¹Division of Dermatology, University of Calgary, Calgary, AB, Canada
²Queen’s University School of Medicine, Queen’s University, Kingston, ON, Canada

Conflict of interest:
The authors have no conflicts to disclose.

Abstract
The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vitiligo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.

Key Words:
Janus kinase inhibitors, JAK inhibitors, JAK-STAT pathway, tofacitinib, ruxolitinib, alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host disease, psoriasis, vitiligo

The JAK-STAT Pathway

The development and function of various human cells are controlled by a group of secreted factors known as cytokines. One large subgroup of cytokines, which play a critical role in the signaling systems that underlie normal cell growth and immunoregulation, bind to type 1 or 2 cytokine receptors. The cytokines in this group use the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway as a mode of signal transduction.¹

When a cytokine binds to a type 1 or 2 receptor on the cell membrane, the receptor dimerizes, allowing the associated cytoplasmic JAK protein to autophosphorylate and phosphorylate the receptor chains.^2,3 This process induces recruitment of signaling intermediaries including STAT proteins that transduce the signal from the cytokine receptor to the nucleus, leading to DNA transcription and regulation of gene expression.¹

There are four different members of the JAK family – JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Mutations and polymorphisms within this JAK-STAT pathway have been implicated in both autoimmune and malignant processes. For example, mutations of JAK3 and TYK2 are known causes of immunodeficiency, whereas polymorphisms of JAK2 and STAT3 contribute to a range of autoimmune diseases, including inflammatory bowel disease, psoriasis, ankylosing spondylitis and Behcet’s disease.¹ Acquired mutations in JAK2 have been noted in more than half of patients with myeloproliferative neoplasms, including polycythemia rubra vera, essential thrombocythemia, and primary myelofibrosis.⁴

JAK inhibitors, or jakinibs, inhibit the kinase component of JAKs, thereby preventing them from phosphorylating and stopping the transduction of intracellular signaling. First generation jakinibs, which include the drugs tofacitinib and ruxolitinib, inhibit multiple JAKs. Tofacitinib, which is approved as monotherapy or in combination with methotrexate for the treatment of rheumatoid arthritis, inhibits JAK1 and JAK3, and to a lesser extent the other JAK isoforms. Ruxolitinib, which is approved for use in myelofibrosis and polycythemia rubra vera, inhibits JAK1 and JAK2.⁵ Second generation jakinibs are still under investigation and more selectively target only one JAK isoform, thereby inhibiting a narrower range of cytokines.⁶ (Table 1)

Adverse Events

The most extensive safety data for JAK inhibitors has come from studies looking at their use in rheumatoid arthritis and myelofibrosis patients. The most common adverse events (AEs) reported in patients treated with tofacitinib are infections (>50%) and gastrointestinal symptoms (>20%), with nasopharyngitis, upper respiratory tract infections, urinary tract infections, and diarrhea being the most common in these categories.^7,8 Serious infections have been reported (incidence ratio [IR] = patients with events/100 patient years: 2.7), with the most common being herpes zoster, pneumonia, urinary tract infections, and cellulitis. These rates are similar to those observed with other targeted immunotherapies. Rare but serious AEs include disseminated herpes zoster (IR 0.3), opportunistic infections (IR 0.3), tuberculosis (IR 0.2), and gastrointestinal perforation (IR 0.1).⁹ A systematic review of patients treated with tofacitinib compared to placebo found that they are significantly more likely to develop laboratory abnormalities including neutropenia, dyslipidemia, elevated creatinine and liver enzyme abnormalities. However, these changes were found to improve over time or return to baseline spontaneously or with discontinuation of the drug.¹⁰

The most common AEs reported in patients with myelofibrosis treated with ruxolitinib include anemia (>98%) and thrombocytopenia (>83%). This is not surprising given ruxolitinib’s inhibition of JAK2, which is essential in mediating signals from erythropoietin and thrombopoietin. Other commonly reported AEs include fatigue, diarrhea, ecchymosis, dizziness, headache, and urinary tract infections.^{11, 12}

Both tofacitinib and ruxolitinib cause immunosuppression, leading to a theoretical increased risk of malignancy. An analysis of malignancies occurring in patients treated with tofacitinib found that standardized incidence ratios (SIR) were within the range expected for patients with moderate to severe rheumatoid arthritis, and that the SIR remained stable over time with increasing tofacitinib exposure.¹³ Overall, the risk of malignancy associated with JAK inhibitors is unclear, and more long-term studies are required.

Clinical Uses in Dermatology

Psoriasis and Psoriatic Arthritis

Many of the cytokines involved in the pathogenesis of psoriasis operate through the JAK-STAT signaling pathway. Most studies in psoriasis have involved tofacitinib, which inhibits the expression of interleukin (IL)-23 and differentiation of T helper type 1 (Th1) cells. IL-23 is a key cytokine that controls Th17 cells, therefore tofacitinib’s downstream effects include reducing Th17 cell differentiation and its production of IL-17.14 Several phase III randomized controlled trials (RCTs) have shown that significantly more patients achieve a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) while on tofacitinib compared with placebo. These patients also demonstrated a dose-dependent improvement of PASI 75 on tofacitinib 10 mg twice daily as compared with 5 mg twice daily.^15,16 A phase III non-inferiority trial revealed that tofacitinib 10 mg twice daily was non-inferior to etanercept 50 mg twice weekly.¹⁷ More recently, a post hoc analysis of the patients included in the above RCTs demonstrated significant improvements in Nail Psoriasis Severity Index (NAPSI) scores on tofacitinib 10 mg twice daily.¹⁸

Two newer JAK inhibitors, baricitinib and solcitinib, have shown promise in psoriasis. A study of baricitinib demonstrated significantly more patients achieved PASI 75 as compared with placebo.¹⁹ A multi-center study found solcitinib 400 mg twice daily to have similar efficacy to both tofacitinib and baricitinib, with 57% of patients achieving PASI 75.²⁰ However, further developments in solcitinib have been discontinued.⁶

