops any of the following
–	New scleroderma renal crisis (43)
–	Decline in forced vital capacity (FVC)% predicted ≥15% (relative), confirmed by another FVC% within a month, high resolution computer tomography (HRCT) to confirm interstitial lung disease (ILD; if previous high resolution computer tomography of chest did not show ILD) and FVC% predicted below 80% predicted*
–	New onset of left ventricular failure (defined as left ventricular ejection fraction ≤45%) requiring treatment*
–	New onset of pulmonary arterial hypertension (PAH) on right heart catheterization (44) requiring treatment*. PAH is defined as mean pulmonary artery pressure ≥ 25 mm Hg at rest and an end-expiratory pulmonary artery wedge pressure ≤ 15 mm Hg and a pulmonary vascular resistance >3 Wood units
•
*=	Attributable to systemic sclerosis
Step 2: For the remaining subjects, Step 2 involves computing the predicted probability of improving for each subject using the following equation (equation to derive predicted probabilities from a logistic regression model): $$\frac{\mathit{exp}[-5.54-0.81\ast {\mathit{\Delta }}_{\mathit{MRSS}}+0.21\ast {\mathit{\Delta }}_{\mathit{FVC}\text{\%}}-0.40\ast {\text{Δ}}_{\mathit{Pt}-\mathit{glob}}-0.44\ast {\mathit{\Delta }}_{\mathit{MD}-\mathit{glob}}-3.41\ast {\mathit{\Delta }}_{\mathit{HAQ}-\mathit{DI}}]}{1+\mathit{exp}\left[-5.54-0.81\ast {\mathit{\Delta }}_{\mathit{MRSS}}+0.21\ast {\mathit{\Delta }}_{\mathit{FVC}\text{\%}}-0.40\ast {\mathit{\Delta }}_{\mathit{Pt}-\mathit{glob}}-0.44\ast {\mathit{\Delta }}_{\mathit{MD}-\mathit{glob}}-3.41\ast {\mathit{\Delta }}_{\mathit{HAQ}-\mathit{DI}}\right]}$$ where ΔMRSS indicates the change in MRSS from baseline to follow-up, ΔFVC denotes the change in FVC% predicted from baseline to follow-up, ΔPt-glob indicates the change in patient global assessment, ΔMD-glob denotes the change in physician global assessment, and ΔHAQ-DI is the change in HAQ-DI. All changes are absolute change (Time2 –Timebaseline).
Definition of scleroderma renal crisis [adapted from (43)] Hypertensive SRC (fulfills both A1 and A2) New onset hypertension, defined as any of the following: Systolic blood pressure ≥ 140 mgHg Diastolic blood pressure ≥ 90 mgHg Rise in systolic blood pressure ≥ 30 mmHg Rise in diastolic blood pressure ≥ 20 mmHg AND One (1) of the following five (5) features: Increase in serum creatinine by 50+% over baseline OR serum creatinine ≥120% of upper limit of normal for local laboratory Proteinuria ≥2+ by dipstick Hematuria ≥2+ by dipstick or ≥10 RBCs/HPF Thrombocytopenia: <100,000 platelets/mm3 Hemolysis defined as anemia not due to other causes and either of the following: Schistocytes or other RBC fragments seen on blood smear increased reticulocyte count Normotensive SRC (fulfills both B1 and B2) Increase in serum creatinine >50% over baseline OR serum creatinine ≥120% of upper limit of normal for local laboratory AND One (1) of the following five (5) features: Proteinuria ≥2+ by dipstick Hematuria ≥2+ by dipstick or ≥10 RBCs/HPF Thrombocytopenia: <100,000/mm3 Hemolysis defined as anemia not due to other causes and either of the following: Schistocytes or other RBC fragments seen on blood smear Increased reticulocyte count Renal biopsy findings consistent with scleroderma renal crisis (microangiopathy)