Patients should be considered for targeted immune therapy in a variety of circumstances: if severe psoriasis,15–17 defined as involvement of greater than 10% of the total Body Surface Area (BSA), a PASI or a DLQI scores greater than 10 or compromised of specific locations (hands, feet, scalp, face, or genital area), when psoriasis causes intractable pruritus or has serious emotional consequences with a disease duration greater than 6-months,15 or is unresponsive to conventional therapy, or cannot receive standard systemic therapy due to patient’s general condition, comorbidities, or has a severe disease such as erythrodermic, pustular psoriasis or psoriatic arthritis.15–17

There are multiple targeted immune therapy for psoriasis. Targeted therapies like anti-TNF-α, anti‐IL17, anti-IL23, and anti‐IL12/23 can reach PASI-90 in more patients than previous systemic treatment (i.e., cyclosporin and methotrexate).18 Anti‐IL17 (i.e., ixekizumab, secukinumab, and brodalumab) and anti‐IL23 (risankizumab, tildrakizumab and guselkumab) treatments showed a higher proportion of patients reaching PASI 90 compared to all the systemic interventions evaluated in the last network meta-analysis.18

TNF-α inhibitors were the first biologics drugs approved for the treatment of psoriasis.12,19 Meta-analysis shows that among this class infliximab has the highest efficacy, followed by certolizumab, adalimumab, and etanercept.18,19 The FDA approved sequentially etanercept (2004), infliximab (2005), adalimumab (2008), golimumab (2017), and certolizumab (2018).

IL-17 inhibitors reach a total clearance of disease (i.e. PASI-100) in about half of the patients11,12 and have the fastest onset of action. The drugs approved by FDA to treat psoriasis are secukinumab (2015), ixekizumab (2016), and brodalumab (2017).

IL-23 inhibitors risakuzumab and guselkumab have recently demonstrated a better efficacy and safety profile compared to anti-IL-17 and a convenient dosing regimen.20,21 The drugs approved by FDA are guselkumab (2017), tildrakizumab (2018) and risankizumab (2019). Ustekinumab (2013) is a mAbs that inhibits IL-12 and IL-23.

JAKis (deucravacitinib, peficitinib, baricitinib, solcitinib, itacitinib, abrocitinib, brepocitinib, ruxolitinib and tofacitinib) have also been used for the treatment of psoriatic patients.22,23 Although we still lack complete data on their final clinical impact on psoriasis treatment, recent trials are showing a better response than certain conventional therapies (e.g., methotrexate, cyclosporine) but inferior to targeted immune therapy (e.g., risankizumab).18 Deucravacitinib24,25 a selective allosteric Tyrosine Kinase 2 (TYK2) inhibitor is the only JAKi approved by the FDA (2022), achieving a 70% PASI-75 at week 24.

In recent years (2004 to 2020), 51 clinical guidelines addressing the management of psoriasis have been published, and 41 of these mention the use of biologics.26 During 2021–2022 several dermatological societies have updated their clinical guidelines considering the approval of new molecules by drug regulatory agencies.27–33 Guidelines recognize anti-IL-23 and anti-IL-17 drugs as part of the first-line treatment profile for psoriasis management. A major concern results from their high cost and accessibility. The final decision for the selection of a drug for the treatment of a psoriatic patient depends on several clinical and epidemiological factors (Table 1).

The safety profile of targeted immune therapy for psoriasis is well described, the most common adverse events being upper respiratory tract infections and injection site reactions for all drug classes.34,35 General considerations should be taken concerning reactivation of tuberculosis, hepatitis B and C. The usage of JAKis should also consider previous infections by viruses of the Herpes family.36,37

Current evidence shows that targeted immune therapy does not increase the risk of major adverse cardiovascular events such as myocardial infarction, cerebrovascular accident cardiovascular death, or the incidence of malignancies.35,37–39

A common cutaneous adverse reaction is the phenotypic switch from psoriasis to atopic eczema that occurs in up to 1%–12.1% of patients taking anti-TNF-α or anti-IL-17/IL-23 drugs.40 Topical treatment was successful in some cases, but in others, the biologic treatment needs to be discontinued.