Topical JAK inhibitors for mild-moderate psoriasis have also been investigated. Tofacitinib showed variable results in a phase IIa trial. Differences in efficacy were speculated to be due to variability in moisturizing properties of the formulations tested.²¹ Ruxolitinib (INCB018424) was studied in a non-blinded and nonvehicle- controlled trial and was found to reduce the mean area and severity of psoriatic lesions.²²

In December 2017, tofacitinib was approved by the US FDA for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs.²³ This was based on the results of two phase III trials, which showed that patients on tofacitinib 5 mg and 10 mg twice daily demonstrated statistically significant improvements in American College of Rheumatology 20 (ACR20) response and change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at 3 months, as compared to placebo.^24,25

Atopic Dermatitis

The pathogenesis of atopic dermatitis is multifactorial, but IL-4 is known to play a pivotal role, signaling through the JAK-STAT pathway via JAK1 and JAK2 to increase the immunity of T helper type 2 cells and enabling further release of various implicated cytokines.²⁶ One small study of tofacitinib in six patients with moderate to severe atopic dermatitis who had failed standard therapy showed promising results. The average Severity Scoring of Atopic Dermatitis (SCORAD) index decreased by 54.8% at 14 weeks of treatment with tofacitinib 5 mg once or twice daily. A significant reduction in pruritus and sleep loss scores was also noted.²⁷ A phase IIa, randomized, double-blind, vehicle-controlled study has been completed using 2% tofacitinib ointment in 69 adult patients with mild to moderate atopic dermatitis. Although the change from baseline in the Eczema Area and Severity Index (EASI) was significantly greater for tofacitinib versus the vehicle after 4 weeks of treatment, further development of this preparation for atopic dermatitis has been discontinued.²⁸

Two new oral agents have recently shown promise in phase II studies. In results presented at the 2017 European Academy of Dermatology and Venereology Congress, PF-04965842 and baricitinib were found to improve clinical and patient-reported outcomes in atopic dermatitis as compared to placebo.^29,30

Alopecia Areata

Alopecia areata (AA) is a T cell-mediated autoimmune disease resulting in premature follicular senescence. Interferon-γ (IFN-γ) has been determined to be crucial in the pathogenesis of activating autoreactive T cells, and global transcriptional profiling in AA has identified up-regulation of many interferon-regulated genes and cytokines such as IL-2 and IL-15. Importantly, both IFN-γ and IL-15 signal through JAK1 and JAK3. IL-15 signaling also involves STAT5.³¹ Systemic ruxolitinib and tofacitinib were shown in a mouse model to stop the IFN-γ gene expression response and subsequent development of AA. Both systemic and topical administration of these drugs have led to reversal of established disease in mice with widespread AA.³²

Human studies also demonstrate benefit of jakinibs in AA. A case report published in 2014 featured a patient with concomitant psoriasis and alopecia universalis who experienced complete hair regrowth while on tofacitinib for psoriasis.³³ Several other case reports and studies have since been published demonstrating successful treatment of AA, including the associated nail changes.^34-36 A retrospective study found that 58% of patients deemed to be potential responders to therapy (meaning those with alopecia totalis or alopecia universalis with duration of disease of 10 years or less, or AA) had greater than 50% change in their Severity of Alopecia Tool (SALT) score while on tofacitinib.³⁷ An open-label trial demonstrated tofacitinib 5 mg twice daily to be efficacious, with 32% of patients reaching 50% or greater improvement in their SALT score. However, with drug discontinuation, relapse occurred within 8.5 weeks.³⁸ A small series of adolescent patients demonstrated hair regrowth in approximately 70% of patients.³⁹

Jakinibs, other than tofacitinib, are also efficacious in AA. A case report from 2015 described a male patient with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome with concomitant AA. He was enrolled in a trial of baricitinib and experienced complete hair regrowth.40 Ruxolitinib demonstrated sustained, nearcomplete regrowth when used in two patients with AA, and a small open-label trial of 12 patients demonstrated that 75% achieved 92% hair regrowth by the end of treatment. As reported with tofacitinib, however, relapse of hair loss occurred after drug discontinuation.^41,42

Vitiligo

The pathogenesis of vitiligo remains unclear, although most evidence implicates T-lymphocytes in the destruction of melanocytes. As with AA, IFN-γ likely plays a key role. A case report of a patient with generalized vitiligo treated with tofacitinib 5 mg once daily showed near complete repigmentation after 5 months of treatment.⁴³ An additional case report of a patient with concurrent vitiligo and AA who was treated with ruxolitinib 20 mg twice daily demonstrated both hair regrowth and regained pigment. However, the majority of the pigment that returned during treatment was not sustained after treatment was discontinued.⁴⁴ More recently, a small open-label trial of topical ruxolitinib 1.5% cream showed significant repigmentation for facial vitiligo, with 76% improvement in Vitiligo Area Scoring Index (VASI) scoring for four patients with facial vitiligo.⁴⁵

Dermatomyositis

Several case reports have suggested efficacy of jakinibs in refractory dermatomyositis. The first report was of a patient with refractory dermatomyositis on ruxolitinib for concurrent myelofibrosis whose dermatomyositis improved significantly while on ruxolinitib.⁴⁶ It was unclear, however, if improvement in the dermatomyositis was a direct effect of the JAK inhibitor or an indirect effect through treatment of the malignancy.⁴⁷ Since then, a case series of three patients treated with tofacitinib found that they had significant improvement in their Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.⁴⁸ An additional case report described a patient with dermatomyositis treated with tofacitinib and experienced improvement of her cutaneous disease, muscle strength, and arthritis.⁴⁹

