- Email: [email protected]
Clinical Features, Etiologic Factors, Associated Disorders, and Treatment of Palmoplantar Pustulosis
ORIGINAL ARTICLE
Clinical Features, Etiologic Factors, Associated Disorders, and Treatment of Palmoplantar Pustulosis: The Mayo Clinic Experience, 1996-2013 Jeannette M. Olazagasti, MD; Janice E. Ma, BS; and David A. Wetter, MD Abstract Objective: To further characterize clinical characteristics, etiologic factors, associated disorders, and treatment of palmoplantar pustulosis (PPP). Patients and Methods: We conducted a retrospective review of patients with PPP at Mayo Clinic between January 1, 1996, and December 31, 2013. Results: Of 215 patients with PPP identified, 179 (83%) were female, and the mean age at onset was 45.3 years. Most patients (n¼165, 77%) were current or former smokers. At diagnosis, 15 patients (7%) had an anxiety diagnosis and 9 (4%) had an infection. Nineteen cases (9%) were drug induced. Comorbid conditions included thyroid disease in 18 patients (8%), gluten sensitivity in 3 (1%), and type 2 diabetes mellitus in 21 (10%). In all, 194 patients (90%) received topical corticosteroids, 55 (26%) received phototherapy, and 54 (25%) received systemic agents. Conclusion: More than three-fourths of the patients in this study had a history of smoking, which is considered a triggering or aggravating factor for PPP. Regarding comorbid conditions, gluten sensitivity and thyroid disease were found less frequently than previously reported in the literature. Treatment regimens and responses in this cohort varied considerably. ª 2017 Mayo Foundation for Medical Education and Research
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almoplantar pustulosis (PPP) is a chronic, relapsing, pustular eruption localized to the palms and soles.1,2 Brown macules representing resolving pustules, erythema, scale, and fissures are additional frequent findings.1 Although skin involvement in PPP is limited, the condition may be painful and disabling. In severe cases, discomfort associated with skin involvement hinders walking or use of the hands. The cause is unknown, and it is unclear whether it is a distinct entity or a localized pustular variant of psoriasis.3,4 Clinical observations suggest that smoking,1 emotional stress (eg, anxiety),5 focal infections (eg, acute or chronic tonsillitis, dental infection, chronic sinusitis),6 and certain drugs (eg, tumor necrosis factor [TNF]-a inhibitors)7 contribute to the development or exacerbation of PPP. Furthermore, PPP has been linked to systemic abnormalities such as SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome,8 thyroid
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disease,9,10 gluten sensitivity,11 and type 2 diabetes mellitus (DM).12 Many treatments have been suggested for PPP, but none have been generally accepted as being reliably effective. Topical corticosteroids used under occlusion, oral psoraleneUV-A, and acitretin have shown benefit in treating PPP.13 The aim of this study was to retrospectively examine the features of PPPdincluding clinical characteristics, etiologic factors, associated disorders, and responses to treatmentdin patients at Mayo Clinic in Rochester, Minnesota.
From the University of Texas Southwestern Medical Center, Dallas (J.M.O.); and Department of Dermatology (D.A.W) and Mayo Clinic School of Medicine, Mayo Clinic College of Medicine and Science (J.E.M.), Mayo Clinic, Rochester, MN.
PATIENTS AND METHODS Data Collection We retrospectively searched the institutional medical index and text retrieval system for the records of patients with a diagnosis of PPP who were treated at Mayo Clinic between January 1, 1996, and December 31, 2013. The
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study received approval from the Mayo Clinic Institutional Review Board. Patients who denied research authorization were excluded from this study. The following information was obtained from the medical records: patient characteristics, clinical characteristics, disease duration, identifiable causes of PPP, comorbid conditions, laboratory test results, histopathologic data, patch test data, response to therapies, and follow-up information since diagnosis. Definition of PPP Per the methods of Brunasso et al,1 PPP was defined as “recurrent, discrete, 1- to 10-mm sterile pustules that often coalesce and resolve with brownish discoloration, frequently associated with well-demarcated erythema, hyperkeratosis, and desquamation, located symmetrically or asymmetrically on the palms and/or soles in the absence of pustules involving other areas of the body, and/or erythroderma.”p1244 Also using the same criteria as Brunasso et al,1 we excluded patients with more than 5% body surface area involvement outside of the palmoplantar region. Etiologic Factors Smoking. Patients were classified as having smoking-induced PPP if they were current or former smokers at disease onset. Following the definitions of the Centers for Disease Control and Prevention regarding cigarette smoking, we defined current smokers as those who reported having smoked at least 100 cigarettes in their lifetime and who, at the time of disease onset, smoked either every day or some days.14 Former smokers were defined as those who reported having smoked at least 100 cigarettes in their lifetime and who, at the time of disease onset, did not smoke at all. Never smokers were defined as those who reported never having smoked 100 cigarettes. Stress. Patients were classified as having stress-induced PPP if they experienced symptoms of anxiety in association with their skin eruption(s). Comparable with a previous study, patients needed to have anxiety diagnosed by a psychologist or psychiatrist using appropriate psychological tests.5 2