A paradoxical reaction – psoriatic worsening and/or new psoriatic lesions – has been reported with the use of certain drugs (e.g., anti-TNF-α drugs and ustekinumab). These reactions usually do not require cessation of therapy and are self-limited.37 Other relevant adverse reactions with anti-TNF-α class are urinary tract infection, back pain, arthralgia, pruritus and erysipelas, invasive fungal infections, lymphoma, heart failure, cytopenia, induction or exacerbation of demyelinating disease and lupus-like syndrome (e.g., infliximab).40

Anti-IL-17 and anti-IL-12/23 drugs have less data about their safety profile. An adverse reaction of interest in IL-17 and IL-12/23 inhibitors is mucocutaneous candidiasis (1.7% in patients treated with secukinumab, 3.3% ixekizumab, 4.0% brodalumab, 2.3% ustekinumab).41 Episodes of exacerbation of inflammatory bowel disease have also been observed using these drugs. Patients with a history of Crohn's disease or ulcerative colitis should be treated with another targeted immune therapy.37

For JAKis the most common adverse effects were herpes simplex reactivation, mouth ulcers, pneumonia, COVID-19, malignancies including lymphoma, rhabdomyolysis, increased creatine phosphokinase, increased triglycerides, and increased transaminases.23

With the available data the, rates of any adverse effect were the lowest for tildrakizumab, certolizumab, and etanercept.34 For serious AE the lowest were for certolizumab, risankizumab, and etanercept. In the long-term treatment, risankizumab had the most favorable benefit-risk profile.34

Pregnancy: the only FDA-approved mAbs for use in pregnant patients is certolizumab pegol. It is a PEGylated Fab mAb directed against TNF-α that does not cross the placental membrane.12,19

Pediatric: The mAbs authorized by the FDA for children over 4 years of age are etanercept and adalimumab, secukinumab from 6 years, and ustekinumab from 12 years old.18,19,42

Both children and adults can be considered for targeted immune therapy if they have severe disease, defined as; involvement of greater than 10% of the total BSA, Investigator Global Assessment (IGA) of at least 3, Eczema Area and Severity Index (EASI) ≥16, Scoring Atopic Dermatitis (SCORAD) ≥50, and Peak Pruritus Numerical Rating Scale (PP-NRS) severity score ≥4, or when it causes intractable pruritus or it has serious emotional consequences.45,46

Multiple targeted therapies are available for AD that must be selected according to different clinical criteria in each patient (Table 2). Dupilumab has demonstrated similar efficacy to higher-dose cyclosporine in patients older than 6 months with a more reliable response and superiority to methotrexate and azathioprine with considerably fewer side effects.44 This has made targeted immune therapy very promising for AD, but the comparison of efficacy and safety between targeted therapies is difficult.44,47 Four systemic drugs have been approved by the FDA (dupilumab,48 tralokinumab,49 abrocitinib,50 upadacitinib51) and other drugs are used off-label or in clinical trials.

Compared with dupilumab, abrocitinib, 200 mg daily, and upadacitinib, 30 mg daily, were associated with higher reductions in EASI scores meanwhile baricitinib and tralokinumab, reductions in EASI scores were similar or slightly worse than dupilumab.44

Dupilumab is an anti-IL-4/13 mAb approved by the FDA in 2017 for the treatment of moderate to severe AD from 6 months.52 The therapeutic effect of dupilumab is primarily mediated through its inhibition of the alpha subunit of the Interleukin-4 Receptor (IL-4Rα).53,54

