psoriasis is a chronic inflammatory skin disease that affects 3% of the united states population . it manifests as well - demarcated , scaly patches on the skin , and it is associated with psoriatic arthritis and other comorbidities [ 24 ] . the choice of psoriasis treatment varies depending on the severity and extent of skin involvement . topical therapies are reserved for mild or localized disease , whereas phototherapy and systemic therapies are used for those with moderate - to - severe disease . limitations with extended use of traditional oral systemic therapies include suboptimal efficacy , slow onset of therapeutic effect , toxicities , and teratogenicity ; these limitations have propelled the use of targeted therapies into the forefront of treatment for chronic inflammatory diseases such as psoriasis , psoriatic arthritis ( psa ) , and rheumatoid arthritis ( ra ) . over the last decade , biologic agents targeting specific components of the tumor necrosis factor ( tnf-) pathway have gained wide adoption for treatment of psoriasis as they achieved rapid clinical improvement with minimal side effects in multiple clinical trials and ongoing studies [ 69 ] . however , high costs , potential risk for adverse events , and lack of persistent effects in some patients have fueled continued search for alternative therapies that target various components of the psoriasis inflammatory cascade . cytokines and growth factors such as interleukin ( il)-1 , il-6 , il-12 , il-17 , il-20 , il-23 , interferon ( ifn)- , and tnf- within the abnormally upregulated th1 and th17 pathways have been implicated as key mediators in the immunopathogenesis of psoriasis by driving the activation and proliferation of epidermal keratinocytes [ 1014 ] . after the identification of increased protein tyrosine kinase activity in immunologic diseases , therapeutic agents targeting the protein tyrosine kinases have been developed , and they are effective and well - tolerated medications . the janus family of kinases is a subset of the protein tyrosine kinases . preclinical studies have identified a number of cytokines involved in the psoriasis inflammatory cascade that utilize the janus family kinase ( jak ) signaling pathway . in this paper , we discuss the molecular pathway of the jak - stat signaling cascade and the mechanism of action of the jak inhibitors . we also examine in detail the treatment efficacy and safety of the currently available jak inhibitors for psoriasis treatment . we also briefly discuss currently available data on treatment efficacy and safety in other chronic immune - mediated diseases such as ra and ulcerative colitis ( uc ) . cytokine receptor signaling involves pathways such as the jak - stat pathway and the map kinase cascade . the jak family consists of four members : jak1 , jak2 , jak3 , and tyk2 . the activated stats dimerize and translocate into the cell nucleus to influence dna transcription , thus regulating gene expression . the various combinations of jak pairs recruit different stat proteins , of which there are up to six types , and this allows for the wide range of downstream activities seen in the jak - stat pathways . the jak - stat pathways activate or suppress the transcription of a wide array of genes that affect cell growth and apoptosis such as socs , nmi , bcl - xl , p21 , myc , and nos2 . however , jaks associate with specific cytokine receptors and therefore influence different aspects of immune cell development and function . jak1 is associated with ifn , il-6 , il-10 receptors , and receptors containing common  chains [ 21 , 22 ] . jak2 is primarily involved in hematopoietic receptors as well as il-12 and il-23 . when dimerized with jak1 , jak3 acts selectively on receptors containing the common  chain , which include il-2 , il-4 , il-7 , il-9 , il-15 , and il-21 , which are crucial to lymphocyte function . tyk2 is associated with ifn , il-12 , and il-23 receptors in conjunction with jak2 [ 19 , 23 , 24 ] . jak dysfunction has been associated with myeloproliferative diseases such as polycythemia vera , essential thrombocytopenia , and myelofibrosis as well as inherited immunodeficiencies including severe combined immunodeficiency and hyperimmunoglobulin e syndrome . dysregulation of jak signaling has also been identified in multiple autoimmune disorders . due to their ability to selectively modulate immune function , targeted jak inhibitors are attractive candidates for immune - mediated diseases . tofacitinib , a jak1 and jak3 inhibitor , and ruxolitinib , a jak1 and