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Focal Infection. Patients were classified as having infection-induced PPP if they had evidence of tonsillitis, dental infection, or chronic sinusitis associated with their skin eruption. As in a previous study,6 patients needed to have a focal infection diagnosed through examinations such as a tonsil test, radiologic test, and blood test. TNF-a Inhibitor. Patients were classified as having TNF-a inhibitoreinduced PPP if they were receiving TNF-a inhibitor therapy at the time of disease onset. Associated Disorders SAPHO Syndrome. Patients were classified as having associated SAPHO syndrome if they had a personal history of SAPHO syndrome or clinical characteristics suggestive of SAPHO syndrome (ie, synovitis, acne, pustulosis, hyperostosis, or osteitis).8 Thyroid Disease. Patients were classified as having associated thyroid disease if they had a personal history of thyroid disease or blood test results suggestive of thyroid disease (eg, abnormal thyrotropin, abnormal thyroxine, or increased antimicrosomal or antithyroglobulin antibody levels).9,10 Gluten Sensitivity. Patients were classified as having associated gluten sensitivity if they had a personal history of gluten sensitivity or blood test results suggestive of gluten sensitivity (eg, increased antigliadin or tissue transglutaminase antibody levels).11 Type 2 DM. Patients were classified as having associated type 2 DM if they had a personal history of type 2 DM or blood test results suggestive of type 2 DM (eg, increased fasting plasma glucose or glycated hemoglobin A1c levels).12 Response to Treatment Patient response to therapy was assessed and classified as complete response, partial response, or no response. Resolution of old lesions with a lack of any new lesions indicated complete response. Healing of some lesions with reduced severity and frequency of flares indicated partial response. Persistence of
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lesions and development of new ones indicated no response. A disease-free period of at least 2 years indicated remission of disease. Literature Search We searched MEDLINE, 1946 to present, with the search term (Palmoplantar or [palm* adj plant*]) adj2 Pustulosis).tw. We limited the search to English-language articles, and we narrowed the study types to cohort, epidemiologic, and cross-sectional studies. Single case reports and small case series were excluded. RESULTS Clinical Characteristics The database search identified 215 patients, of whom 179 (83%) were female (Table 1). The mean age at PPP onset was 45.3 years (range, 4-83 years), and the mean total duration of PPP was 6.5 years (range, 0-59 years). Most patients (n¼129, 60%) had involvement of both palms and soles; 21 (10%) had nail involvement. Biopsy results compatible with a diagnosis of PPP were available for 83 patients (39%). Thirty patients (14%) had a personal history positive for minimal or mild psoriasis vulgaris, 7 (3%) had a positive family history of PPP, and 38 (18%) had a positive family history of psoriasis. The mean followup duration after PPP diagnosis was 1.6 years (range, 0-15.3 years). Remission of PPP occurred in 21 patients (10%). Figure illustrates the clinical appearance and classic distribution patterns of PPP. Etiologic Factors and Associated Disorders Most patients were either active smokers (n¼93, 43%) or former smokers (n¼72, 34%) (Table 1). At the time of diagnosis, 15 patients (7%) had anxiety and 9 (4%) had a focal infection. Nineteen cases (9%) were considered drug induced, mostly by TNF-a inhibitor therapy. Regarding comorbid conditions, 8 patients (4%) had SAPHO syndrome, 18 (8%) had thyroid disease, 3 (1%) had gluten sensitivity, and 21 (10%) had type 2 DM. Patch Testing Twenty-two of 215 patients with PPP (10%) underwent patch testing. Four of the 22 Mayo Clin Proc. n XXX 2017;nn(n):1-8 www.mayoclinicproceedings.org
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TABLE 1. Patient and Disease Characteristics Characteristic Patient/disease characteristics Age at disease onset (y), mean SD Female sex (No. [%]) Location of PPP (No. [%]) Palms Soles Palms and soles Skin biopsy consistent with PPP (No. [%]) Nail involvement (No. [%]) Personal history of psoriasis (No. [%]) Timing of psoriasis related to PPP (No. [%]) Before Synchronous After Inflammatory arthritis/arthralgia/joint pain (No. [%]) Family history of PPP (No. [%]) Family history of psoriasis (No. [%]) Disease duration at time of diagnosis (y), mean SD Total duration of PPP (y), mean SD Remission (No. [%]) Follow-up since diagnosis (y), mean SD Potential causative factors (No. [%]) Smoking Current Former Never Unknown Emotional stress (eg, anxiety) Focal infection Tonsillitis Dental infection Chronic sinusitis Drugs used TNF-a inhibitors Other medication (eg, b-blockers) Associated disorders (No. [%]) SAPHO syndrome Thyroid disease Hyperthyroidism (eg, Graves disease) Hypothyroidism Gluten sensitivity Type 2 diabetes mellitus
Value (N¼215) 45.314.6 179 (83) 29 57 129 83 21 30
(13) (27) (60) (39) (10) (14)
9 12 9 18 7 38 4.9 6.5 21 1.6
(30) (40) (30) (8) (3) (18) (8.2) (8.5) (10) (6.0)
93 72 33 17 15 9 2 0 7 19 17 2
(43) (34) (15) (8) (7) (4) (1)
8 18 7 11 3 21
(4) (8) (3) (5) (1) (10)
(3) (9) (8) (1)
PPP ¼ palmoplantar pustulosis; SAPHO ¼ synovitis, acne, pustulosis, hyperostosis, osteitis; TNF ¼ tumor necrosis factor.
patients were patch tested at an outside institution, and relevancy data to specific allergens were unavailable. Of the 18 patients patch tested at Mayo Clinic, 2 (11%) had negative patch test results, and the remaining 16 (89%) tested positive to at least 1 allergen. The most common positive reactions included gold sodium thiosulfate in 5 patients, fragrance mix in 4, and balsam of Peru, benzoic
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FIGURE. A-E, Palmoplantar pustulosis. Discrete (and sometimes coalescing) pustules admixed with brown macules on a background of erythema. Involved areas of the palms and soles are typically well-demarcated, bilateral, and often symmetrical. Note the evolution of yellow pustules to brown macules with resultant desquamating collarettes of scale. Part D is adapted from CMAJ,2 with permission.