A retrospective, multi-center survey was conducted in Europe and the US with 95 patients who had been given ruxolitinib as salvage therapy for corticosteroid-refractory graft-versus-host disease (GVHD). In patients with both acute and chronic corticosteroidrefractory GVHD, a cohort known to have poor outcomes, response rates were greater than 80% on ruxolitinib.⁵⁰ Another retrospective study in patients with severe sclerodermatous chronic GVHD demonstrated partial improvement of skin softness in the majority of cases. However, fewer patients demonstrated a complete response and the response rate overall was lower than the study mentioned previously.⁵¹ A retrospective study involving pediatric patients with steroid-refractory acute GVHD showed an overall response rate of 45% to ruxolitinib.⁵²

Future Directions

Several other case reports and preclinical evidence suggest that JAK inhibitors may be useful in the treatment of other inflammatory, autoimmune, and malignant skin conditions. These include cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.^53-59

Conclusion

JAK inhibitors show promise in the treatment of a wide variety of dermatologic disorders. Compared with other targeted immunosuppressants, jakinibs have similar safety profiles including the rate of serious infection. Longer term studies are needed to assess malignancy risk. Given the interest in this class of drugs and the numerous trials underway, JAK inhibitors have the potential to become widely used in dermatology.

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¹College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
²Section of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT
Chronic urticaria is defined as hives, typically occurring daily, for greater than 6 weeks duration. Chronic idiopathic urticaria, which has no discernable external cause, comprises the majority of cases of chronic urticaria. Over half of all cases of chronic idiopathic urticaria are thought to occur by an autoimmune mechanism, primarily autoantibodies against the high affinity immunoglobulin E (IgE) receptor (FcεRI). Chronic urticaria is hypothesized to occur because of a predilection in the patient to develop reactions to self. Supporting this hypothesis, a strong association has been found between chronic urticaria and additional autoimmune diseases, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, celiac disease and type 1 diabetes, among others. Herein, we review the associations between chronic urticaria, thyroid disease, and other autoimmune disorders, as well as the implications that these correlations hold for therapeutic intervention in chronic urticaria.

Key Words:
angioedema, antibodies, autoimmune disease, chronic disease, comorbidities, complications, hives, hypersensitivity, inflammation, thyroid disease, urticaria

Introduction

It is estimated that urticaria will affect 25% of the population at some point in their lifetime.¹ Chronic urticaria (CU) involves hives, typically occurring daily, for greater than 6 weeks duration. CU generally lasts 1 to 5 years, but can have a prolonged course beyond 5 years in roughly 14% of patients.² Individuals affected by CU have reported emotional distress, feelings of isolation and fatigue in response to their condition, similar to findings in patients with ischemic heart disease.³ This underscores the importance of managing CU appropriately to minimize both physical and psychological impacts of this disease.

CU can occur in response to drugs, physical stimuli, as part of inflammatory or inherited diseases, or can be idiopathic in nature. Acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drug (NSAID) intolerant CU is hypothesized to occur due to inhibition of the cyclooxygenase pathway, which causes enhanced production of leukotrienes.⁴ The physical urticarias (classically divided into heat, cold, solar, vibration, delayed-pressure, dermatographism, aquagenic and cholinergic induced urticaria) occur in response to external stimuli.⁵ Urticarial vasculitis involves the appearance of urticarial lesions lasting greater than 24 hours in the hisopathological setting of vasculitis.⁶ Inherited syndromes with CU include the spectrum of cryopyrinopathies, such as Familial Cold Autoinflammatory syndrome, Muckle- Wells syndrome, and Neonatal-Onset Multisystem Inflammatory Disease/Chronic Infantile Neurologic Cutaneous Articular syndrome (NOMID/CINCA).⁷ Urticaria presents as a feature of many inflammatory disorders, such Schnitzler syndrome,⁸ Still’s disease,⁹ and Gleich’s syndrome¹⁰. Chronic idiopathic urticaria, unlike the physical urticarias and ASA or NSAID intolerant variants, has no discernable external cause.¹¹

Chronic idiopathic urticaria is the most common type of CU, comprising up to 90% of all cases of CU.¹ It has been estimated that chronic idiopathic urticaria will affect between 0.6%¹² to 5%¹³ of the population during their lifetime. Over half of all cases of chronic idiopathic urticaria are thought to be caused by an autoimmune mechanism.¹⁴ This is supported by the observation that 60% of patients with chronic idiopathic urticaria will have a wheal and flare reaction to intradermal autologous serum injections in the autologous serum skin test (ASST).¹⁵ Approximately 50% of patients with chronic idiopathic urticaria have IgG antibodies that are specific for the high affinity IgE receptor (FcεRI).^14,16 These autoantibodies activate mast cells in the skin, circulating basophils, and the complement system.¹⁴ Additional immunological abnormalities described to play a causative role in CU include IgG antibodies directed against IgE antibodies and the low affinity IgE receptor (FcεRII),¹⁷ antiendothelial antibodies,¹⁸ and complement C8 alpha-gamma (C8α-γ) deficiency¹⁹.

In patients with chronic idiopathic urticaria, approximately 35% will experience episodes of angioedema and 25% are positive for dermatographism.²⁰ Like many autoimmune diseases, chronic idiopathic urticaria has a higher incidence in women than men, with the reported ratio of females to males ranging from 2:1^21,22 to 4:1²³. Numerous autoimmune conditions have been associated with chronic idiopathic urticaria, including thyroid disease, celiac disease, and rheumatoid arthritis (RA).

The purpose of this review is to discuss the association of CU with thyroid disease and other autoimmune diseases, as well as the implications that these associations hold for therapeutic intervention in CU.