Tralokinumab is an anti-IL-13 mAb approved by the FDA in 2021 for the treatment of moderate-to-severe AD in adults. In 2 RCTs, tralokinumab 300 mg every 2 weeks achieved an EASI 75 in 25%–33.2% of patients at 16 weeks of treatment. These RCTs also showed early improvements in pruritus, sleep interference, and DLQI. Patients maintained these responses after 52 weeks of treatment with tralokinumab without any rescue medication.49,55 Lebrikizumab, a mAb that targets IL-13 in two randomized, double-blind, placebo-controlled, phase 3 trials in >12-years old patients with moderate to severe AD showed an EASI-75 response in 58.8% and 52.1% of patients respectively at week 16.56

Abrocitinib is a JAK-1 inhibitor approved by the FDA for the treatment of AD in adults in 2022. In moderate to severe AD, abrocitinib showed consistent responses to treatment and presented no new safety concerns compared with dupilumab.46,57–59 It is used at a dose of 200 mg daily, achieving 70% of EASI 75 at week 12 of treatment.58

Upadacitinib is a JAK-1 inhibitor approved by the FDA (2022) for the treatment of AD in patients >12 years old. It shows an improvement in EASI 75 of 71% at week 16 with a dose of 30 mg per day orally.60

Recently baricitinib, a first-generation inhibitor of JAK 1–2 not yet approved by FDA in AD, has completed phase 2 and 3 RCTs in combination with topical corticosteroids in adults with moderate-to-severe AD. At 16 weeks baricitinib 4 mg provided 54.9% and 59.4% improvement in EASI score in BREEZE-AD1 and BREEZE-AD2 respectively.61

Tezepelumab is a human mAb that binds thymic stromal lymphopoietin (TSLP, an epithelial cell-derived cytokine that induces the production of Th2 cytokines, including IL-4, IL-5, and IL-13)62 used for the treatment of asthma. It has been tested at doses of 280 mg every 2 weeks in phase 2 studies, achieving an EASI 50 in 65% of patients at week 12 of treatment.63 Fezakinumab, a human mAb against IL-22 is in phase 2 studies, induction doses of 600 mg followed by 300 mg every 2 weeks have demonstrated an improvement in IGA score from 12 weeks of use.64 Nemolizumab is an experimental anti-IL-31RA mAb in phase 2 studies. It was reported that 42% of patients treated showed an improvement in the EASI score at 12 weeks of use.65 Etokimab is another experimental mAb that binds IL-33 in the initial phase of development. At the moment, studies have tested doses of 300 mg IV once, achieving EASI 50 in 100% of the participants at 140 days.66

New topical targeted immune therapy for AD has recently appeared as a therapeutic tool. Ruxolitinib 1.5% cream (approved by FDA in 2021) for patients >12 years old shows improvements of 71.6% in EASI score after 4 weeks of use.67 Tofacitinib 2% cream had shown improvements of 82% on EASI score after 4 weeks of use and is awaiting FDA approval.68,69

The most common adverse events were upper respiratory tract infections and injection site reactions for all classes.44,45 General considerations should be taken in relation to the reactivation of tuberculosis, and hepatitis B, and in the case of JAKis also consider infections by viruses of the Herpes family.58,60 Another common adverse effect in all classes was eye symptoms (conjunctivitis, keratitis, blepharitis, ocular pruritus, dryness and discomfort in the eye). Dupilumab and tralokinumab do not require laboratory monitoring but abrocitinib, baricitinib, and upadacitinib need laboratory follow-up. It can produce creatine phosphokinase elevation, thrombocytopenia, and neutropenia.45 Other adverse effects reported for JAKis are nausea, headache, diarrhea, fatigue, acne, abdominal pain, and myalgias.70

Recently it has been observed an increased risk of seronegative inflammatory arthritis and psoriasis in patients using dupilumab.71 Based on current evidence, it appears that the use of anti-TNF-α for psoriasis and anti-IL-4/13 for atopic dermatitis are inversely related. The dual blockade with dupilumab is associated with psoriasiform diseases, while biologics for psoriasis can cause a phenotypic switch to eczema.72

