As described so far, a great variety of factors is involved in the pathogenesis of vitiligo. Several attempts have been made by the scientific community to find an effective treatment and one of the therapeutic approaches is mainly based on the use of pro-inflammatory cytokines as targets. In this context, monoclonal antibodies have been synthesized, either derived from human immortalized cells or from other animals, targeting the key factors involved in the physiopathology of different diseases, including vitiligo [
68]. For instance, several biologics have been used in order to achieve repigmentation or halt the depigmentation processes. Ustekinumab, a monoclonal antibody blocking both IL 12 and IL-23, is one of these molecules. Originally developed for psoriasis [
69], this monoclonal antibody has been used in several patients. Since psoriasis is a much more common condition than vitiligo, it has been used in patients affected both by psoriasis and vitiligo. A case report demonstrated that the antagonism of IL-12/23 action led to the resolution of psoriatic plaques, along with a remarkable improvement of the concomitant alopecia and vitiligo in a patient affected by psoriasis, alopecia areata and vitiligo at the same time. Therefore, it has been hypothesized that cases of vitiligo that are resistant to common treatments could benefit from the use of this antibody [
70]. Unfortunately, this case report is the only positive result regarding the use of ustekinumab in vitiligo. One nation-wide study, in fact, demonstrated the new onset of white patches in three patients treated with ustekinumab, thus worsening the pre-existing vitiligo in one more patient [
71]. In another study, 15 patients developed vitiligous patches after ustekinumab treatment [
72] and another case report described a similar reaction [
73]. However, the relationship between ustekinum abuse and the appearance of vitiligo patches should be further investigated. Secukinumab is another tested monoclonal antibody (MAB) that may be considered as a suitable candidate for vitiligo treatment. This biological drug targets IL-17A, an interleukin involved in the pathogenesis of vitiligo, psoriasis and psoriatic arthritis. Again, the studies published to date have led to contrasting results. One case report from 2020 revealed that adalimumab, a TNF-alpha inhibitor, failed in treating psoriasis, but this patient also showed an onset of vitiligo lesions over his body. After the switch to secukinumab, an improvement of the psoriatic lesions and the clearance of vitiligo patches were observed [
74]. On the other hand, two studies denied this possibility. In a 2020 case report, two patients who failed a previous systemic treatment for psoriasis switched to secukinumab and vitiligo-like patches appeared over their skin; vitiligo was treated as a side effect with topical tacrolimus, stopping the progression of previous patches [
75]. The other study was a 2019 clinical trial. Eight patients were enrolled to challenge the efficacy of IL-17 inhibition but unfortunately most patients developed more lesions than when they started (7/8 patients) and the study was interrupted. Although the trial was prematurely interrupted, the hypothesis of the shift towards the Th1 profile of the lymphocytic population and the intermediate step of Th17.1 was imagined to be the crucial pathogenetic event [
76]. New-onset vitiligo may occur as paradoxical skin reaction during treatment with TNFα-IL-17 and IL-12/IL23 inhibitors in patients with other inflammatory diseases [
71]. A retrospective study showed that new cases of vitiligo were related to infliximab and adalimumab use (72.2%) and to ustekinumab and secukinumab (22.2%) [
71]. However, adalimumab was the major trigger of new-onset vitiligo [
71]. The maintenance of the biological therapy after the onset of vitiligo led to stable disease or repigmentation in the majority of cases, whereas the use of biological agents in patients with pre-existing vitiligo had an unfavorable outcome, with vitiligo progression in 43.7% of cases and repigmentation in only one out of eighteen patients [
71]. The onset of vitiligo during the treatment with adalimumab [
74,
77,
78,
79,
80,
81] and infliximab [
82,
83,
84,
85,
86,
87,
88] for other inflammatory diseases has been widely reported in the literature. The occurrence of vitiligo in patients treated with anti-TNFα has limited their use, although they appear hopeful in stopping the progression of the disease. In a group of six patients treated with anti-TNFα, five patients did not develop any new depigmented patches, although repigmentation was not observed [
89]. Some authors suggested that anti-TNFα may be useful to stabilize vitiligo rather than to favor repigmentation [
90]. The results are inconclusive about the use of etanercept, another TNFα inhibitor, in patients with vitiligo, and the low number of patients treated with this biological agent does not allow us to give a final opinion. Etanercept led to a mild improvement of vitiligo in two patients who showed strong cytoplasmic staining for TNF-α in the samples obtained from their margin lesions [