Thyroid Disease and Chronic Urticaria

Thyroid disease is the most commonly reported autoimmune condition in patients with CU. In the literature, the frequency of thyroid autoimmunity in patients with CU encompasses a vast range of values, varying from 6.5%²⁴ to 57%²⁵. Patients with coexistent thyroid autoimmunity and CU have a more severe and prolonged course of urticaria than those without thyroid autoimmunity.²⁶

In patients affected by both CU and thyroid autoimmunity, there is an increased risk of developing angioedema. Leznoff and Sussman reported that the triad of thyroid autoimmunity, CU, and angioedema occurred in 15% of patients with CU.²⁷ The risk of developing angioedema in patients with thyroid autoimmunity and CU is estimated to be 16.2 times greater than those with CU without thyroid autoimmunity.²⁸

In a recent large study of 12,778 CU patients by Cofino-Cohen et al., it was found that 9.8% of patients had hypothyroidism, compared with 0.6% in the control group.²¹ Hypothyroidism was the most commonly detected thyroid disease in patients with CU. Females were more likely to be affected by the combination of hypothyroidism and CU than their male counterparts. Patients with hyperthyroidism and CU comprised 2.7% of the study population, compared to 0.09% in the control group. In most patients, the thyroid disease was identified in the 10 years following the diagnosis of CU. This implies that thyroid autoimmunity developed subsequent to the initial presentation of CU. In the same study, anti-thyroid antibodies were significantly more common in CU patients than controls. Of the patients with CU who were clinically euthyroid, anti-thyroperoxidase antibodies were found in approximately 2.7% and antithyroglobulin antibodies were found in 0.6%. Aamir et al. also noted the association between anti-thyroid antibodies and CU, as anti-thyroglobulin and anti-microsomal antibody levels were significantly increased in patients with CU and hypothyroidism.²⁵

The development of thyroid disease is often considered to be a marker of autoimmunity. Thyroid disease has been connected to a variety of autoimmune diseases, including pernicious anemia, celiac disease, type 1 diabetes and systemic lupus erythematosus (SLE), in addition to CU.²⁹ Although a specific mechanism linking the development of thyroid disease and CU has yet to be firmly elucidated, it is widely thought that both diseases occur because of a propensity within the patient to develop reactions to self. It has been hypothesized that thyroid disease may worsen urticaria and angioedema through activation of the complement system. Blanchin et al. demonstrated the thyroperoxidase enzyme contains a domain that binds to complement protein C4, cleaving it to C4a and activating the classical pathway of the complement cascade.³⁰ Kirpatrick noted that C4a levels decrease when thyroid disease is treated, resulting in remission of CU.³¹ Therefore, while it is hypothesized that thyroid disease and CU may coexist due to a patient’s predilection for autoimmunity, thyroid disease may additionally exacerbate urticaria and angioedema through direct mechanisms that result in complement activation.

Other Autoimmune Diseases and Chronic Urticaria

Beyond thyroid disease, a variety of additional autoimmune diseases have been examined for associations with CU. Confino- Cohen et al. found that 12.5% of patients had one additional autoimmune disease, 2.1% had two diseases, 0.1% had three diseases, and single patients each had an additional four or five diseases. Of patients with CU and hypothyroidism, RA was the most frequently identified additional autoimmune disease. The odds of having RA were 13.25 times higher in those with CU than in the control group.²¹ The major laboratory marker of RA, rheumatoid factor, was reported by Ryhal et al. to be significantly increased in patients with CU.³²

The risk of developing type 1 diabetes is increased in CU patients of both genders. In women with CU, the development of Sjögren’s syndrome, celiac disease, or SLE was significantly higher than controls. Most patients received their diagnosis of an additional autoimmune disease in the 10 years following the CU diagnosis,²¹ which emphasizes that these diseases developed subsequently and were not incidentally picked up at the time of CU diagnosis. The association of celiac disease and CU has previously been highlighted in the pediatric population.^33,34 Raynaud’s phenomenon with positive anti-centromere antibodies was described with CU by Asero et al.³⁵ Additional autoimmune diseases such as vitiligo and pernicious anemia have also been associated with CU.³⁶

CU has been shown to have a genetic association to the human leukocyte antigen (HLA)-DR4 and HLA-DQ8 alleles.³⁷ Interestingly, HLA-DR4 is strongly associated with RA,³⁸ and HLADQ8holds associations with celiac disease³⁹ and type 1 diabetes⁴⁰. Complement deficiencies have been associated with autoimmune diseases, such as Sjögren’s syndrome,⁴¹ RA,⁴² and SLE,⁴³ and Park et al. have reported the development of CU, anti-nuclear antibodies and spondyloarthropathy in a 9 year old boy with C8α-γ deficiency¹⁹. CU was described in a 10 year old boy with a strong autoimmune phenotype.⁴⁴ The full inventory of diseases experienced by this patient included alopecia totalis, vitiligo, psoriasis, Graves’ disease, CU, an autoimmune form of Lambert- Eaton myasthenic syndrome, and IgA deficiency. This patient had HLA genes that are found within the extended haplotype 8.1 AH (ancestral haplotype), which has been associated with the development of many autoimmune conditions.⁴⁵ These cases highlight that CU may occur as part of a larger constellation of autoimmune diseases in affected patients.

Therapeutic Interventions

Guidelines for the treatment of CU have been established using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system.^46,47 Second generation nonsedating H1 antihistamines are the first-line treatment for patients with CU.^48,49 If the patient fails first-line therapy after 2 weeks, secondline therapy involves increasing the dose of antihistamines used, up to four times the standard dose.⁵⁰ Patients should be advised that symptoms of sedation and drug interactions may occur with the increased dose of antihistamines. Cetirizine, desloratadine, fexofenadine, and bilastine (the latter is not licensed for use in Canada) were determined to be the safest antihistamines to up dose.⁵¹ In an estimated 50% of patients, symptoms persist following the use of antihistamines alone.^52,53 Third-line treatment involves changing the antihistamine used or adding a leukotriene antagonist. Leukotriene antagonists have been shown to improve patients with ASA or NSAID intolerant CU, ASST positive CU, and food-additive hypersensitivity induced CU, but not chronic idiopathic urticaria.⁵⁴ A short 3 to 7 day course of systemic steroids may be used in conjunction with the thirdline treatment options.⁵⁵ If third-line therapy fails, fourth-line therapeutic options include adding cyclosporine A, H2 blockers, dapsone or omalizumab.⁵⁶

The most effective fourth-line treatment in CU is thought to be omalizumab,⁵⁶ a humanized monoclonal antibody against IgE, approved for treatment of severe asthma. Maurer et al. published a randomized, double-blind study assessing the efficacy of omalizumab in patients with CU that had failed first-line treatment and found it significantly reduced CU symptoms.⁵⁷ Omalizumab reduces free IgE and the levels of the high affinity IgE receptor present on mast cells and basophils,⁵⁸ thereby resulting in decreased activation of mast cells and basophils, the cells hypothesized to be responsible for the development of hives in CU.