For topicals, mild local irritation was the most common adverse effect.67,68

There are insufficient data to determine whether any targeted immune therapy is safer than another for AD. Abrocitinib, 100 mg daily, was associated with 2.6 times the odds of serious adverse events compared with dupilumab, but with a higher dose (i.e., abrocitinib, 200 mg daily) the odds were lower (1.4).44

Lower rates of serious adverse events were observed for dupilumab compared with placebo.44 Dupilumab is also associated with a non-significant increase in Herpes infection. The reason for a decrease in cutaneous infections, including eczema herpeticum is unknown, but improvement in the skin barrier and microbiome caused by targeted immune therapy may explain this observation.73

Management with targeted immune therapy should be considered early in severe cases. International guidelines recommend starting a targeted treatment for recalcitrant moderate-to-severe HS, defined as Hurley stage II‒III, or total abscess and inflammatory-nodule count ≥3 at baseline and an inadequate response to oral antibiotic treatment for at least 90 days.

There are a few targeted therapies for HS that must be selected according to different clinical criteria in each patient (Table 3). Adalimumab84 is the only biologic treatment approved by the FDA for HS (2015) and it is recommended as the first-line biologic drug in all guidelines, making infliximab the second option.74 Anakinra and bermekimab may be considered following failure of anti-TNF-α agents but evidence to support their efficacy in HS is limited.74

Adalimumab showed a 41.8%–58.9% improvement in Hidradenitis Suppurativa Clinical Response (HiSCR) in 50% of patients at 12 weeks.84 Infliximab demonstrated a 25%–50% improvement in Hidradenitis Suppurativa Severity Index (HSSI) in 60% of patients at 8 weeks.85 Other anti-TNFs are not used to treat HS such as etanercept or golimumab since paradoxical reactions of worsening or inducing the disease.74,86

Anti-IL-1 drugs have proven their efficacy in small placebo-controlled-RCT.87,88 Anakinra showed a >50% of improvement in Disease Activity Score (DAS) in 78% of patients at 12 weeks of treatment.87 Bermekimab showed a 60% of improvement in HiSCR at 12 weeks of treatment.88 These drugs should be considered when patients are not candidates for anti-TNF-α therapy.

Clinical guidelines also mention other biologics that have been used in case series successfully for the treatment of HS (guselkumab, risankizumab, secukinumab, bimekizumab, and upadacitinib), but the results in patients who have been treated with these drugs are based mainly on isolated case reports, which is not sufficient to recommend their use in the clinical setting.86

The safety profile of anti-TNF-α drugs has been discussed in a previous section (see Psoriasis). For anti-IL-1 drugs, the general considerations are similar between them. The most common adverse effects are injection site reactions and upper respiratory tract infections. Other adverse effects reported are headache, abdominal pain, diarrhea, and flu-like symptoms.89

We suggest considering targeted immune therapy in PG after a thorough study to establish the diagnosis of this condition.94 The disease must be recalcitrant or with moderate-severe intensity (BSA > 10%, complex anatomical sites, or excruciating pain).

There are a few targeted therapies for PG that must be selected according to different clinical criteria for each patient (Table 4). The drug with more data for PG treatment is infliximab.94 Infliximab demonstrated improvement of lesions at week 4 (20/29 patients), with complete remission in 21% at week 6.94 Infliximab has also been used successfully in combination with other drugs (oral systemic corticosteroids, azathioprine, mycophenolate mofetil and cyclosporine).92,93,95

There are case reports of PG treated with adalimumab and etanercept.95 Based on these observational data, no significant differences in the partial or complete response rates to infliximab, adalimumab, and etanercept were found. In a semi-systematic review for TNF-α inhibitors, an 87% partial response rate and a 67% complete response were found.95 Corticosteroids and cyclosporine can achieve 90% of partial response rates and only 47% complete response rates after 6 months.95

