driver of OA inflammation seems to be difficult, and broader approaches targeting general pro-inflammatory signaling pathway components might be more favorable . Interference with pro-inflammatory signaling pathways Targeting single cytokines has so far had little effect. Recent strategies aim to interfere with further upstream initiators of the pro-inflammatory signaling cascade. Hydroxychloroquine (HC), a chloroquine derivative used to treat malaria and inflammatory autoimmune disorders like RA, supposedly exerts its effects via Toll-like receptor (TLR) 7/9 85. Several studies using HC in hand OA have failed to show effects so far 30, 31, and results from a study in knee OA are not obtainable yet (NCT01645176). TLR downstream targets include molecules like MyD88, TRAF3/6, p38 MAPK, Janus kinases, and transcription factors like NF-κB 86. Several attempts have been made to interfere with signaling molecules to inhibit inflammation in OA. The I-κB kinase inhibitor SAR113945 was tested in four trials of knee OA (NCT01113333, NCT01598415, NCT01511549, and NCT01463488), but, though the compound showed a good safety and tolerability profile, a larger proof-of-concept study failed to show superior efficacy 32. A small subgroup of patients with effusion at baseline elicited a reduced WOMAC pain score after 56 days. Local delivery of a potent p38 MAPK inhibitor (PH-797804) reduced joint destruction and inflammation in a murine destabilization OA model 87. The efficacy of PH-797804 compared to naproxen was evaluated in a clinical trial involving knee OA patients, but the results have not yet been disclosed (NCT01102660). FX-005, another therapeutic p38 MAPK inhibitor with sustained-release kinetics, was evaluated in a phase I/II knee OA trial where it promoted pain relief superior to placebo after 4 weeks (NCT01291914) ( Table 1C). Direct targeting of the TLR would provide even higher upstream interference with OA immune activation, e.g. the application of a miR-21 inhibitor targeting TLR7 was able to induce long-lasting analgesia in an OA rat model 88. As for anti-cytokine therapy, careful evaluation of individual patient inflammatory status will probably help to identify more responsive patient subgroups or joints. Other immune system targets The complement system might also be a potential source of therapeutic targets for OA therapy 89, 90. An increasing number of drugs targeting different factors of the complement cascade are available and were tested in the clinic for various diseases 91, but, to the best of our knowledge, none of them has been tested in OA patients so far. Similarly, there is increasing awareness that adaptive immune mechanisms might be involved in OA pathophysiology 92, 93, but these insights have not been translated into therapeutic approaches so far. Identification of more immune system entities contributing to OA development and progression will provide even greater numbers of targets for potential OA therapeutics but requires meticulous analysis of timely and spatial involvement in disease-related processes. Gene therapies Novel genetic approaches are currently under evaluation for safety in clinical phase I studies. They include i.a. injection of recombinant adeno-associated virus type 2/5 (rAAV2.5) vector encoding IL-1 receptor antagonist (IL-1Ra) into one knee joint of patients with moderate OA of the knee (NCT02790723) and FX201, a helper-dependent non-integrating adenovirus, containing the human IL-1Ra gene under the control of an inflammation-sensitive promoter (NCT04119687). Moreover, new gene therapeutic targets include interferon (INF)-β (rAAV2.5 vector encoding human IFN-β under control of a NF-κB promoter, ART-I02) in subjects with RA or OA and active arthritis of the hand (NCT02727764) as well as XT-150, a plasmid DNA carrying a variant of the human IL-10 transgene (NCT03477487). Although results of these studies are not available yet, gene therapy offers great therapeutic potential as it is aimed at prolonged, site-specific, and