Additional treatment options reported in the literature for patients that fail fourth-line treatment include mycophenolate mofetil,⁵⁹ hydroxychloroquine,⁶⁰ methotrexate,⁶¹ tacrolimus,⁶² sulfasalazine⁶³ and intravenous immunoglobulin (IVIG)⁶⁴.

Treatment of concomitant thyroid disease was reported to induce remission of CU.⁶⁵ Kirkpatrick performed a study on CU patients with evidence of clinical or serological thyroid autoimmunity.⁶⁶ These patients had previously failed firstline treatment with antihistamines. It was demonstrated that in patients with thyroid autoimmunity and CU levothyroxine induced remission of angioedema and urticaria in all six subjects. Rumbryt reported that seven out of ten euthyroid patients with anti-thyroid antibodies experienced clinical remission of CU following treatment with thyroxine, but relapsed once therapy was stopped.⁶⁷ These studies suggest that in patients with CU the clinical identification and management of thyroid autoimmunity with levothyroxine may play a role in inducing remission of CU. However, Magen et al. recently reviewed patients with CU and thyroid disease treated with levothyroxine and compared them to untreated euthyroid controls.⁶⁸ The patients treated with levothyroxine experienced a clinical improvement in urticaria; however, the same improvement in symptoms was also noted in the euthyroid controls. This led to the conclusion that improvement of clinical symptoms in CU occurred spontaneously, independent of thyroid treatment. The conflicting literature regarding the impact of treatment of thyroid autoimmunity on the clinical course of CU indicates the need for larger studies to establish the role of levothyroxine in patients with CU.

NSAID use has been shown to aggravate CU symptoms in approximately 20% of patients with a prior CU diagnosis.⁶⁹ NSAIDs are commonly used to manage the pain and inflammation associated with RA, inflammatory spondyloarthropathies, and lupus arthritis. Autoimmune inflammatory arthropathies, especially RA, have been shown to occur more frequently in patients with CU than the general population.²¹ Therefore, exacerbation of symptoms due to NSAID use should be monitored in patients with CU and autoimmune inflammatory arthropathies. Zembowicz et al. demonstrated that selective COX-2 inhibitors do not induce urticaria in patients with CU that is aggravated by NSAIDs.⁷⁰ This suggests that selective COX-2 inhibitors may be preferred over general NSAIDs to prevent exacerbation of CU symptoms.

Helicobacter pylori (H. pylori) infection has been previously hypothesized to be an etiological factor in CU. This was based on reports demonstrating a high prevalence of H. pylori infection amongst CU patients,⁷¹ and improvement of clinical symptoms following H. pylori eradication^72,73. However, this hypothesis was brought into question by the fact that other authors have found no difference in the prevalence of H. pylori between those with CU and controls,⁷⁴ and no difference in autoantibody production,²⁴ as well as the additional finding that H. pylori eradication did not affect clinical outcomes⁷⁵. This divergence in the literature has been speculated to occur because of different detection methods, resistance to therapy, and the possibility of recurrences of H. pylori shortly after therapy.⁷⁶ To further complicate the issue, recent evidence suggests that H. pylori eradication may trigger CU.⁷⁷ Shakouri et al. completed a review of the literature regarding H. pylori eradication and CU using the GRADE system, and concluded that the evidence for treatment was weak and larger studies are needed to establish if H. pylori eradication is beneficial to CU patients.⁷⁸

Conclusion

CU is defined as hives lasting longer than 6 weeks. Currently, it is thought that up to 50% of CU is caused by autoimmune mechanisms.¹⁴ Autoantibodies to the high affinity IgE receptor are the most commonly identified offender, activating mast cells, basophils, and the complement system, resulting in the wheal and flare reaction.^14,16 CU is hypothesized to occur because of a predisposition in the patient to develop autoimmune diseases. In concordance with this hypothesis, additional autoimmune diseases are observed in patients with CU. Thyroid disease, particularly hypothyroidism, is the most common additional autoimmune disease diagnosed.²¹ Furthermore, thyroid disease may directly exacerbate CU severity by activating the complement system.^30,31 Other autoimmune diseases that occur more frequently in patients with CU include RA, SLE, vitiligo, pernicious anemia, celiac disease, and Sjörgen’s syndrome.^21,36 In case reports, CU has been identified as part of a larger autoimmune phenotype.^19,45 These associations support the theory that patients who develop CU do so because of an innate propensity to mount autoimmune reactions. Treatment of thyroid disease has been reported in the literature to have varying effects on CU, as it has been demonstrated to induce remission^65-67 and alternatively to have no effect on the clinical symptoms of CU⁶⁸. Autoimmune diseases occurring in patients with CU, especially thyroid disease, may be an important therapeutic target, but further studies are needed to establish the role of treatment on the clinical course of CU.