Anti-IL-1 drugs have also been used to treat PG.91 There are 29 cases reported in the literature of the use of anakinra in patients with comorbidities such as rheumatoid arthritis, psoriasis, PASH and PAPA syndrome at a dose of 100 mg per day.91,92 In an uncontrolled trial canakinumab was used in five steroid-refractory PG patients. Four showed a decrease in target-lesion size and three achieved complete remission.96

Other targeted immune therapies used successfully are ustekinumab (anti-IL-12/23)97 and ruxolitinib (anti-JAK1-2).91,92

There are reported cases of paradoxical induction of PG with the use of adalimumab, etanercept and to a lesser extent with infliximab.90

Specific adverse reactions for canakinumab are worsening of rheumatoid arthritis, pyrexia, vomiting, sinusitis, and arthralgia and for anakinra weight gain, musculoskeletal pain and vertigo.96

Adults and adolescents 12 years of age and older can be considered for targeted immune therapy if they remain symptomatic despite H1 antihistamine treatment up to 4 times of standard dose, or if they persist symptomatic with combination therapy (H1 antihistamines 4-times the standard dose plus H2-antihistamines and/or leukotriene receptor antagonist).98,100

There is only one targeted immune therapy currently approved for CSU, and other options must be selected in refractory cases or research contexts (Table 5). Omalizumab, an anti-IgE mAb, was approved by the FDA in 2014 for use in patients >12 years old for CSU. This authorization was based on two RCTs (ASTERIA I and ASTERIA II).101 RCTs showed that at 40 weeks, 75.3% of CSU patients achieved complete response and 14.6% had partial response.102

Ligelizumab an anti-IgE mAb is still under study but recent clinical trials for CSU treatment are showing an efficacy similar to omalizumab.103,104

Lirentelimab is an anti-Sialic acid-binding Immunoglobulin-Like Lectin 8 mAb (anti-SIGLEC-8, an inhibitory receptor presents on eosinophils and mast cells). Ligation to Siglec-8 induces eosinophils death, inhibits mast cells IgE-mediated degranulation and de novo synthesis of prostaglandin D2. Results of a phase 2 trial with lirentelimab for the treatment of CSU and for the treatment of inducible urticaria demonstrated a 92% complete response at week 22 and only 36% complete response in patients previously refractory to omalizumab treatment.105

Dupilumab has demonstrated partial response in case reports.106 Benralizumab and mepolizumab, both experimental anti-IL-5R and anti-IL-5 respectively molecules, have also been used.107 In both cases treated patients had clinical improvement.108 Secukinumab has been used in case reports for the treatment of CSU in refractory patients to H1-antihistaminics and omalizumab treatment, showing a significant reduction in disease activity from baseline.109

The most common but manageable side effects of omalizumab are headache, upper abdominal pain, pyrexia, and local reaction at the injection site. More serious side effects such as anaphylactic reaction, syncope and angioedema have been reported with a frequency of less than 1/1000.98

For lirentelimab the most common adverse events included infusion-related reactions, nasopharyngitis, and headache. No treatment-related serious adverse events occurred.105

Patients should be considered for JAKis treatment if they have moderate or severe disease (≥30% total scalp hair loss for at least 3–6 months as measured using Severity of Alopecia Tool (SALT) score) or refractory response to conventional treatment for the last 6 months. There is no limitation for previous duration of alopecia and trials have considered patients with a wide range of duration of AA as candidates for JAKis treatment.110,111