acid, cobalt chloride, imidazolidinyl urea, methyldibromoglutaronitrile, or neomycin in 3. Of the 16 patients with positive patch test results, 6 (37.5%) had at least 1 relevant positive allergen; the remaining 10 (62.5%) had positive patch test results with either questionable or no relevance. Relevant allergens included bronopol, chromium chloride (2 patients), cobalt, colophony, diazolidinyl urea, DMDM hydantoin, D-phenylguanidine, formaldehyde, fragrance mix, imidazolidinyl urea, nickel, and quaternium-15. Treatment and Responses Most patients with PPP (n¼194, 90%) received topical corticosteroids (Table 2). The next most common treatments were phototherapy (n¼55, 26%) and systemic immunosuppressive or anti-inflammatory 4
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agents (n¼54, 25%), the most common of which were acitretin (24 patients) and methotrexate (20 patients). Several patients used more than 1 systemic agent for PPP. None of the patients required hospitalization. The responses to treatment are also shown in Table 2. Of the 194 patients treated with topical corticosteroids, 23 (12%) had complete response and 23 (12%) had partial response. Among the treatments that elicited complete response were phototherapy (11 of 55 patients; 20%), acitretin (6 of 24; 25%), methotrexate (2 of 20; 10%), and cyclosporine (2 of 4; 50%). Leflunomide, used for only 1 patient, also elicited a complete response. Several treatmentsddapsone (3 patients), etanercept (3 patients), and prednisone (5 patients)delicited no response only. We
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were unable to assess whether allergen avoidance in those with relevant contact allergens led to improvement of PPP due to confounding factors, including initiation of new treatment regimens or inadequate follow-up. DISCUSSION The study findings had similarities and differences compared with the published literature on PPP. Age at onset of PPP and the female predominance observed in these patients were comparable with data reported in previous studies (Table 3).1,15,16,18,20,22 Minimal plaque psoriasis occurred in 14% of the present patients, which corroborates previous studies1,3,15,17,18,20,21 reporting that the prevalence of psoriasis in patients with PPP is higher than that in the general population. However, the present prevalence of psoriasis in patients with PPP was most consistent with that of Eriksson et al18 and Asumalahti et al.20 Both studies by Brunasso et al1,3 found a much higher prevalence of psoriasis in patients with PPP: 73.18% and 61.6%. The present patients with PPP had a comparable prevalence of positive family history of psoriasis (18%) as in the published literature.10,16-18,21 The prevalence of nail involvement (10%) was lower than what has been previously reported (range, 30%-76%).1,3,17,21 Concomitant arthritis/arthralgia was found in 8% of the present patients, whereas other studies report a prevalence of 13% to 64%. The cause of PPP is not well understood. However, environmental factors (eg, smoking,1 stress,5 infection,6 and certain drugs7) are believed to contribute to the development or exacerbation of PPP. In the present study, 165 of 215 patients (77%) were current or former smokers. This is consistent with previous studies1,3,10,11,17-19,21 reporting a prevalence of ever-smoking in patients with PPP ranging from 42% to 100%. At the time of PPP diagnosis, 15 patients (7%) had anxiety and 9 (4%) had a focal infection. Nineteen cases (9%) were drug induced, mostly by TNF-a inhibitor therapy. No recent comparable studies have been published on these associations. Contact sensitivities have also been associated with PPP.24 In the present cohort, only a few patients diagnosed as having PPP underwent formal patch testing. Although most of Mayo Clin Proc. n XXX 2017;nn(n):1-8 www.mayoclinicproceedings.org
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TABLE 2. Treatment for Palmoplantar Pustulosis Treatment Topical corticosteroids
Patients (No. [%]) (N¼215)
Response to Treatment
194 (90)
23 CR 23 PR 39 NR 109 NA 11 CR 12 PR 9 NR 23 NA
Phototherapy
55 (26)
Any systemic agent Acitretin
54 (25) 24 (11)
Methotrexate
20 (9)
Tetracycline/doxycycline/minocycline
7 (3)
Adalimumab
5 (2)
Prednisone Cyclosporine
5 (2) 4 (2)
Dapsone
4 (2)
Etanercept Infliximab
3 (1) 3 (1)
Leflunomide Ustekinumab
1 (0.5) 1 (0.5)
6 CR 2 PR 8 NR 8 NA 2 CR 1 PR 10 NR 7 NA 1 CR 5 NR 1 NA 2 PR 2 NR 1 NA 5 NR 2 CR 1 NR 1 NA 3 NR 1 NA 3 NR 1 PR 1 NR 1 NA 1 CR 1 NA
CR ¼ complete response; NA ¼ not available; NR ¼ no response; PR ¼ partial response.