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17. Puccetti A, Bason C, Simeoni S, et al. In chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine release via eosinophil activation. Clin Exp Allergy. 2005 Dec;35(12):1599-607.
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47. Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA.LEN/EDF/WAO guideline: management of urticaria. Allergy. 2009;64(10):1427-43.
48. Ortonne JP. Chronic urticaria: a comparison of management guidelines. Expert Opin Pharmacother. 2011 Dec;12(17):2683-93.
49. Belsito DV. Second-generation antihistamines for the treatment of chronic idiopathic urticaria. J Drugs Dermatol. 2010 May;9(5):503-12.
50. Zuberbier T. Pharmacological rationale for the treatment of chronic urticaria with second-generation non-sedating antihistamines at higher-than-standard doses. J Eur Acad Dermatol Venereol. 2012 Jan;26(1):9-18.
51. Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy. 2010;93:1-13.
52. Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30.
53. Humphreys F, Hunter JA. The characteristics of urticaria in 390 patients. Br J Dermatol. 1998 Apr;138(4):635-8.
54. Di Lorenzo G, D’Alcamo A, Rizzo M, et al. Leukotriene receptor antagonists in monotherapy or in combination with antihistamines in the treatment of chronic urticaria: a systematic review. J Asthma Allergy. 2008 Dec 9;2:9-16.
55. Grattan CE, Humphreys F; British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol. 2007 Dec;157(6):1116-23.
56. Zuberbier T. Chronic urticaria. Curr Allergy Asthma Rep. 2012 Aug;12(4):267-72.
57. Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013 Mar 7;368(10):924-35.
58. Beck LA, Marcotte GV, MacGlashan D, et al. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 2004 Sep;114(3):527-30.
59. Shahar E, Bergman R, Guttman-Yassky E, et al. Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids. Int J Dermatol. 2006 Oct;45(10):1224-7.
60. Reeves GE, Boyle MJ, Bonfield J, et al. Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation. Intern Med J. 2004 Apr;34(4):182-6.
61. Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol. 2010 Jan;162(1):191-4.
62. Kessel A, Bamberger E, Toubi E. Tacrolimus in the treatment of severe chronic idiopathic urticaria: an open-label prospective study. J Am Acad Dermatol. 2005 Jan;52(1):145-8.
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ABSTRACT

Hand eczema affects up to 10% of the population and encompasses a diverse range of morphological presentations and underlying pathophysiological processes. This article will review the new and existing treatments that are available for this common dermatologic problem.

Key Words:
botulinum toxin; calcineurin inhibitors; corticosteroids; hand eczema; immunomodulators; iontophoresis; phototherapy; retinoids; systemic immunosuppressive therapy

There is not, as yet, a standardized system for the classification of hand eczema. Warshaw et al., however, outlined a comprehensive clinical classification of hand eczema based on an extensive literature review, as well as from personal experience.¹ Clinical manifestations of the disorder include erythema, edema, scaling, hyperkeratosis, vessiculation, fissuring, papules, and plaques. Morphological subtypes and patterns of distribution may suggest causation, but these are not reliable predictors and etiology is usually multifactorial.^2,3 Atopic skin diathesis is believed to play a role in hand eczema in up to 50% of cases.⁴ The 2 other most important causative factors are contact allergy and irritant exposure. Additional contributory factors include friction, occupation, low humidity, psychological stress, low socio-economic status, and hyperhidrosis.^5,6 A specific etiology cannot be identified in some patients with hand eczema.⁵

Hand eczema often runs a chronic, relapsing, and remitting course despite appropriate preventative measures and treatment.^5,7,8 Several studies have demonstrated the psychosocial burden of chronic hand eczema on patients’ lives, as well as its burden on society.^9-11 Despite the enormity of the problem, few well-designed, randomized controlled trials evaluating therapies have been carried out. In all hand eczema trials since 1977,3 only 2,142 patients have been enrolled, and a recent European survey conducted on hand eczema identified only 31 randomized controlled trials involving a total of 1,200 participants.¹² The paucity of evidence-based data on therapeutic options for hand eczema has left clinicians with no clear direction for treating those patients who do not respond to conventional therapy.

Management – Preventative Measures

The regular use of hand emollients and avoidance of frequent contact with irritants such as water, soap and detergents are the mainstays of therapy. Rubber gloves can exacerbate hand eczema, which can usually be avoided by wearing cotton liners. Contact allergy is responsible for hand eczema in as many as 47% of cases and all patients should be considered for patch testing to identify relevant allergens.¹³ A recent study demonstrated the persistence of contact sensitivity in up to 74% of hand eczema patients who were followed for 8 years,14 emphasizing the importance of continued allergen avoidance over time. Common contact allergens that can cause hand dermatitis include nickel, potassium dichromate, rubber chemicals, and biocides.

Topical Treatments

Corticosteroids

Considered as the first-line therapy in the treatment of hand eczema, several trials have evaluated the efficacy of mild, moderate, or potent topical corticosteroids for hand eczema.^15-17 However, there are no standard recommendations about how these agents should be used.

Generally, the choice of steroid potency is influenced by factors such as eczema severity, morphology, and the area involved. Drug delivery is enhanced with an ointment vehicle, as well as occlusion. In addition, water soaks for 20 minutes prior to steroid application appears to give superior results.¹⁸ Agents such as salicylic acid, tar derivatives, and anthralin are adjunctive therapies and are especially useful for hyperkeratotic eczema.

It is important to keep in mind that topical corticosteroids may also be allergens. Consquently, the possibility of a corticosteroid allergy should always be considered before attributing treatment failure to the disease itself.

Immunomodulators

The effectiveness of topical calcineurin inhibitors in the treatment of atopic dermatitis has been well established; however, their therapeutic role in hand eczema has not been studied in randomized, double-blind, controlled trials.

In a prospective, open, multicenter study of 29 patients with occupational hand eczema, tacrolimus 0.1% (Protopic®, Astellas Pharma) was applied twice daily for 4 weeks, followed by a 2 month optional treatment period, which resulted in complete clearance in 44% of subjects.19 At least a 50% improvement was achieved in 52% of patients. While only 59% of the patients continued medication usage during the optional treatment period, all subjects continued to improve during this time.