There is only one targeted immune therapy currently approved for AA, but other options have been used with success and must be selected according to different clinical criteria in each patient (Table 6). The FDA has approved baricitinib (2022) a JAK 1-2i for the treatment of AA in adults. Its efficacy was evaluated in two randomized, double-blind, placebo-controlled trials (BRAVE AA-1 and BRAVE AA-2).110 Patients in these studies received 2 or 4 mg of baricitinib per day. Final results at week 36 showed a 22% adequate response with 2 mg and 38% with 4 mg. Similar results were observed in BRAVE AA-2 (19% adequate response with 2 mg and 35% with 4 mg).110 Tofacitinib, a JAK 1-3i has been used to treat moderate to severe cases of AA with >50% of scalp hair loss in adults, achieving complete response in 20% of treated patients and 77% of partial response at 4–18-months of treatment.112 In 2023 the FDA approved Ritlecitinib for the treatment of AA in people over 12 years of age based on the results of ALLEGRO, where 23% of patients achieved hair recovery of at least 80% after 6 months of treatment.113 Ruxolitinib is the last JAKi used for the treatment if AA achieving overall responses in 93% of patients and complete response in 21% of patients treated at 6 months of follow-up.111

The safety profile of JAK inhibitor drugs has extensively been studied and in general, all JAKis used for AA treatment are well tolerated. Upper respiratory tract infections, hypercholesterolemia, elevated creatine phosphokinase, headache, diarrhea, and nasopharyngitis are the most frequently reported adverse reactions. Less common side effects included other infections such as herpes zoster, herpes simplex, urinary tract infections, and gastroenteritis.110–112

Patients are candidates for targeted immune therapy as a first-line option in cases of new-onset moderate to severe PV/PF or previously treated patients who do not achieve clinical remission with systemic corticosteroids or immunosuppressive adjuvants.114 The severity of the disease must be measured with the Pemphigus Disease and Area Index (PDAI) score. Multiple mucosal involvement (oral, nasopharyngeal, conjunctival, genital) or a PDAI ≥15 are considered moderate disease. Patients with PDAI score ≥45 or oral lesions, dysphagia and weight loss belong to a severe state of the disease.115,116

Rituximab is the only biologic approved by the FDA (2018) for bullous diseases and is considered the first therapeutic option for PV and PF by international guidelines.116 This approval was based on the results of Rituxi3,115 in which 89% of pemphigus patients treated with rituximab and oral prednisolone were disease-free and without requirement of any further treatment after 24 months, compared to 34% with prednisolone alone. Rituximab treatment also reduced the dose of corticosteroids required for clinical remission, reducing the side effects associated with high-dose steroids117 (Table 7).

Efgartigimod is a human IgG1 antibody targeting the neonatal Fc receptor. The blockade of the neonatal Fc receptor diminishes the availability of pathogenic IgG antibodies and it has been tested for the treatment of PF and PV.118 In a phase 2 trial, single use of efgartigimod demonstrated early disease control in 90% of patients after 17 days. Combined with prednisone led to complete clinical remission in 64% of patients after 6 months.119 Two phase 3 clinical trials evaluating the efficacy and safety of efgartigimod in adults with pemphigus (NCT04598451 and NCT04598477) are underway.117

B-cell Activating Factor (BAFF), also known as B-lymphocyte Stimulator (BLyS) is an important B-cell activator.120 Ianalumab is an experimental mAb that binds to BLyS, A phase 2 clinical trial was conducted to determine the doses, benefits, and safety of ianalumab in patients with PV, showing a 73% decrease in mean PDAI score at week 12 in seven patients with pemphigus compared with placebo-treated controls.121

Treatment with rituximab, omalizumab and dupilumab is reported in patients with bullous pemphigoid. Cao et al.122 conducted a systematic review to evaluate the use of these 3 biologics in patients with BP who had been refractory to the use of other systemic therapies such as systemic corticosteroids, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine and cyclophosphamide. They found that rituximab led to complete remission in 70.5% and partial remission in 23.8% of patients within 6 months of follow-up with a recurrence rate of 20.5%.122 Omalizumab led to complete remission in 67.9% and partial remission in 20.8% of patients within 6 months, with a recurrence rate of 5.7%.122 Dupilumab led to complete remission in 66.7% and partial remission in 19.4% of patients within 4.5 months of treatment, with a recurrence rate of 5.6%.123,124

Although rituximab is an excellent drug for severe PV or PF, it is also associated with well-known severe adverse events. The most well-documented are infusion reactions, infections, cardiac disorders, and cases of fatal progressive multifocal leukoencephalopathy.114 Most of these adverse effects can clinically be controlled if they are recognized early stage.

