Prevention of Recurrence of Herpes Simplex in Autoimmune Rheumatic Diseases

Proportion of patients with autoimmune rheumatic diseases (ARDs) and history of recurrent HS who experience clinical reactivation of HSV (oral and/or genital) during the 12-month treatment period and during the following 12 months. Reactivation will be defined by clinical signs and symptoms of HS, detection of HSV DNA by PCR in mucocutaneous swabs in doubtful cases.

Frequency and severity of adverse events (e.g., gastrointestinal discomfort, headache, rash) reported during the 12-month treatment phase.

Incidence of SAEs (hospitalization, death, drug-related complications) in the acyclovir and placebo groups.

Proportion of participants who discontinue acyclovir or placebo due to adverse events.

Number of days from randomization to first documented HSV reactivation.

Analysis of clinical (disease activity) and treatment-related factors (e.g., corticosteroid dose, immunosuppressive drugs and biologic therapy) associated with increased risk of HSV reactivation.

Systemic Lupus Erythematosus (SLE): An increase of more than three points in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K).

Score: 0 - No activity; 1 - 4 mild activity; > 6 high activity

Rheumatoid Arthritis (RA): An absolute increase in Disease Activity Score - C-reactive protein (DAS28-CRP) > 1.2, or an increase in DAS28-CRP > 0.6 if baseline DAS28-CRP > 3.2.

Juvenile Idiopathic Arthritis (JIA): An increase in Juvenile Arthritis Disease Activity Score (JADAS-27) > 5 points, or clinical worsening of ≥ 2 active joints requiring therapy escalation, in accordance with ACR Pediatric Response criteria.

Ankylosing Spondylitis (AS): An increase in Ankylosing Spondylitis Disease Activity Score (ASDAS) > 0.9.

Psoriatic Arthritis (PsA): Worsening in disease activity classification by Disease Activity Index for Psoriatic Arthritis (DAPSA). If the patient was already in the worst status, clinical judgment and therapy increments were applied. For the following diseases, the definition of flare relied on clinical judgment and the need for increased therapy, supported by various disease scores.

Dermatomyositis/Polymyositis (DM/PM): Based on the International Myositis Assessment and Clinical Studies Group (IMACS) core set: Myositis Disease Activity Assessment (MYOACT), Health Assessment Questionnaire (HAQ), Patient's and Physician's Visual Analog Scales (VAS), ACR/EULAR Myositis Response Criteria (MRC) and the MMT8.

Systemic Sclerosis (SSc): Increase in the modified Rodnan skin score, development of new digital ulcers, worsening dyspnea classified by NYHA functional scale, or increase in the EULAR Systemic Sclerosis Impact of Disease Index (ScleroID).

Systemic Vasculitis (ANCA-associated vasculitis, including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis): Increase in Birmingham Vasculitis Activity Score (BVAS).

Primary Sjögren's Syndrome (SjD): EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI).

Mixed Connective Tissue Disease (MCTD): Increase in the Kahn & Appelboam MCTD Activity Score.

Chronic Recurrent Multifocal Osteomyelitis (CRMO): Recurrence or emergence of ≥ 1 new bone lesion confirmed by MRI, or increase ≥ 2 points in the Pediatric/Adult CRMO Activity Score (PCAS/ACAS), accompanied by the need for escalation of anti-inflammatory or disease-modifying therapy.

Sarcoidosis: Increase ≥ 2 points in the Sarcoidosis Activity Assessment Tool (SAAT) or worsening in the Sarcoidosis Clinical Activity Classification (SCAC), defined by recurrence or progression of pulmonary infiltrates, increase in serum ACE levels > 30%, or new extrapulmonary organ involvement requiring treatment intensification.

Behçet's Syndrome: Based on the Behçet's Disease Current Activity Form simplified version (BDCAF-s), considering recurrence of oral or genital ulcers, new ocular inflammation, vascular or neurological involvement, or any increase ≥ 2 points in BDCAF-s global score.