jak2 inhibitor , are the most extensively studied jak inhibitors in psoriasis . blocking these upstream components of the proinflammatory signaling pathways results in alterations in the immune response and suppresses the abnormal activation of the inflammatory cascade in diseases such as psoriasis ( figure 1 ) . in murine models , tofacitinib suppressed the expression of il-23 receptors , il-17a , il-17f , and il-22 when t cells were stimulated with proinflammatory cytokines such as il-6 and il-23 . inhibition of il-23 receptor expression results in suppression of th17 cell differentiation , which is a key driving factor in the pathogenesis of psoriasis . additionally , tofacitinib 's inhibition of il-15 may play an important role in treating psoriasis as il-15 is highly expressed with enhanced binding activity in psoriatic lesions and associated with increased resistance to keratinocyte apoptosis . ruxolitinib acts by inhibiting jak1 and jak2 pathways through blocking stat3 phosphorylation due to il-6 , il-12 , or il-23 , resulting in the suppression of pathogenic th17 cells differentiation [ 2931 ] . this leads to a dose - dependent decrease in production of il-17 , il-20 , and il-22 . additionally , the suppression of stat3 phosphorylation reduces ifn- expression , which is one of the most potent activators of keratinocyte proinflammatory function . in a study by fridman et al . , topical application of ruxolitinib in murine models reduced lymphocytic infiltration , inhibited acanthosis , and suppressed production of il-22 induced by intradermal il-23 . jak inhibitors act on multiple cell lines that contribute to the clinical manifestations of psoriasis [ 14 , 32 ] . tofacitinib , a jak1 and jak3 inhibitor , has undergone the most extensive clinical studies of jak inhibitors in psoriasis treatment [ 3337 ] . in a phase 30  mg b.i.d . , 50  mg b.i.d . , and 60  mg once daily ( q.d . ) was administered to 59 patients with mild - to - moderate psoriasis . on day 14 had dose - dependent improvement in the least squares mean ( lsm ) of percentage change in the psoriatic lesion severity sum ( plss ) score compared to the placebo group ( p < 0.01 ) . three of the eight patients receiving tofacitinib 50  mg had plss scores of 0 by day 14 from baseline scores of 46 . on day 14 , the physician 's global assessment ( pga ) score improvement , defined as  almost clear  or clear  and a 2-point pga score improvement , in patients receiving 50  mg b.i.d . of the skin biopsy samples obtained , marked histological improvements were noted in patients receiving a dosage of 30  mg b.i.d . when compared to their baseline , while lesional biopsies from the placebo group showed minimal or no change compared to baseline . of the 16 adverse events in 10 patients within this study , headaches ( n = 5 ) and nausea ( n = 3 ) were most common , and all suspected treatment - related adverse effects were considered mild . of the laboratory studies conducted , boy et al . reported elevated total cholesterol , low - density lipoprotein cholesterol , and triglyceride in the treatment groups when compared to the placebo group . in a 12-week phase iib study , papp et al . described the efficacy and safety of oral tofacitinib 2  mg b.i.d . , 5  mg b.i.d . , or 15  mg b.i.d . in 197 moderate - to - severe psoriasis patients . papp et al . reported psoriasis area and severity index ( pasi ) 75 response rates of 25.0% ( 2  mg ; p < 0.001 ) , 40.8% ( 5  mg ; p < 0.0001 ) , and 66.7% ( 15  mg ; p < 0.0001 ) versus 2.0% in the placebo group at week 12 . more pasi 75 responders were observed in all treatment groups as early as week 4 and maintained through week 12 compared to placebo patients ( p < 0.05 to p < 0.001 ) . upper respiratory tract infections , nasopharyngitis , and headache were the most common adverse effects reported by the patient cohort . three patients experienced five serious adverse events including angina pectoris , pyelonephritis , urosepsis , and atrial fibrillation . discontinuation from the study was reported in 2.0% , 4.1% , and 6.1% of patients in the 2 , 5 , and 15  mg b.i.d . serum creatinine increased ( mean 0.04  mg  dl ) in the 15  mg b.i.d . one case of alanine aminotransferase elevated greater than 2.5 times the upper limit of normal was documented in the 15  mg b.i.d . tofacitinib treatment was associated with mild , dose - dependent decreases in hemoglobin of 0.15 , 0.20 , 0.14 , and 0.71  g  dl for placebo and tofacitinib 2 , 5 , and 15  mg b.i.d . groups , respectively , at week 12 [ 34 , 