JAK inhibitors in dermatology: The promise of a new drug class.

New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

Janus kinase inhibitors in dermatology: A systematic review.

BACKGROUND: Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions. OBJECTIVE: Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases. METHODS: This is a systematic review of PubMed and ClinicalTrials.gov. RESULTS: One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events. Eighteen clinical trials were found. JAK inhibitors have been extensively studied for psoriasis, showing beneficial results that were comparable to the effects achieved by etanercept. Favorable results were also observed for alopecia areata. Promising preliminary results were reported for vitiligo, dermatitis, graft versus host disease, cutaneous T cell lymphoma, and lupus erythematosus. The most common adverse events reported were infections, mostly nasopharyngitis and upper respiratory tract infections. LIMITATIONS: It was not possible to perform a meta-analysis of the results. CONCLUSIONS: This systematic review shows that while JAK inhibitors hold promise for many skin disorders, there are still gaps regarding the correct dosing and safety profile of these medications for dermatologic indications. Additional trials are necessary to address these gaps.

Reversal of Alopecia Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules. METHODS: A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib. FINDINGS: The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment. INTERPRETATION: Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.

Langerhans cells that express matrix metalloproteinase 9 increase in human dermis during sensitization to diphenylcyclopropenone in patients with alopecia areata.

BACKGROUND: We know little of the initial events during the sensitization phase of contact allergy in humans. Alopecia areata (AA), a disease of unknown pathogenesis characterized by patchy hair loss, may be treated by inducing contact allergy to diphenylcyclopropenone (DPC), later followed by its topical application. OBJECTIVES: To learn more about the initial events during sensitization in human skin, we studied the early events during induction of contact allergy to DPC in patients with AA. METHODS: DPC 2% and sodium lauryl sulphate (SLS) 4% were applied on the backs of eight patients with AA. Punch biopsies were taken 6 and 24 h after application. The biopsies were snap-frozen and cryostat sections were evaluated with immunohistochemistry using antibodies against CD1a, HLA-DR, CD3, CD54 and matrix metalloproteinase 9 (MMP-9). RESULTS: After 24 h all subjects exhibited erythema on the DPC-treated areas. Histological evaluation of biopsies from these areas showed hydropic degeneration and a significantly increased number of MMP-9+ cells in the dermis (P < 0.0005). The MMP-9+ cells were identified with double immunofluorescence staining as CD1a + Langerhans cells. The expression of the other markers studied remained unaltered irrespective of treatment, including treatment with SLS. CONCLUSIONS: Our findings show that DPC induces an irritant reaction leading to an increased number of MMP-9+ CD1a+ cells in the dermis during the initial phase of sensitization.

Expression of neuropeptide-degrading enzymes in alopecia areata: an immunohistochemical study.

BACKGROUND: Much clinical evidence suggests that the nervous system, including psychological factors, can influence the course of alopecia areata (AA). However, there has been little substantial evidence of specific participation of cutaneous neurogenic factors in the disease process. OBJECTIVES: As previous studies have demonstrated that stress elicits the release of the neuropeptide substance P (SP) from peripheral nerves and that some patients with AA show prominent SP expression in nerves surrounding their hair follicles, we aimed to evaluate the role of SP in AA. METHODS: We used immunohistochemistry to examine the expression of SP and SP-degrading enzymes in scalp biopsies from patients with AA and from healthy controls. RESULTS: Affected hair follicles in the centre of the areas of hair loss of patients with AA were richly innervated by SP-staining nerve fibres. Strong expression of the SP-degrading enzyme, neutral endopeptidase (NEP), was observed in hair follicles not only in the acute progressive phase of AA but also in the chronic stable phase. Expression of NEP in hair follicles from the margins of areas of hair loss was stronger than in normal controls, but was weaker than in the centre of the areas of hair loss. In addition, endothelial immunoreactivity for angiotensin-converting enzyme (also capable of degrading SP) was not observed in the centre of the areas of hair loss, which was in significant contrast to normal controls as well as to the margins of areas of hair loss where it was expressed. Further, intense expression of endothelial leucocyte adhesion molecule-1 on vessels and many degranulating mast cells was observed adjacent to affected hair follicles in AA, in admixture with dense lymphocytic inflammation. CONCLUSIONS: These findings suggest that SP is endogenously released by dermal nerve fibres around hair follicles and that it may play an important part in epithelial-mesenchymal-neuroectodermal interactions in AA. This study reveals that SP and its degrading enzymes are involved in the pathogenesis of AA, which in turn might explain the pathological significance of neurogenic and psychogenic aspects in the disease process.

Identification of tyrosine hydroxylase as an autoantigen in autoimmune polyendocrine syndrome type I.

Patients with the autosomal recessively inherited autoimmune polyendocrine syndrome type I (APS I) have autoantibodies directed against several endocrine and nonendocrine organs. In this study a new autoantigen related to this syndrome, tyrosine hydroxylase, was identified in sera from patients with alopecia areata through immunoscreening of a scalp cDNA library. Immunoreactivity against in vitro expressed tyrosine hydroxylase was found in 41 (44%) of the 94 APS I patients studied and this reactivity correlated with the presence of alopecia areata (P = 0.02). These findings further stress the importance of enzymes involved in neurotransmitter biosynthesis as important immune targets in APS I.

Immunohistochemical and electron microscopic characterization of the cellular infiltrate in alopecia (areata, totalis, and universalis).

The inflammatory cell infiltrates in scalp skin of 35 patients, 20 with alopecia areata (AA), 7 with totalis, and 8 with universalis were characterized with the ANAE (alpha-naphthylacetate esterase) marker, monoclonal antibodies, and electron microscopy. As demonstrated by the ANAE staining, no clear difference in the main lymphocyte subclasses (T and B cells) or macrophages was seen between the different types of alopecia or as compared to control patients' scalp skin. However, T lymphocytes and macrophages were seen most frequently and in greater numbers perivascularly and infiltrating the hair bulb in those cases of AA where active hair loss took place. Using monoclonal OKT (OKT-3, -4, and -8) antibodies and the avidin-biotin immunoperoxidase method on frozen sections, a concentration of OKT-8 reactive cells (suppressor/cytotoxic T cells) was seen peribulbarly and invading the hair infundibulum. The cells affecting the hair infundibulum were further studied by electron microscopy. They could be classified into three main types: small lymphocytes (60%), macrophages (30%) and cells closely resembling large granular lymphocytes (LGL) (10%). LGL have previously been considered to be human natural killer (HNK) cells. Thus the hair follicle seems to be the target for the cellular immune response in alopecia. Whether HNK cells participate in the destruction of hair bulbs remains to be investigated.