those tested had positive patch test results, many of the reactions were deemed by the treating dermatologist to be of either questionable or no relevance to the PPP. Future studies should be performed to elucidate a potential role of contact sensitivities in the development of PPP. Previous studies have suggested that some systemic abnormalities, such as thyroid disease,9,10 gluten sensitivity,11 and type 2 DM,12 may occur at increased frequency in patients with PPP. In a study by Gimenez-Garcia et al,10 the prevalence of thyroid disease in patients with PPP was as high as 18%; we found
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6 TABLE 3. Published Epidemiologic and Clinical Data on Palmoplantar Pustulosis Study Enfors and Molin15
Hellgren and Mobacken16
Burden and Kemmett17
Eriksson et al18
Hagforsen et al19
Asumalahti et al20
GimenezGarcia et al10
Michaelsson et al11
Miot et al21
Adisen et al22
Brunasso and Massone3
Brunasso et al1
Trattner et al23
Present study
Participants (No.) Age at onset (y) Sex, M/F (%) Positive smoking (%) Family history of psoriasis (%) Nail involvement (%) Arthritis (%)
248 20-60 22/78 NA 43
78 40-60 18/82 NA 10
50 NA 17/83 96 33
59 4212 12/88 95 22
45 NA 13/87 96 NA
156 48 15/85 NA NA
17 NA 24/76 100 12
63 NA 6/94 100 NA
25 NA 16/84 96 16
52 40 37/63 NA NA
19 NA 42/58 42 42
39 45 33/67 54 28
102 5314 85/15 94 27
215 45 17/83 77 18
NA 13
NA NA
30 NA
NA 42 (includes arthralgia)
NA NA
NA NA
NA 65
NA NA
76 48
NA NA
47 26
41 26
43 18
Psoriasis outside the palmoplantar area (%)
24 confirmed, 47 suspected
8
10
NA
18
Patients with psoriasis were excluded
NA
16
NA
73
62
19
10 8 (includes arthralgia and joint pain) 14
Study characteristic
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NA NA NA NA NA NA
NA NA NA NA NA NA
NA NA NA NA NA NA
NA 14 NA NA 8 6
NA 4 NA NA NA NA
NA NA NA NA NA NA
NA 18 6 12 NA NA
NA 11 3 8 30 8
NA NA NA NA NA NA
NA NA NA NA NA NA
NA NA NA NA NA NA
NA 2 0 2 NA NA
1 16 NA NA 1 19
4 8 3 5 1 10
Distribution of lesions (%) Palmar Plantar Both
6 14 61
12 27 61
NA NA NA
5 21 69
NA NA NA
NA NA NA
NA NA NA
NA NA NA
0 36 64
NA NA 73
32 21 47
15 18 67
11 13 56
13 27 60
DM ¼ diabetes mellitus; NA ¼ not available; SAPHO ¼ synovitis, acne, pustulosis, hyperostosis, osteitis. Adapted from Br J Dermatol,1 with permission.
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Associated disorders (%) SAPHO syndrome Thyroid disease Hyperthyroidism Hypothyroidism Gluten sensitivity Type 2 DM
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a prevalence of 8%. Michaelsson et al11 reported a prevalence of gluten sensitivity in patients with PPP of 30%, whereas the prevalence in the present study was 1%. The prevalence of type 2 DM in patients with PPP has been reported to be as high as 25% in a study by Hagforsen et al,12 but it was 10% herein. Thus, in the present study, these disorders were found less frequently than previously reported in the literature. These findings are corroborated by a recent cross-sectional study of 102 patients with PPP that also found a low frequency of associated SAPHO syndrome (1%) and celiac disease (1%).24 Treatment of PPP is often challenging. Topical corticosteroids used under occlusion, oral psoraleneUV-A, and acitretin have shown benefit in treating PPP.13 Most patients in the present study (n¼194, 90%) were treated with topical corticosteroids. None of the systemic therapies used in this cohort were uniformly effective in treating PPP. The present findings are especially relevant for general practitioners and internal medicine subspecialists for several reasons. The high frequency of smoking history among patients with PPP in this cohort reinforces the importance of counseling these patients on smoking cessation. Thoroughly reviewing medication lists for common culprits such as TNF-a inhibitors7 in patients suspected of having PPP is also paramount, particularly given the widespread use of TNF-a inhibitors for the treatment of a variety of commonly encountered conditions, including rheumatoid arthritis and inflammatory bowel disease. Palmoplantar pustulosis can be associated with rare but important autoinflammatory syndromes such as SAPHO syndrome, thus potentially serving as a key diagnostic clue for general practitioners and subspecialists who are evaluating patients with complex and undiagnosed multisystem systemic disease. Furthermore, the present study found a lower frequency of associated systemic diseases among patients with PPP than previously reported. These findings suggest that patients with PPP may not need to be routinely screened for systemic disorders, although additional studies are necessary to further elucidate the association between PPP and thyroid disease, gluten sensitivity, and type 2 DM. It is also important to manage patient Mayo Clin Proc. n XXX 2017;nn(n):1-8 www.mayoclinicproceedings.org
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expectations and discuss the challenging nature of treatment of PPP. Finally, knowledge of the clinical features of PPP can aid its prompt recognition and can guard against misdiagnosing it as a condition that is more commonly seen in the primary care setting, such as tinea pedis or dyshidrotic eczema. This study is limited by its retrospective design. As such, findings from this study should be interpreted cautiously and may not be generalizable to other populations. In particular, because data regarding comorbidities were not collected in a standardized manner, the study may have underestimated the frequency of association of systemic disorders with PPP. Furthermore, there was a lack of uniform treatment and follow-up data on patients in this cohort. Larger, welldesigned studies are warranted to make conclusive recommendations for patients with PPP.
CONCLUSION To our knowledge, this cohort represents one of the largest single-center series of PPP in the literature and, thus, provides useful clinical information for providers who care for patients with PPP. Specifically, we found that an association of PPP with systemic disorders (eg, thyroid disease, gluten sensitivity, and type 2 DM) was less frequent than previously reported. Similar to previous studies, an association between PPP and smoking was also observed; approximately threefourths of patients in this study were current or former smokers. Treatment regimens in this cohort varied considerably. Overall, approximately a fourth of patients with PPP in this study cohort required treatment with oral medications to manage their disease. Further studies are needed to elucidate consistently effective treatment regimens for PPP. ACKNOWLEDGMENTS This study’s contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. Dr Olazagasti and Ms Ma contributed equally to this work.
