b. Cytotoxic agents

• Antimetabolites

Methotrexate (MTX) administered typically in a dose of 5–25 mg once a week, inhibits dihydrofolate reductase (DHFR) and therefore decreases DNA synthesis. Its action is on rapidly dividing cells including B and T lymphocytes, making it the widely used immunosuppressive drug in the first-line treatment of PUK in RA. It presents less severe drug toxicity than the majority of other immunosuppressants [1, 67, 68].

Azathioprine is administered by 1–2.5 mg/kg/day; a purine synthesis inhibitor, which inhibits DNA synthesis in proliferating cells. It has been reported that among patients with RA-associated PUK unresponsive to steroid therapy, both MTX and azathioprine show high efficacy. Additionally, azathioprine is considered a much safer but less effective drug than cyclophosphamide [67, 69, 70].

Mycophenolate mofetil is administered as 1–1.5 g twice daily; an inosine-5<sup>0</sup> monophosphate dehydrogenase inhibitor, thereby inhibiting the purine synthesis pathway required for replication of lymphocytes. It comes as an effective treatment when combined with steroids. The drug seems to be more effective and safer in the treatment of PUK, compared to MTX and azathioprine, especially in cases where the side effects of the former drugs are not well tolerated [71, 72].

• Alkylating agents

Trigger an irreversible DNA crosslinking, leading to apoptosis in rapidly dividing cells such as T lymphocytes. These drugs are reserved for the treatment of immune disorders unresponsive to steroids and antimetabolites. They have demonstrated efficiency in the treatment of chronic PUK [63].

Cyclophosphamide is administered at a dose of up to 2 mg/kg/d; it has shown good efficacy in the treatment of GPA-related PUK. Treatment of patients with RA-related PUK, in the combination with systemic steroid treatment along with local treatment, has also shown promising results.

Considering its high cytotoxicity, during therapy, morphology should be repeated every 2–3 weeks [64, 67, 73, 74].

Chlorambucil [75].

• T-cell inhibitors

Cyclosporine A (CsA) administered at a dose of 1.25 mg/kg b.i.d., with an increase by 0.5 mg after 8 weeks and subsequently as per response (maximum daily dose 4 mg/kg). It is a calcineurin inhibitor, suppresses transcription of IL-2, affecting T-cell activity and promotes healing of epithelial defects therefore reducing associated pain. It shows success in the management of bilateral progressive PUK that is not responsive to treatment with the standard agents. However, there is limited application of this drug considering its serious side effects including nephrotoxicity, hepatotoxicity, and increased incidence of lymphoma [52, 67, 76, 77].

Tacrolimus [78].

	- Rituximab

A monoclonal antibody, interacts with the CD-20 receptor found on the surface of B lymphocytes. This is the most widely used agent for maintaining remission in ANCA-associated vasculitis (e.g., GPA and MPA). It shows to be more potent in maintaining remission compared to azathioprine or cyclophosphamide [79–82].

• TNF-α inhibitors

Etanercept (decoy receptor for TNF-α); infliximab, adalimumab, golimumab (monoclonal anti-TNF-α antibodies) inhibit the activity of TNF-α (a proinflammatory cytokine released by macrophages and other inflammatory cells) along with the production of MMPs. They are used for PUK refractory to treatment with other immunosuppressive therapeutics. Preliminary studies demonstrate similar efficacy of rituximab and TNF-α inhibitors in the management of PUK in the course of various rheumatologic diseases [4, 5, 83]. Infliximab has the potential to cause serious side effects such as myocardial infarction, pulmonary embolism, deep vein thrombosis, infusion related reactions, and reactivation of tuberculosis [84]. Etanercept is less effective than infliximab and can cause secondary scleritis, which limits its applications in autoimmune diseases [85]. Adalimumab shows a more effective, safer profile and better patient compliance among anti-TNF-α agents [86, 87].

• Tocilizumab

Anti-IL-6 monoclonal antibody. To date, relatively few studies exist on their efficacy in PUK, but these drugs are likely to have better results than TNF-α inhibitors in PUK that are resistant to standard therapy [29].
