This paper provides a detailed analysis of systemic diseases associated with periodontal tissue loss, focusing on their clinical presentation and etiopathogenesis. It also introduces a framework for categorizing these diseases according to their principal pathological pathways and their periodontal effects. Periodontitis arises from a disruption of host-microbe homeostasis, which leads to a dysbiotic microbiota, chronic inflammation, and subsequent periodontal tissue loss. Complex systemic diseases, particularly those causing systemic inflammation or having an autoimmune component (e.g., diabetes mellitus, osteoporosis, arthritis, and inflammatory bowel disease), can exacerbate pre-existing periodontal inflammation and cause further tissue loss. As their inflammatory and pathological pathways are intertwined with periodontitis, their periodontal manifestations are not considered distinct forms of the disease. In contrast, other systemic diseases disrupt host-microbe homeostasis by causing specific defects in the immune response, whereas others impair tissue metabolism or disrupt the physiology and integrity of epithelial and connective tissues. These diseases can lead to significant periodontal destruction and are considered distinct forms of periodontitis. Examples include Down syndrome, leukocyte adhesion deficiency syndromes, Papillon-Lefèvre syndrome, Haim-Munk syndrome, Chediak-Higashi syndrome, neutropenia, primary immunodeficiency diseases, Cohen syndrome, glycogen storage diseases, Gaucher disease, hypophosphatasia, hypophosphatemic rickets, Hajdu-Cheney syndrome, epidermolysis bullosa, hypoplasminogenemia, and Ehlers-Danlos syndrome. A third category encompasses diseases that induce periodontal tissue loss through mechanisms independent of periodontitis. Examples of this group include Langerhans cell histiocytosis, hyperparathyroidism, and giant cell granulomas. In conclusion, systemic diseases contribute to periodontal tissue loss through overlapping inflammatory pathways, immune dysfunction, or other independent mechanisms. Grouping these diseases by their primary pathological pathways offers a clearer understanding of their effect on periodontal health. This framework may also help direct research toward uncovering shared and unique mechanisms of systemic disease-related periodontal pathology, potentially leading to more targeted therapies and improved disease management.

Cathepsin C (CTSC) is a lysosomal cysteine protease constitutively expressed at high levels in the lung, kidney, liver, and spleen. It plays a key role in the activation of serine proteases in cytotoxic T cells, natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G, neutrophil elastase, proteinase 3) underscoring its pivotal significance in immune and inflammatory defenses. Here, we comprehensively review the structural attributes, synthesis, and function of CTSC, with a focus on its variants implicated in the etiopathology of several syndromes associated with neutrophil serine proteases, including Papillon-Lefevre syndrome (PLS), Haim-Munk Syndrome (HMS), and aggressive periodontitis (AP). These syndromes are characterized by palmoplantar hyperkeratosis, and early-onset periodontitis (severe gum disease) resulting in premature tooth loss. Due to the critical role played by CTSC in these and several other conditions it is being explored as a potential therapeutic target for autoimmune and inflammatory disorders. The review also discusses in depth the gene variants of CTSC, and in particular their postulated association with chronic obstructive pulmonary disease (COPD), COVID-19, various cancers, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, sudden cardiac death (SCD), atherosclerotic vascular disease, and neuroinflammatory disease. Finally, the therapeutic potential of CTSC across a range of human diseases is discussed.

Papillon-Lefèvre syndrome (PLS) is a rare hereditary disease characterized by palmoplantar hyperkeratosis (PPK) and periodontitis in the primary and permanent dentition, usually resulting in edentulism in youth. Subsiding of PLS-associated periodontitis through specific therapy has occasionally been reported. We aimed to systematically assess periodontal treatment strategies that may decelerate disease progression. A systematic literature search was conducted at PubMed/LIVIVO/Ovid (Prospero registration number CRD42021223253). Clinical studies describing periodontal treatment success-defined as loss of ≤four permanent teeth because of periodontitis and the arrest of periodontitis or probing depths ≤ 5 mm-in individuals with PLS followed up for ≥24 months. Out of the 444 primarily identified studies, 12 studies reporting nine individuals were included. The timely extraction of affected or, alternatively, all primary teeth, compliance with oral hygiene instructions, supra- and subgingival debridement within frequent supportive periodontal care intervals, and-in eight patients-adjunctive systemic antibiotic therapy (mostly amoxicillin/metronidazole) effected a halt in disease progression. The suppression of Aggregatibacter actinomycetemcomitans below the detection limit was correlated with the subsiding of periodontitis. Successful controlling of PLS-associated periodontitis may be achieved if high effort and patient compliance are provided.