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Abbreviations and Acronyms: CR = complete response; DM = diabetes mellitus; NA = not available; NR = no response; PPP = palmoplantar pustulosis; PR = partial response; SAPHO = synovitis, acne, pustulosis, hyperostosis, and osteitis; TNF = tumor necrosis factor Grant Support: This study was supported in part by Clinical and Translational Science Award grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Correspondence: Address to David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
REFERENCES 1. Brunasso AM, Puntoni M, Aberer W, et al. Clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study. Br J Dermatol. 2013;168(6):1243-1251. 2. Wetter DA. Palmoplantar pustulosis. CMAJ. 2013;185(11):982. 3. Brunasso AM, Massone C. Can we really separate palmoplantar pustulosis from psoriasis? J Eur Acad Dermatol Venereol. 2010; 24(5):619-621. 4. Mrowietz U, van de Kerkhof PC. Management of palmoplantar pustulosis: do we need to change? Br J Dermatol. 2011;164(5): 942-946. 5. Saez-Rodriguez M, Noda-Cabrera A, Alvarez-Tejera S, et al. The role of psychological factors in palmoplantar pustulosis. J Eur Acad Dermatol Venereol. 2002;16(4):325-327. 6. Akiyama T, Seishima M, Watanabe H, Nakatani A, Mori S, Kitajima Y. The relationships of onset and exacerbation of pustulosis palmaris et plantaris to smoking and focal infections. J Dermatol. 1995;22(12):930-934. 7. Shmidt E, Wetter DA, Ferguson SB, Pittelkow MR. Psoriasis and palmoplantar pustulosis associated with tumor necrosis factora inhibitors: the Mayo Clinic experience, 1998 to 2010. J Am Acad Dermatol. 2012;67:e179-e185. 8. Kundu BK, Naik AK, Bhargava S, Srivastava D. Diagnosing the SAPHO syndrome: a report of three cases and review of literature. Clin Rheumatol. 2013;32(8):1237-1243. 9. Rosen K, Lindstedt G, Mobacken H, Nystrom E. Thyroid function in patients with pustulosis palmoplantaris. J Am Acad Dermatol. 1988;19(6):1009-1016. 10. Gimenez-Garcia R, Sanchez-Ramon S, Cuellar-Olmedo LA. Palmoplantar pustulosis: a clinicoepidemiological study: the relationship between tobacco use and thyroid function. J Eur Acad Dermatol Venereol. 2003;17(3):276-279.
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11. Michaelsson G, Kristjansson G, Pihl Lundin I, Hagforsen E. Palmoplantar pustulosis and gluten sensitivity: a study of serum antibodies against gliadin and tissue transglutaminase, the duodenal mucosa and effects of gluten-free diet. Br J Dermatol. 2007;156(4):659-666. 12. Hagforsen E, Michaelsson K, Lundgren E, et al. Women with palmoplantar pustulosis have disturbed calcium homeostasis and a high prevalence of diabetes mellitus and psychiatric disorders: a case-control study. Acta Derm Venereol. 2005; 85(3):225-232. 13. Marsland AM, Chalmers RJ, Hollis S, et al. Interventions for chronic palmoplantar pustulosis. Cochrane Database Syst Rev. 2006;(1):CD001433. 14. From the Centers for Disease Control and Prevention: annual smoking attributable mortality, years of potential life lost and economic costs: United States, 1995-1999. JAMA. 2002; 287(18):2355-2356. 15. Enfors W, Molin L. Pustulosis palmaris et plantaris: a follow-up study of a ten-year material. Acta Derm Venereol. 1971;51(4): 289-294. 16. Hellgren L, Mobacken H. Pustulosis palmaris et plantaris: prevalence, clinical observations and prognosis. Acta Derm Venereol. 1971;51(4):284-288. 17. Burden AD, Kemmett D. The spectrum of nail involvement in palmoplantar pustulosis. Br J Dermatol. 1996; 134(6):1079-1082. 18. Eriksson MO, Hagforsen E, Lundin IP, Michaelsson G. Palmoplantar pustulosis: a clinical and immunohistological study. Br J Dermatol. 1998;138(3):390-398. 19. Hagforsen E, Awder M, Lefvert AK, et al. Palmoplantar pustulosis: an autoimmune disease precipitated by smoking? Acta Derm Venereol. 2002;82(5):341-346. 20. Asumalahti K, Ameen M, Suomela S, et al. Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J Invest Dermatol. 2003;120(4):627-632. 21. Miot HA, Miot LD, Lopes PS, Haddad GR, Marques SA. Association between palmoplantar pustulosis and cigarette smoking in Brazil: a case-control study. J Eur Acad Dermatol Venereol. 2009;23(10):1173-1177. 22. Adisen E, Tekin O, Gulekon A, Gurer MA. A retrospective analysis of treatment responses of palmoplantar psoriasis in 114 patients. J Eur Acad Dermatol Venereol. 2009;23(7):814-819. 23. Trattner H, Blüml S, Steiner I, Plut U, Radakovic S, Tanew A. Quality of life and comorbidities in palmoplantar pustulosis: a cross sectional study on 102 patients [published online March 2, 2017]. J Eur Acad Dermatol Venereol. http://dx.doi.org/10. 1111/jdv.14187. 24. Yiannias JA, Winkelmann RK, Connolly SM. Contact sensitivities in palmarplantar pustulosis (acropustulosis). Contact Dermatitis. 1998;39(3):108-111.