38 ] . additionally , mean absolute neutrophil counts decreased at higher doses of tofacitinib with a maximum mean decrease of 0.9  10  mm in patients receiving 15  mg b.i.d . at week 4 . however , these values began to return to baseline values from weeks 4 to 8 [ 34 , 38 ] . in this same study cohort , mamolo et al . described the patient - reported outcomes of these 197 patients with moderate - to - severe psoriasis through six patient questionnaires . at week 12 , the authors reported greater lsm changes from baseline for the dermatology life quality index , itch severity score , and short form-36 questionnaire mental component for all active drug arms versus placebo ( p < 0.05 ) . a total of 35.1% , 38.5% , and 74.4% of patients in the 2 , 5 , and 15  mg groups , respectively , reported  clear  or  almost clear  on the patient global assessment of psoriasis versus 2.9% for the placebo group ( p < 0.0001 for all doses ) . tofacitinib has also been utilized as a topical formulation . in a vehicle - controlled phase iia trial studying a topical tofacitinib ointment formulation , ports et al . reported the data on 71 mild - to - moderate psoriasis patients treated with tofacitinib 2% ointment 1 b.i.d . versus tofacitinib 2% ointment 2 b.i.d . for 2 weeks to a single , fixed 300  cm treatment area containing a target plaque . this study noted improvement in the target plaque severity score ( tpss ) at week 4 for ointment 1 ( lsm-54.4% ) versus vehicle 1 ( lsm-41.5% ; one sided 90% upper confidence limit < 0 ) but not for ointment 2 ( lsm-24.2% ) versus vehicle 2 ( lsm-17.2% ; one sided 90% upper confidence limit > 0 ) . systemic concentrations ( > 0.100  ng  ml ) were detected in 12 ( 60% ) of 20 patients receiving ointment 1 for at least one time point compared to 6 ( 26% ) of 23 patients receiving ointment 2 . however , these serologic levels were 40-fold lower than the systemic concentration achieved at the lowest oral dose tested ( 2  mg b.i.d . ) . a total of 25 out of 71 patients reported adverse effects ; all of them were categorized as mild or moderate . nasopharyngitis ( n = 4 ) and urinary tract infections ( n = 3 ) were the most common . clinical trials testing tofacitinib administered either orally or topically for psoriasis have shown statistically significant symptom improvement in patients with psoriasis when compared to their placebo counterparts . there are multiple phase iii trials ( nct01186744 , nct01276639 , nct01309737 , nct01163253 , and nct01815424 ) studying the efficacy and safety of tofacitinib in psoriasis patients . one phase iii trial ( nct01241591 ) has compared oral tofacitinib 5  mg or 10  mg b.i.d . versus etanercept 50  mg twice weekly for 12 weeks for patients with moderate - to - severe psoriasis , and the results are pending at the time of writing of this paper . two phase iia trials ( nct01246583 and nct00678561 ) and one phase iib trial ( nct01831466 ) of tofacitinib ointments are under way as well . additional phase iii studies ( nct01519089 , nct01976364 , and nct01877668 ) are examining the efficacy and safety of tofacitinib in patients with psa . one phase iii study ( nct01882439 ) has begun recruiting participants for tofacitinib in psa patients with inadequate response to at least one tnf inhibitor . ruxolitinib , a jak1 and jak2 inhibitor , has primarily been studied as a topical ointment for mild - to - moderate psoriasis , and it has been compared to other topical therapies , which include topical steroids and topical calcipotriene [ 19 , 40 ] . in a phase ii study , punwani et al . described the treatment of 28 patients with limited psoriasis ( < 20% body surface area ) who were divided into 5 treatment groups : ruxolitinib 0.5% cream q.d . versus vehicle ( group 1 ) , ruxolitinib 1.0% cream q.d . versus vehicle ( group 2 ) , ruxolitinib 1.5% cream b.i.d . versus vehicle ( group 3 ) , ruxolitinib 1.5% cream versus calcipotriene 0.005% cream b.i.d . ( group 4 ) , or ruxolitinib 1.5% cream versus betamethasone dipropionate 0.05% cream b.i.d . for 28 days ( group 5 ) . the lesions were evaluated by the total lesion score ( 012 ) , which was a composite of the target lesion scores for erythema , scaling , and thickness , each rated on a scale of 0 to 4 . on day 28 , the total lesion scores were relatively similar to the vehicles in patients receiving ruxolitinib 0.5% cream , whereas the total lesion scores decreased by 53% and 54% in patients receiving ruxolitinib 1.0% cream q.d . and ruxolitinib 1.5% cream b.i.d . , respectively , versus 32% and 