Topical tacrolimus was shown to be as effective as mometasone furoate 0.1% ointment in the treatment of dyshidrotic palmar eczema.²⁰ After a 2 week washout period, 16 patients were randomized to apply 1 of the 2 study drugs to either a palm or sole twice daily for 4 weeks. There was a comparable reduction in dyshidrotic area and severity index (DASI) scores for both study drugs when used to treat palmar eczema. However, mometasone furoate was superior to tacrolimus in the treatment of plantar eczema. For time to relapse after the active treatment phase, no difference was noted between the 2 agents.

In a multicenter, randomized, vehicle controlled trial, the effectiveness of 1% pimecrolimus cream (Elidel®, Novartis) compared with vehicle was evaluated for the treatment of chronic hand dermatitis.²¹ Two hundred and ninety-four patients with chronic hand dermatitis of varied and mixed types were randomized to receive either vehicle or 1% pimecrolimus cream twice daily using occlusion at night. At the conclusion of the trial, on day 22, there was a trend toward greater clearance in the pimecrolimus group. Almost 28% of pimecrolimus-treated patients vs. 18% of vehicle-treated patients were clear or almost clear at the end of the study. Irritant contact dermatitis and dorsal hand involvement showed the most favorable response.

In an open-label, uncontrolled study, pimecrolimus 1% cream, applied twice daily with occlusion at night, showed favorable response for hand eczema in 85% of patients (n=12) at 3 weeks. The drug was well tolerated and measurement of pimecrolimus blood levels indicated low systemic exposure.²²

Given the chronic nature of hand eczema, topical calcineurin inhibitors may provide the greatest benefit as a maintenance therapy between flares, which is akin to that adopted for the treatment of atopic dermatitis. Based on the information derived from a small number of studies, their use appears to be limited to treatment of non-hyperkeratotic hand eczema.^20-22

Retinoids

Bexarotene (Targretin®, Eisai) is a new synthetic retinoid which, in both topical and systemic forms, has been studied in the treatment of cutaneous T-cell lymphoma. In a phase 1-2 trial, 1% bexarotene gel was evaluated for safety, tolerability, and efficacy in the treatment of severe chronic hand dermatitis.²³ Fifty-five patients were randomized to receive treatment with either bexarotene gel alone or in combination with topical 0.1% mometasone furoate ointment or with 1% hydrocortisone ointment. Bexarotene was initially applied every other day and increased in a stepwise approach to 3 times daily as tolerated. Topical steroids were applied twice daily. Patients were evaluated regularly during the 22 week treatment period and then 4 weeks post treatment. Forty-two of 55 patients completed the study with 36% of all patients showing more than 90% clearance, and 71% showing at least a 50% improvement. The response rates in the 3 treatment groups were not statistically different. The drug was well tolerated by most patients; however, there was a 30% incidence of irritation in all treatment arms.

Phototherapy

Phototherapy is one of the most effective treatments for hand eczema.

Ultraviolet B (UVB)

Narrow band UVB therapy has shown clinical efficacy in the treatment of psoriasis and atopic dermatitis.²⁴ However, there is little information about its role in the management of hand eczema.

The safety and efficacy of narrow band UVB therapy for the treatment of chronic hand eczema (dry and dyshidrotic types) was evaluated in a randomized, controlled, prospective study of 15 patients who had failed conventional topical therapy.²⁵ Patients were treated with narrow band UVB (NBUVB) on 1 hand and topical photochemotherapy using 0.1% 8-methoxypsoralen (8-MOP) gel on the other 3 times weekly for 9 weeks. Patients were assessed every 3 weeks during the treatment period and then evaluated 10 weeks following the last treatment. All of the 12 subjects who completed the trial showed improvement noting no statistical difference between modalities.

Both broad band and narrow band UVB appear to be as effective as topical/bath psoralen + UVA (PUVA) therapy in the treatment of chronic hand dermatitis.²⁶ However, the risks of phototoxicity and dyspigmentation associated with local PUVA therapy make UVB therapy a preferable initial therapeutic option.

PUVA

Several studies have reported benefits from both topical and systemic PUVA therapy for chronic hand dermatitis.^27-29 PUVA may be the phototherapy of choice for hyperkeratotic hand eczema given the ability for the UVA’s longer wave lengths to penetrate deeper into the skin.

There appears to be little difference in efficacy between topical and systemic PUVA. In a retrospective study on localized topical and systemic photochemotherapy for chronic hand and foot dermatoses, Hawk and Grice30 noted no difference in efficacy between these modalities in their treatment of 40 patients.

However, the study population was mixed, with some patients having chronic eczema, while others had palmo-plantar pustulosis and psoriasis. A more recent open-label, randomized, controlled trial compared the efficacy of home administered oral PUVA with hospital delivered bath PUVA for chronic hand dermatitis in 150 patients.²⁹ The investigators found no difference between treatment groups at the end of 10 weeks of treatment and at follow-up 8 weeks later.

UVA-1

UVA-1 therapy has been established as an effective treatment of atopic dermatitis in several clinical trials.^31,32 UVA-1 was first reported to be beneficial for dyshidrotic hand eczema in an uncontrolled trial of 12 patients.³³ Subjects received daily treatment with local UVA-1 irradiation at a dose of 40 J/cm2 for 3 weeks. Eczema severity was evaluated using the DASI. Conditions for 10 out of 12 patients were judged to be cleared or almost cleared at the end of the treatment course and patients remained relapse free during a 3 month follow-up period. In a randomized, double-blind, placebo controlled trial, 28 patients with chronic dyshidrotic hand eczema were randomized to receive UVA-1 irradiation or placebo 5 times/week for 3 weeks. Change in DASI was the primary endpoint and patients were assessed weekly during the treatment phase and then at 3 and 6 weeks post treatment. Therapeutic response was noted in the treatment group at 2 weeks and a significant sustained reduction in DASI persisted at 6 weeks following the last treatment.