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Clinical Features, Etiologic Factors, Associated Disorders, and Treatment of Palmoplantar Pustulosis: The Mayo Clinic Experience, 1996-2013 Jeannette M. Olazagasti, MD; Janice E. Ma, BS; and David A. Wetter, MD Abstract Objective: To further characterize clinical characteristics, etiologic factors, associated disorders, and treatment of palmoplantar pustulosis (PPP). Patients and Methods: We conducted a retrospective review of patients with PPP at Mayo Clinic between January 1, 1996, and December 31, 2013. Results: Of 215 patients with PPP identified, 179 (83%) were female, and the mean age at onset was 45.3 years. Most patients (n¼165, 77%) were current or former smokers. At diagnosis, 15 patients (7%) had an anxiety diagnosis and 9 (4%) had an infection. Nineteen cases (9%) were drug induced. Comorbid conditions included thyroid disease in 18 patients (8%), gluten sensitivity in 3 (1%), and type 2 diabetes mellitus in 21 (10%). In all, 194 patients (90%) received topical corticosteroids, 55 (26%) received phototherapy, and 54 (25%) received systemic agents. Conclusion: More than three-fourths of the patients in this study had a history of smoking, which is considered a triggering or aggravating factor for PPP. Regarding comorbid conditions, gluten sensitivity and thyroid disease were found less frequently than previously reported in the literature. Treatment regimens and responses in this cohort varied considerably. ª 2017 Mayo Foundation for Medical Education and Research
P
almoplantar pustulosis (PPP) is a chronic, relapsing, pustular eruption localized to the palms and soles.1,2 Brown macules representing resolving pustules, erythema, scale, and fissures are additional frequent findings.1 Although skin involvement in PPP is limited, the condition may be painful and disabling. In severe cases, discomfort associated with skin involvement hinders walking or use of the hands. The cause is unknown, and it is unclear whether it is a distinct entity or a localized pustular variant of psoriasis.3,4 Clinical observations suggest that smoking,1 emotional stress (eg, anxiety),5 focal infections (eg, acute or chronic tonsillitis, dental infection, chronic sinusitis),6 and certain drugs (eg, tumor necrosis factor [TNF]-a inhibitors)7 contribute to the development or exacerbation of PPP. Furthermore, PPP has been linked to systemic abnormalities such as SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome,8 thyroid
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disease,9,10 gluten sensitivity,11 and type 2 diabetes mellitus (DM).12 Many treatments have been suggested for PPP, but none have been generally accepted as being reliably effective. Topical corticosteroids used under occlusion, oral psoraleneUV-A, and acitretin have shown benefit in treating PPP.13 The aim of this study was to retrospectively examine the features of PPPdincluding clinical characteristics, etiologic factors, associated disorders, and responses to treatmentdin patients at Mayo Clinic in Rochester, Minnesota.
From the University of Texas Southwestern Medical Center, Dallas (J.M.O.); and Department of Dermatology (D.A.W) and Mayo Clinic School of Medicine, Mayo Clinic College of Medicine and Science (J.E.M.), Mayo Clinic, Rochester, MN.
PATIENTS AND METHODS Data Collection We retrospectively searched the institutional medical index and text retrieval system for the records of patients with a diagnosis of PPP who were treated at Mayo Clinic between January 1, 1996, and December 31, 2013. The
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study received approval from the Mayo Clinic Institutional Review Board. Patients who denied research authorization were excluded from this study. The following information was obtained from the medical records: patient characteristics, clinical characteristics, disease duration, identifiable causes of PPP, comorbid conditions, laboratory test results, histopathologic data, patch test data, response to therapies, and follow-up information since diagnosis. Definition of PPP Per the methods of Brunasso et al,1 PPP was defined as “recurrent, discrete, 1- to 10-mm sterile pustules that often coalesce and resolve with brownish discoloration, frequently associated with well-demarcated erythema, hyperkeratosis, and desquamation, located symmetrically or asymmetrically on the palms and/or soles in the absence of pustules involving other areas of the body, and/or erythroderma.”p1244 Also using the same criteria as Brunasso et al,1 we excluded patients with more than 5% body surface area involvement outside of the palmoplantar region. Etiologic Factors Smoking. Patients were classified as having smoking-induced PPP if they were current or former smokers at disease onset. Following the definitions of the Centers for Disease Control and Prevention regarding cigarette smoking, we defined current smokers as those who reported having smoked at least 100 cigarettes in their lifetime and who, at the time of disease onset, smoked either every day or some days.14 Former smokers were defined as those who reported having smoked at least 100 cigarettes in their lifetime and who, at the time of disease onset, did not smoke at all. Never smokers were defined as those who reported never having smoked 100 cigarettes. Stress. Patients were classified as having stress-induced PPP if they experienced symptoms of anxiety in association with their skin eruption(s). Comparable with a previous study, patients needed to have anxiety diagnosed by a psychologist or psychiatrist using appropriate psychological tests.5 2