A recent study showed that treatment with rituximab was associated with a lower risk of developing cardiovascular and metabolic comorbidities, so it might be particularly preferred in individuals with cardiovascular and metabolic risk factors, for whom corticosteroid-related adverse events must be strictly avoided.125

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a rare serious mucocutaneous disease caused by exposure to certain drugs, the most frequent being sulfonamides, anticonvulsants, non-steroidal anti-inflammatory drugs, allopurinol, and penicillins.126 Due to its low incidence the reported use of biologics in this disease has been limited mostly to case series and only two trials.126–128 With current data the efficacy and safety of biologic monotherapy and combination therapy cannot be conclusively determined, and the final role of these drugs is still under research.

The largest number of cases reported are related with etanercept. The most used therapeutic regime is 25 mg (in children weighing <65 kg) and 50 mg (adults or children >65 kg) on days 0 and 3. Etanercept monotherapy achieved re-epithelialization in 13 days and a mortality rate of 7.6%, while patients treated with etanercept in combination with corticosteroids achieved re-epithelialization in 11.1 days and had a mortality rate of 7.7%.126 Wang et al.127 conducted a RCT in which 96 patients with SJS/TEN were enrolled to compare the effects of etanercept to traditional corticosteroids. The study demonstrated that etanercept decreased the TEN-specific severity of illness score (SCORTEN)-based predicted mortality in about 9.4% compared to traditional corticosteroids.127 Infliximab was generally used in a dose of 5 mg/kg once.126 In case reports of patients treated with infliximab monotherapy the average number of days to reepithelization was 10.4 and there were no cases of mortality reported.126 In case reports of TEN treated with the combination infliximab/systemic corticosteroids the average number of days to reepithelization was 14.2 and the average mortality rate was 22.2%. A recent Cochrane review showed that etanercept 25 mg (50 mg if >65 kg) twice weekly until skin lesions healed may reduce disease‐specific mortality compared to corticosteroids (RR = 0.51, 95% CI 0.16 to 1.63) however, the CIs were consistent with possible benefit and possible harm.129

Regarding the use of targeted immune therapy used in SJS/TEN compared to corticosteroids, there was no statistical difference observed between the 2 treatment groups in the incidence of adverse events, however, there was a lower incidence of GI hemorrhage reported with biologics versus traditional corticosteroid.126,127,130

Drug-induced Hypersensitivity Syndrome/Drug Reaction with eosinophilia and Systemic Symptoms (DiHS/DRESS) is a severe drug reaction with a 10% mortality.131 Successful cases have been published using targeted immune therapy. In a recent report studying two cases of DRESS associated with myocardial involvement, tofacitinib 5 mg/bid was used (during 3-years) sequentially associated with corticosteroids, cyclosporin, methotrexate or IVIg.132 The two cases demonstrated remission when tofacitinib was utilized.132

A previous case report study of 10 patients with DRESS demonstrated a median healing time of 8.5 days after a 50-mg subcutaneous injection of etanercept.131 Finally there is a single case report of a patient treated successfully with mepolizumab.133