91] and in a patient affected by both vitiligo and psoriasis [
92]. Nevertheless, an open-label pilot study treatment with etanercept in four patients with vitiligo reported neither improvement nor aggravation of the disease [
93]. Hence, the authors did not recommend etanercept as a first-line treatment for vitiligo [
92]. A more promising therapy seems to be tofacitinib, a Janus kinase (JAK) inhibitor already used in several inflammatory-mediated diseases. Several studies have been proposed, mostly pilot studies, both paired with and without narrow-band UVB therapy (NB-UVB). Scarce results were observed in the improvement of vitiligo lesions with the use of oral tofacitinib alone [
94], two case reports also demonstrated a partial and progressive resolution of depigmentation in a patient treated with oral tofacitinib [
95,
96] and another pilot study with 16 patients using topical tofacitinib showed positive results, especially in darker skin types and younger patients [
97] and one more patient treated with increasing doses of oral tofacitinib after failing UVB therapy [
98]. Although all these studies have reported positive results regarding this therapy alone (not paired with NB-UVB), not just regarding the progression but also the re-pigmentation of previously affected areas, confounding factors persist, such as previous NB-UVB therapy and the scarcity of numbers, preventing researchers from drawing any conclusion. On the other hand, several studies have evaluated the combination of phototherapy and tofacitinib together. One of these studies suggests that NB-UVB therapy is mandatory for re-pigmentation to let the melanocytes repopulate affected areas, whereas tofacitinib acts as the immune system inhibitor [
99]. This consideration was further proposed by another case report that described a male patient which improved both his vitiligo, alopecia areata and psoriasis lesions after oral tofacitinib and UVB therapy in a three-month period [
100]. Finally, a retrospective study with a more consistent number of patients affected by vitiligo reported an almost complete re-pigmentation of vitiligo patches (92% patients) following oral tofacitinib and UVB therapy, compared to patients treated solely with UVB therapy (77% re-pigmentation rate) [
101]. All these studies can be summarized by the final considerations of the model proposed by Liu et al.: tofacitinib is a safe drug to use, with only mild side effects, such as plasmatic levels of lipids growing or some moderate weight gain. Both the immunosuppressive and repopulating effects derived from tofacitinib require light exposure, especially for re-pigmentation; oral tofacitinib alone might be useful in monotherapy just for maintenance [
102]. On the downside of this treatment, the high cost of this therapy and the chance of developing leukopenia and secondary infections might be considered as two important limitations to the use of this therapeutic approach on a large scale. In fact, a topical administration has been mainly considered, for visible areas such as in the face [
103], and in children as well [
104], with positive results. Recently, ruxolitinib, a JAK1/2 inhibitor, has been proposed for the treatment of vitiligo. Although JAK1/2 inhibition seems to be a better treatment option compared to JAK1/3 inhibition by tofacitinib, the results obtained from a randomized trial [
105] showed comparable effects, whereas other case reports [
106,
107] have confirmed a lack of significant improvement. As mentioned, IL-6 is implicated in the immunopathogenesis of vitiligo, in particular in active disease [
53]. Tocilizumab is an anti -interleukin -6 (IL -6) receptor humanized monoclonal antibody, approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). Nadesalingam et al. reported the onset of vitiligo, halo naevi and alopecia areata during treatment of JIA with tocilizumab [
108]. This effect is the consequence of the blockade of the IL-6 receptor that inhibits the interaction of IL-6 with its receptors, thus increasing IL-6 levels in serum [
108]. Moreover, the increase in IL-6 levels during treatment with tocilizumab may lead to melanocyte damage [
108]. In contrast, tocilizumab was used in a patient with seronegative rheumatoid arthritis and the almost complete resolution of simultaneous lesions of vitiligo was observed; nevertheless, the recurrence of depigmentation at the original sites has been noted after the discontinuation of tocilizumab and the treatment has not resolved genital vitiligo [
109]. All these possible targets have been summarized recently in a review about biologic-induced vitiligo, showing that we still lack sufficient knowledge to address the reasons why a drug targeting a specific cytokine involved in the pathogenesis of this condition leads to paradoxical results.
Table 1 presents a short summary of the most common attempted treatments.