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Focal Infection. Patients were classified as having infection-induced PPP if they had evidence of tonsillitis, dental infection, or chronic sinusitis associated with their skin eruption. As in a previous study,6 patients needed to have a focal infection diagnosed through examinations such as a tonsil test, radiologic test, and blood test. TNF-a Inhibitor. Patients were classified as having TNF-a inhibitoreinduced PPP if they were receiving TNF-a inhibitor therapy at the time of disease onset. Associated Disorders SAPHO Syndrome. Patients were classified as having associated SAPHO syndrome if they had a personal history of SAPHO syndrome or clinical characteristics suggestive of SAPHO syndrome (ie, synovitis, acne, pustulosis, hyperostosis, or osteitis).8 Thyroid Disease. Patients were classified as having associated thyroid disease if they had a personal history of thyroid disease or blood test results suggestive of thyroid disease (eg, abnormal thyrotropin, abnormal thyroxine, or increased antimicrosomal or antithyroglobulin antibody levels).9,10 Gluten Sensitivity. Patients were classified as having associated gluten sensitivity if they had a personal history of gluten sensitivity or blood test results suggestive of gluten sensitivity (eg, increased antigliadin or tissue transglutaminase antibody levels).11 Type 2 DM. Patients were classified as having associated type 2 DM if they had a personal history of type 2 DM or blood test results suggestive of type 2 DM (eg, increased fasting plasma glucose or glycated hemoglobin A1c levels).12 Response to Treatment Patient response to therapy was assessed and classified as complete response, partial response, or no response. Resolution of old lesions with a lack of any new lesions indicated complete response. Healing of some lesions with reduced severity and frequency of flares indicated partial response. Persistence of
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lesions and development of new ones indicated no response. A disease-free period of at least 2 years indicated remission of disease. Literature Search We searched MEDLINE, 1946 to present, with the search term (Palmoplantar or [palm* adj plant*]) adj2 Pustulosis).tw. We limited the search to English-language articles, and we narrowed the study types to cohort, epidemiologic, and cross-sectional studies. Single case reports and small case series were excluded. RESULTS Clinical Characteristics The database search identified 215 patients, of whom 179 (83%) were female (Table 1). The mean age at PPP onset was 45.3 years (range, 4-83 years), and the mean total duration of PPP was 6.5 years (range, 0-59 years). Most patients (n¼129, 60%) had involvement of both palms and soles; 21 (10%) had nail involvement. Biopsy results compatible with a diagnosis of PPP were available for 83 patients (39%). Thirty patients (14%) had a personal history positive for minimal or mild psoriasis vulgaris, 7 (3%) had a positive family history of PPP, and 38 (18%) had a positive family history of psoriasis. The mean followup duration after PPP diagnosis was 1.6 years (range, 0-15.3 years). Remission of PPP occurred in 21 patients (10%). Figure illustrates the clinical appearance and classic distribution patterns of PPP. Etiologic Factors and Associated Disorders Most patients were either active smokers (n¼93, 43%) or former smokers (n¼72, 34%) (Table 1). At the time of diagnosis, 15 patients (7%) had anxiety and 9 (4%) had a focal infection. Nineteen cases (9%) were considered drug induced, mostly by TNF-a inhibitor therapy. Regarding comorbid conditions, 8 patients (4%) had SAPHO syndrome, 18 (8%) had thyroid disease, 3 (1%) had gluten sensitivity, and 21 (10%) had type 2 DM. Patch Testing Twenty-two of 215 patients with PPP (10%) underwent patch testing. Four of the 22 Mayo Clin Proc. n XXX 2017;nn(n):1-8 www.mayoclinicproceedings.org
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TABLE 1. Patient and Disease Characteristics Characteristic Patient/disease characteristics Age at disease onset (y), mean SD Female sex (No. [%]) Location of PPP (No. [%]) Palms Soles Palms and soles Skin biopsy consistent with PPP (No. [%]) Nail involvement (No. [%]) Personal history of psoriasis (No. [%]) Timing of psoriasis related to PPP (No. [%]) Before Synchronous After Inflammatory arthritis/arthralgia/joint pain (No. [%]) Family history of PPP (No. [%]) Family history of psoriasis (No. [%]) Disease duration at time of diagnosis (y), mean SD Total duration of PPP (y), mean SD Remission (No. [%]) Follow-up since diagnosis (y), mean SD Potential causative factors (No. [%]) Smoking Current Former Never Unknown Emotional stress (eg, anxiety) Focal infection Tonsillitis Dental infection Chronic sinusitis Drugs used TNF-a inhibitors Other medication (eg, b-blockers) Associated disorders (No. [%]) SAPHO syndrome Thyroid disease Hyperthyroidism (eg, Graves disease) Hypothyroidism Gluten sensitivity Type 2 diabetes mellitus
Value (N¼215) 45.314.6 179 (83) 29 57 129 83 21 30
(13) (27) (60) (39) (10) (14)
9 12 9 18 7 38 4.9 6.5 21 1.6
(30) (40) (30) (8) (3) (18) (8.2) (8.5) (10) (6.0)
93 72 33 17 15 9 2 0 7 19 17 2
(43) (34) (15) (8) (7) (4) (1)
8 18 7 11 3 21
(4) (8) (3) (5) (1) (10)
(3) (9) (8) (1)
PPP ¼ palmoplantar pustulosis; SAPHO ¼ synovitis, acne, pustulosis, hyperostosis, osteitis; TNF ¼ tumor necrosis factor.
patients were patch tested at an outside institution, and relevancy data to specific allergens were unavailable. Of the 18 patients patch tested at Mayo Clinic, 2 (11%) had negative patch test results, and the remaining 16 (89%) tested positive to at least 1 allergen. The most common positive reactions included gold sodium thiosulfate in 5 patients, fragrance mix in 4, and balsam of Peru, benzoic
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FIGURE. A-E, Palmoplantar pustulosis. Discrete (and sometimes coalescing) pustules admixed with brown macules on a background of erythema. Involved areas of the palms and soles are typically well-demarcated, bilateral, and often symmetrical. Note the evolution of yellow pustules to brown macules with resultant desquamating collarettes of scale. Part D is adapted from CMAJ,2 with permission.