32% in patients in their respective vehicle cohorts ( p = 0.033 and 0.056 , resp . ) . the authors also noted that the onset of effect and efficacy of ruxolitinib 1.5% cream b.i.d . mean plasma concentrations of ruxolitinib for the 0.5% , 1.0% , and 1.5% cream were 0.32  0.40 , 0.96  0.82 , and 2.10  1.78  nmol  l , all of which were well below the plasma concentration determined to be pharmacologically active , which suggests that the topical ruxolitinib preparations are unlikely to cause systemic adverse effects . adverse effects including stinging , itching , irritation , pain , dryness , exfoliation , and/or redness at the application site were all mild and reported in 6 ( 20% ) of ruxolitinib - treated lesions , 5 ( 28% ) of the vehicle - treated lesions , 2 ( 33% ) of the calcipotriene - treated lesions , and 2 ( 40% ) of the betamethasone - treated lesions . in a study referenced by ortiz - ibanez et al . , 200 mild - to - moderate psoriasis patients were divided into 3 treatment groups receiving topical ruxolitinib at doses of 0.5% , 1% , and 1.5% cream for 3 months in a phase iib vehicle - controlled trial ( primary publication of the study results are not yet in the literature ) . in the 1% cream cohort , local irritation was cited as the most frequent adverse effect , and respiratory infections were reported in 6.7% of the patients receiving ruxolitinib 1.0% cream versus 2% of patients in the placebo group . of the early clinical studies available , ruxolitinib may be a promising agent for topical treatment of psoriasis . there are two additional jak inhibitors undergoing investigation for the treatment of moderate - to - severe psoriasis . k , a selective jak3 inhibitor , has undergone a phase iia dose escalation study ( nct01096862 ) in a cohort of 124 patients with moderate - to - severe psoriasis ( see http://www.clinicaltrials.gov ) . incb-28050/ly3009104 , a jak1 and jak3 inhibitor , is being examined in a phase iib dose ranging study ( nct01490632 ) in 240 moderate - to - severe psoriasis patients ( see http://www.clinicaltrials.gov ) . additional jak inhibitors have been developed as potential therapies for psoriasis such as vx-509 and r-348 , but there are no documented clinical trials examining these agents in psoriasis patients . jak inhibitors in early phase trials produced significant clinical improvement in psoriasis when compared to placebo groups . these findings show that cytokine signaling through the jak pathway is an important driver in the pathogenesis of psoriasis . the jak pathway is involved in the intracellular signaling that affects various cytokines , which propagate a wide range of downstream effects . the jak inhibitors currently under investigation target one or more members of the jak family . their mechanism of action involves targeted inhibition of both upstream and downstream components of proinflammatory pathways in psoriasis , and these medications represent a promising class of agents for the treatment of psoriasis . tofacitinib and ruxolitinib are the two jak inhibitors that have been most studied in psoriasis . tofacitinib , studied as both an oral and topical administration , has undergone the most extensive clinical testing thus far with ongoing phase iii clinical trials likely completed at the time of publication of this manuscript . phase i and ii clinical trials on tofacitinib , a jak1 and jak3 inhibitor , reported dose - dependent improvement in patients with psoriasis when compared to the placebo groups [ 3336 ] . ruxolitinib , a jak1 and jak2 inhibitor , has exclusively been studied as a topical formulation for the treatment of mild - to - moderate psoriasis . the plasma concentrations of ruxolitinib in patients receiving topical medication were less than 1% of the concentrations required for systemic activity in healthy volunteers , suggesting that ruxolitinib locally inhibits the propagating factors of psoriasis rather than through systemic effects . considering the issues associated with targeted agents requiring invasive administration in psoriasis , the noninvasive administration route of jak inhibitors is a favorable attribute of these drugs . the data discussed herein suggest that jak inhibitors represent an important choice in the current armamentarium of psoriasis therapies . due to the wide array of downstream targets that jak inhibition affects , concerns have been raised that jak inhibitors may impair the body 's ability to fight infections as well as modify hematopoietic development and function . although the safety