Ionizing Radiation

The inflammatory cells operative in eczema are highly radiosensitive.³⁴ Grenz rays and superficial radiotherapy were popular treatments for chronic severe hand eczema 20-30 years ago. However, their association with a greater risk for carcinogenesis coupled with the introduction of megavoltage external beam photon and electron units, has resulted in these treatments falling out of favor. Superficial radiation therapy appears to provide greater benefit than Grenz ray therapy and this is likely because of its deeper penetration into the skin. As a result of non-standardized treatment protocols, it is difficult to critically compare studies and reach valid conclusions about these forms of treatment.^35-39

In a recent case report, low dose external beam megavoltage therapy resulted in complete clearance and a prolonged remission of severe treatment resistant dyshidrotic hand eczema in a 41 year-old woman.⁴⁰ These results are impressive and a reminder that ionizing radiation, an often forgotten intervention for this disease, may be helpful for refractory cases.

Systemic Treatments

Immunosuppressive Therapy

Systemic immunosuppressive therapy may be considered for those cases of hand eczema that are refractory to topical steroids and phototherapy. Systemic glucocorticoids are generally effective in managing acute flares; however, given their side-effect profile, they are not practical over the long-term. Similarly, the usefulness of cyclosporine for this condition seems limited to the short-term. While 1 study demonstrated prolonged disease remission in 74% of patients 1 year after a 6-week course of cyclosporine 3mg/kg/day,⁴¹ other studies have shown high relapse rates within weeks of drug discontinuation.^42,43

Agents such as methotrexate and mycophenolate mofetil (CellCept®, Roche Laboratories) may be more promising for long-term control of severe hand eczema. Methotrexate has been shown to be an effective adjunctive agent in 5 patients with severe recalcitrant dyshidrotic eczema. Patients were treated with methotrexate 15-22.5mg/week and all were subsequently able to significantly reduce or eliminate systemic steroid use.⁴⁴ In a case report of a 39 year-old male with severe dyshidrotic eczema, long-term control was ultimately achieved and maintained with mycophenolate mofetil 2-3gm/day. The drug was well tolerated without serious adverse effects after 1 year of treatment.⁴⁵

Retinoids

Systemic retinoids, including etretinate (Tigason®, Hoffmann-La Roche) and acitretin (Soriatane®, Stiefel), have shown some benefit in the treatment of hand eczema.^34,46 Studies in the past have focused on their treatment of hyperkeratotic eczema.

Alitretinoin (9-cis-retinoic acid) (Toctino®, Basilea Pharmaceuticals) is an oral retinoid that is capable of activating all retinoic acid receptors as well as retinoid X receptors. It is currently approved in Europe for the treatment of solid malignant tumors and as a new once-daily treatment for adults with severe chronic hand eczema unresponsive to potent topical corticosteroids. While it is not approved in North America, this agent, like its related compounds, has been evaluated for the treatment of chronic hand dermatitis.⁴⁷ In a multicenter, randomized, double-blind, placebo controlled trial, 319 patients were allocated to receive either placebo or alitretinoin at 10mg/day, 20mg/day, or 40mg/day for 12 weeks. All types of hand dermatitis were included in the study, but the majority of patients had the hyperkeratotic type. Patients were deemed to be responders if, by physician’s global assessment, the dermatitis was clear or almost clear at the end of the treatment period. Of the 244 patients who completed the 12 week course, 127 were responders. Response rates increased across the dosage range and were 27% for the placebo group and 39%, 41% and 53% for the 10, 20 and 40mg/day groups, respectively. This incremental response rate was independent of the type of hand eczema. The drug was generally well tolerated and adverse events, such as headache, mucocutaneous dryness, photosensitivity, and dyslipidemia occurred more frequently with higher drug doses.

Botulinum Toxin

Hyperhidrosis has been reported to be an aggravating factor in dyshidrotic hand eczema in nearly 40% of cases.48 As such, botulinum toxin – type A (BTX-A), which is an approved treatment for axillary hyperhidrosis and an effective, commonly used treatment of palmar hyperhidrosis, has been explored as an off-label treatment for dyshidrotic eczema.⁴⁹ In an open study of 10 patients with dyshidrotic hand eczema treated with 162 units of intradermal BTX-A in 1 hand only, 7 of 10 patients experienced good or very good improvement in their eczema on the treated hand at 6 weeks.⁵⁰ Sweating was more likely to be an aggravating factor to the eczema in responders to this formulation.

BTX-A was found to be a very effective adjuvant treatment for dyshidrotic eczema in 6 patients, who were treated with topical steroids alone on 1 hand, and a topical steroid plus 100 units of intracutaneous BTX-A at week 0 in the other, more severely affected hand. There was a significantly greater drop in DASI scores in the combination treatment side with a stabilization of hand eczema at 8 weeks, whereas there was a 50% partial or complete relapse rate on the monotherapy side. Pruritus and vessiculation decreased more rapidly in the combination therapy side. The authors concluded that BTX-A inhibition of substance P release may be operative in these antipruritic effects.⁵¹

Iontophoresis

Hyperhidrosis, a recognized risk factor for hand eczema, generally responds well to treatment with tap water iontophoresis.⁵² In a randomized half-side study of 20 patients with mild-to-moderate dyshidrotic eczema, patients received steroid free topical therapy of both hands and daily unilateral tap water iontophoresis. Significant improvement in eczema, as assessed by DASI scores, was noted only in iontophoresis treated hands. The authors attributed improvement to a reduction in sweat secretion and possibly enhanced absorption of topical therapy.⁵³

Conclusion

Hand eczema is a highly prevalent disorder, which in many patients is chronic, debilitating, and associated with impaired quality of life. Both endogenous and exogenous factors play a role in the development of the disease. Lifestyle management, the use of emollients, avoidance of allergens, and topical corticosteroids are effective and sufficient treatments for some patients, but many require additional intervention. The best way to manage these patients is unclear based on the current level of evidence. A standardized, universally accepted classification system of hand eczema and larger scale, well-designed, randomized trials are necessary prerequisites to achieve optimal and successful management of this disorder.

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