A Randomized Multicenter Study for Isolated Skin Vasculitis

Inclusion Criteria:

1. Patients with primary skin vasculitis, not associated with any significantextra-cutaneous involvement that would require specific immunosuppressive therapy.Eligible patients will have a diagnosis of either:

• Isolated cutaneous small vessel (SV) or medium-sized vessel (MV) vasculitis orcutaneous polyarteritis nodosa (PAN)

• IgA vasculitis (IgA, formerly Henoch-Schönlein purpura), without active and/orprogressing renal involvement (stable glomerular filtration rate (GFR) >60ml/min; absence of, or mild-and-stable microscopic hematuria without red bloodcell casts; absence of, or mild-and-stable proteinuria (<1g/24 hours); notrequiring systemic immunosuppressive therapy). These conditions, when skin-limited, are all currently treated in similar manners inpractice. Mild arthralgias, myalgias, peripheral limb edema, fatigue, weight loss ≤6lbs or 3 kg within past 3 months, low-grade fever, and mild anemia (Hb ≥ 10 g/dL)will be allowed.

2. The diagnosis of vasculitis must have been confirmed by skin biopsy prior toenrollment (earlier, at diagnosis, and/or just prior to enrollment) that hasincluded an immunofluorescence study (in the case of small vessel vasculitis).

3. Patients must have active cutaneous vasculitis lasting for at least 1 monthcontinuously and/or have had 2 or more flares over the six months precedingenrollment (post-inflammatory lesions such as hyperpigmentation or healingulceration(s) are not to be considered active vasculitis).

4. Patients must have active / ongoing cutaneous vasculitis lesions at the time ofenrollment (post-inflammatory lesions such as hyperpigmentation or healingulceration(s) are not to be considered active vasculitis).

5. Patients may have a contra-indication to one of the study drug or have been treatedprior to enrollment with one of the study medications but failed to respond to it (according to the study definitions of failure and if they have been on the drug atthe target dose or higher for 3 months or longer) or had to stop it because of anadverse event. Such patients can be enrolled directly in the second stage of thestudy and be randomized to receive one of the two other study drugs. The number ofsuch patients enrolled directly in stage 2 will be capped at 10 (10% of the totalrecruitment target).

6. Patients may have received systemic glucocorticoids for their cutaneous vasculitisbefore enrollment. For the patients on prednisone at the time of enrollment,prednisone should be stopped within a maximum of 6 weeks after enrollment andinitiation of the study drug, following a pre-defined tapering schedule. Patients onlong-term, low and stable dose of glucocorticoids (≤5 mg/day prednisone-equivalent)for other conditions (e.g., asthma or adrenal insufficiency) can be enrolled if thelikelihood of requiring a dose increase for this other condition is low during the 6month study period (these patients will remain on that low and stable dose duringthe study period, with the option to receive one short course of prednisone athigher doses for skin vasculitis flare during the first 3 months of the studyperiod, like any other patients enrolled).

7. Participant age 18 years or greater.

Exclusion Criteria:

1. Presence of significant extra-cutaneous manifestations suggestive of a systemicvasculitis or more diffuse condition. The presence of mild arthralgias, myalgias,peripheral limb edema, fatigue, weight loss ≤6 lbs or 3 kg within past 3 months,low-grade fever, and mild anemia [Hb ≥ 10 g/dL] are not exclusion criteria. Mild andstable microscopic hematuria without RBC casts and/or mild and stable proteinuria (<1g/24 hours) are not exclusion criteria. These latter patients must not requiresystemic immunosuppressive therapy because of possible renal involvement and theirGFR must be >60 ml/min.

2. Known systemic and/or non-skin-isolated vasculitis, such as granulomatosis withpolyangiitis, eosinophilic granulomatosis with polyangiitis, cryoglobulinemicvasculitis, systemic polyarteritis nodosa, central nervous system vasculitis andpatients with detectable antineutrophil cytoplasmic antibody (ANCA) byimmunofluorescence or ELISA.

3. Hypocomplementemic urticarial vasculitis, cryoglobulinemic vasculitis, and otherknown secondary skin vasculitides such as those secondary to systemic lupuserythematosus, Sjögren syndrome, another auto-immune condition, a cancer, ahematological disorder, an ongoing active infection, or an ongoing medication.Investigators should consider such underlying diagnoses and perform and interpretappropriate laboratory work-up where indicated based on clinical presentation.

4. History of significant intolerance, allergy or serious adverse events to any of thestudy medications: such patients can be enrolled directly in the second stage of thestudy and be randomized to receive one of the two other study drugs. The number ofpatients enrolled directly in stage 2 of the study will be capped at 10 (10%).

5. Patients who have contra-indications to two or three of the study drugs (azathioprine, colchicine, or dapsone), or have been treated prior to enrollmentwith two or three of the study drugs but failed to respond to them, or had to stoptwo or three of them because of adverse events.

6. Deficit in glucose-6-phosphate dehydrogenase (G6PD) or history of hemolytic anemia (all patients must be tested for G6PD at the screening visit to assess for theireligibility): such patients can be enrolled directly in the second stage of thestudy and be randomized to receive one of the two other study drugs (azathioprine orcolchicine). The number of patients enrolled directly in stage 2 of the study willbe capped at 10 (10%).

7. Low or absent thiopurine methyltransferase (TPMT) activity (if known, not arequirement for study entry): Patients known to have low or absent TPMT can beenrolled directly in the second stage of the study and be randomized to receive oneof the two other study drugs (dapsone or colchicine).

8. Evidence of significant hepatic insufficiency or liver function tests > 2 times theupper limit of normal.

9. Evidence of significant renal insufficiency or creatinine clearance < 60 mL/min.

10. Evidence of significant or symptomatic anemia or Hb < 10 g/dL.

11. Comorbid condition that has moderate or high likelihood of requiring intermittentcourses of prednisone within the study period, according to the investigator (e.g.chronic obstructive pulmonary disease (COPD), unstable or severe asthma).

12. Active cancer or history of malignancy within the previous 5 years (patient inremission of a cancer >5 years, or with non-metastatic prostate cancer or treatedbasal or squamous cell carcinoma of the skin can be enrolled).

13. Active uncontrolled or serious infection that may compromise or contra-indicate theuse of the study medications.

14. Patient unable to consent.

15. Pregnant or lactating women.