profiles of tofacitinib and ruxolitinib were acceptable in the early phase trials , there is still concern for unknown long - term side effects with these medications [ 3335 , 38 , 40 ] . of the studies investigating tofacitinib , upper respiratory tract infections , headaches , and mild nausea were cited as the most common adverse effects experienced by patients [ 33 , 34 ] . papp et al . noted that the rate and type of adverse effects between the treatment and placebo groups were relatively similar . the safety of tofacitinib has been more extensively studied in phase trials for ra patients , and the side effect profiles were similar to those reported in psoriasis patients . based on murine models , there has also been concern for possible reactivation of tuberculosis and other latent infections with the use of tofacitinib [ 39 , 41 ] . although no cases of tuberculosis were reported in psoriasis patients treated with tofacitinib , cases of tuberculosis have been reported in phase trials for ra patients . tofacitinib treatment was associated with dose - dependent decreases in mean neutrophil counts and hemoglobin . however , these changes did not require intervention and the blood counts normalized during the treatment period . increases in mean low - density lipoprotein cholesterol , high - density lipoprotein cholesterol , total cholesterol , triglycerides , and transaminase levels were also observed in selected patients treated with tofacitinib [ 33 , 34 ] . the manifestation of these serum changes is unclear , and further investigation is needed to determine whether any intervention is required . this was likely due to the minimal systemic absorption based on the mean serum drug levels . punwani et al . also noted that patients treated with ruxolitinib ointment had fewer adverse effects than patients treated with the vehicle , calcipotriene , or betamethasone applications , supporting the safety profile of ruxolitinib . although the safety profiles of both tofacitinib and ruxolitinib appear promising with short - term use , the results must be interpreted with caution as these findings can not confirm their safety with long - term use . findings from trials examining jak inhibitors in other immune - mediated diseases may guide our understanding of these agents in psoriasis patients . jak inhibitors have been studied extensively in other chronic inflammatory conditions such as ra and uc [ 4250 ] . tofacitinib has been the most extensively studied jak inhibitor in the realm of inflammatory diseases , specifically in ra . it is an efficacious treatment option either as monotherapy or in combination with methotrexate in patients with moderate - to - severe ra [ 4244 , 46 , 47 , 49 , 50 ] . of particular interest , tofacitinib achieved significant clinical response in patients who were refractory to treatments such as methotrexate monotherapy , disease - modifying antirheumatic drugs ( dmards ) , or tnf inhibitors in phase ii and phase iii clinical studies [ 42 , 43 , 46 , 47 , 50 ] . in a 12-month phase iii trial , van vollenhoven et al . reported the treatment of 717 ra patients on stable doses of methotrexate and receiving tofacitinib 5  mg b.i.d . the authors found that the clinical response rates were better than placebo ( 28.3% ) in patients receiving tofacitinib 5  mg ( 51.5% ) , 10  mg ( 52.6% ) , and adalimumab ( 47.2% ; p < 0.001 for all comparisons ) , indicating not only does tofacitinib produce clinically significant improvement in ra symptoms but also it achieves a numerically similar response rate as adalimumab [ 41 , 50 ] . tofacitinib is being studied in clinical trials for the treatment of psoriatic arthritis , ankylosing spondylitis , atopic dermatitis , and keratoconjunctivitis sicca . clinical experience with these therapeutic options in inflammatory diseases such as ra and uc has guided the way for their potential use as agents for psoriasis . jak inhibitors are new , promising therapies in psoriasis , and they have different safety profiles from the existing traditional oral systemic medications or biologic medications . of the jak inhibitors studied for psoriasis , tofacitinib has been most extensively studied , and phase iii study results ( nct01241591 ) comparing tofacitinib to etanercept are pending . ruxolitinib , asp015  k , and ly3009104 are among the other jak inhibitors being studied for clinical use . overall , jak inhibitors represent a new class of efficacious treatments to reduce disease severity and improve quality of life among psoriasis patients .