Adalimumab is the only targeted immune therapy recommended by international guidelines for the treatment of cutaneous and mucosal LP, in severe refractory cases.134 Its use improves pruritus and accomplishes healing of skin lesions in a period of 6 months.134 Another targeted immune therapy for LP is topical ruxolitinib that is in phase 2 studies to treat cutaneous LP.135 It has been tested at 1.5% cream twice daily showing clinical and modified Composite Assessment of Index Lesion Severity (mCAILS) score improvement after 4 weeks of treatment.135 The use of tofacitinib has been reported in case series at doses of 5 mg (bid) in follow-up periods ranging from 2 to 9 months to treat lichen planopilaris and hypertrophic LP showing clinical and LPAAI score improvement.136 The use of other JAKis such as upadacitinib or baricitinib is scarce. There are 13 patients reported in case series and case reports using baricitinib for lichen planopilaris, with 5 achieving partial resolution, 7 having no resolution, and only 1 achieving complete resolution. There are only 2 case reports with the use of upadacitinib for LP both of which achieved complete resolution.137 Finally, phase 2 studies are currently being carried out with ixekizumab (cutaneous LP, Lichen planopilaris) and secukinumab (cutaneous LP, Lichen planopilaris and oral LP).138

The FDA approved anifrolumab for Systemic Cutaneous Lupus (SLE) in July 2021.139 Anifrolumab is a fully humanized monoclonal antibody that selectively inhibits the IFN-α receptor 1.139 In TULIP-2 RCT anifrolumab was tested for the treatment of SLE, among patients with at least moderately severe skin disease, 49% of patients achieved a reduction in CLASI score of ≥50% compared to 25% in the placebo group.140 Belimumab is another drug approved by the FDA in 2011 for the treatment of SLE. We still lack final skin-specific outcomes of this drug in CLE. 141

For vitiligo topical ruxolitinib was approved by FDA in 2022 for the treatment of nonsegmental disease compromising <10% of the body’s surface area in adult and pediatric patients >12 years old. In two phase 3 trials (TRuE-V1 and TRuE-V2), subjects were randomized to treatment with ruxolitinib 1.5% cream or placebo twice daily for 2 weeks. At the end of the 24-week treatment period, 30% of ruxolitinib patients had at least 75% improvement in the facial Vitiligo Area Scoring Index (VASI), compared with 10% of placebo patients.142 Also in these studies ruxolitinib cream has shown improvement in acral pigmentation, which has historically been a refractory area for repigmentation for phototherapy, topical corticosteroids and tacrolimus.142 A pilot study of eleven patients with facial vitiligo using tofacitinib 2% cream in conjunction with narrow band UVB showed a reduction of 70% in VASI score after 2–4 months.143 In the other hand a case series of ten patients using tofacitinib 5 mg bid for 10 months and narrow band UVB or photo-exposure had a decrease of only 5.4% in BSA (5 patients) and others (5 patients) did not achieve any repigmentation.144

Granulomatous diseases can be therapeutic challenges. Management may be unsatisfactory with conventional systemic therapy.145 Treatment with anti-TNF has been tried with variable results.146 JAKis targeted immune therapy appears to be a promising option based on the results of a recent case series.147 Tofacitinib 5 mg/bid has been used in patients who were non-responders to corticosteroids. In a case series of only 1 patient complete remission was obtained after 4 months of treatment. For sarcoidosis (3 patients) the same case series showed complete response in 2 patients and 96% improvement in 1 patient.147 Further, RCT studies are needed to establish the real value of JAKis in granulomatous diseases.

A case series of 5 patients refractory to steroids treated with tofacitinib 5 mg/bid showed complete remission in 3 of them and near complete remission in another one.148 The remaining patient was unable to complete treatment with tofacitinib due to insurance reasons and treatment was changed to ruxolitinib 25 mg in the morning and 10 mg in the evening. This patient also achieved complete remission.148

There are cases of success using targeted immune therapy for refractory cases of morphea. In two patients with generalized deep morphea associated with eosinophilic fasciitis who did not respond to corticosteroid therapy, tofacitinib (10 mg/bid) was added to phototherapy and methotrexate, achieving clinical improvement in both of them.149 Tocilizumab (an anti-IL-6 drug) has been reported to be effective in the treatment of pansclerotic morphea.150,151 One 14-year-old girl was treated successfully with infliximab.150