acid, cobalt chloride, imidazolidinyl urea, methyldibromoglutaronitrile, or neomycin in 3. Of the 16 patients with positive patch test results, 6 (37.5%) had at least 1 relevant positive allergen; the remaining 10 (62.5%) had positive patch test results with either questionable or no relevance. Relevant allergens included bronopol, chromium chloride (2 patients), cobalt, colophony, diazolidinyl urea, DMDM hydantoin, D-phenylguanidine, formaldehyde, fragrance mix, imidazolidinyl urea, nickel, and quaternium-15. Treatment and Responses Most patients with PPP (n¼194, 90%) received topical corticosteroids (Table 2). The next most common treatments were phototherapy (n¼55, 26%) and systemic immunosuppressive or anti-inflammatory 4
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agents (n¼54, 25%), the most common of which were acitretin (24 patients) and methotrexate (20 patients). Several patients used more than 1 systemic agent for PPP. None of the patients required hospitalization. The responses to treatment are also shown in Table 2. Of the 194 patients treated with topical corticosteroids, 23 (12%) had complete response and 23 (12%) had partial response. Among the treatments that elicited complete response were phototherapy (11 of 55 patients; 20%), acitretin (6 of 24; 25%), methotrexate (2 of 20; 10%), and cyclosporine (2 of 4; 50%). Leflunomide, used for only 1 patient, also elicited a complete response. Several treatmentsddapsone (3 patients), etanercept (3 patients), and prednisone (5 patients)delicited no response only. We
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were unable to assess whether allergen avoidance in those with relevant contact allergens led to improvement of PPP due to confounding factors, including initiation of new treatment regimens or inadequate follow-up. DISCUSSION The study findings had similarities and differences compared with the published literature on PPP. Age at onset of PPP and the female predominance observed in these patients were comparable with data reported in previous studies (Table 3).1,15,16,18,20,22 Minimal plaque psoriasis occurred in 14% of the present patients, which corroborates previous studies1,3,15,17,18,20,21 reporting that the prevalence of psoriasis in patients with PPP is higher than that in the general population. However, the present prevalence of psoriasis in patients with PPP was most consistent with that of Eriksson et al18 and Asumalahti et al.20 Both studies by Brunasso et al1,3 found a much higher prevalence of psoriasis in patients with PPP: 73.18% and 61.6%. The present patients with PPP had a comparable prevalence of positive family history of psoriasis (18%) as in the published literature.10,16-18,21 The prevalence of nail involvement (10%) was lower than what has been previously reported (range, 30%-76%).1,3,17,21 Concomitant arthritis/arthralgia was found in 8% of the present patients, whereas other studies report a prevalence of 13% to 64%. The cause of PPP is not well understood. However, environmental factors (eg, smoking,1 stress,5 infection,6 and certain drugs7) are believed to contribute to the development or exacerbation of PPP. In the present study, 165 of 215 patients (77%) were current or former smokers. This is consistent with previous studies1,3,10,11,17-19,21 reporting a prevalence of ever-smoking in patients with PPP ranging from 42% to 100%. At the time of PPP diagnosis, 15 patients (7%) had anxiety and 9 (4%) had a focal infection. Nineteen cases (9%) were drug induced, mostly by TNF-a inhibitor therapy. No recent comparable studies have been published on these associations. Contact sensitivities have also been associated with PPP.24 In the present cohort, only a few patients diagnosed as having PPP underwent formal patch testing. Although most of Mayo Clin Proc. n XXX 2017;nn(n):1-8 www.mayoclinicproceedings.org
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TABLE 2. Treatment for Palmoplantar Pustulosis Treatment Topical corticosteroids
Patients (No. [%]) (N¼215)
Response to Treatment
194 (90)
23 CR 23 PR 39 NR 109 NA 11 CR 12 PR 9 NR 23 NA
Phototherapy
55 (26)
Any systemic agent Acitretin
54 (25) 24 (11)
Methotrexate
20 (9)
Tetracycline/doxycycline/minocycline
7 (3)
Adalimumab
5 (2)
Prednisone Cyclosporine
5 (2) 4 (2)
Dapsone
4 (2)
Etanercept Infliximab
3 (1) 3 (1)
Leflunomide Ustekinumab
1 (0.5) 1 (0.5)
6 CR 2 PR 8 NR 8 NA 2 CR 1 PR 10 NR 7 NA 1 CR 5 NR 1 NA 2 PR 2 NR 1 NA 5 NR 2 CR 1 NR 1 NA 3 NR 1 NA 3 NR 1 PR 1 NR 1 NA 1 CR 1 NA
CR ¼ complete response; NA ¼ not available; NR ¼ no response; PR ¼ partial response.
those tested had positive patch test results, many of the reactions were deemed by the treating dermatologist to be of either questionable or no relevance to the PPP. Future studies should be performed to elucidate a potential role of contact sensitivities in the development of PPP. Previous studies have suggested that some systemic abnormalities, such as thyroid disease,9,10 gluten sensitivity,11 and type 2 DM,12 may occur at increased frequency in patients with PPP. In a study by Gimenez-Garcia et al,10 the prevalence of thyroid disease in patients with PPP was as high as 18%; we found
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6 TABLE 3. Published Epidemiologic and Clinical Data on Palmoplantar Pustulosis Study Enfors and Molin15
Hellgren and Mobacken16
Burden and Kemmett17
Eriksson et al18
Hagforsen et al19
Asumalahti et al20
GimenezGarcia et al10
Michaelsson et al11
Miot et al21
Adisen et al22
Brunasso and Massone3
Brunasso et al1
Trattner et al23
Present study
Participants (No.) Age at onset (y) Sex, M/F (%) Positive smoking (%) Family history of psoriasis (%) Nail involvement (%) Arthritis (%)
248 20-60 22/78 NA 43
78 40-60 18/82 NA 10
50 NA 17/83 96 33
59 4212 12/88 95 22
45 NA 13/87 96 NA
156 48 15/85 NA NA
17 NA 24/76 100 12
63 NA 6/94 100 NA
25 NA 16/84 96 16
52 40 37/63 NA NA
19 NA 42/58 42 42
39 45 33/67 54 28
102 5314 85/15 94 27
215 45 17/83 77 18
NA 13
NA NA
30 NA
NA 42 (includes arthralgia)
NA NA
NA NA
NA 65
NA NA
76 48
NA NA
47 26
41 26
43 18
Psoriasis outside the palmoplantar area (%)
24 confirmed, 47 suspected
8
10
NA
18
Patients with psoriasis were excluded
NA
16
NA
73
62
19
10 8 (includes arthralgia and joint pain) 14
Study characteristic
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NA NA NA NA NA NA
NA NA NA NA NA NA
NA NA NA NA NA NA
NA 14 NA NA 8 6
NA 4 NA NA NA NA
NA NA NA NA NA NA
NA 18 6 12 NA NA
NA 11 3 8 30 8
NA NA NA NA NA NA
NA NA NA NA NA NA
NA NA NA NA NA NA
NA 2 0 2 NA NA
1 16 NA NA 1 19
4 8 3 5 1 10
Distribution of lesions (%) Palmar Plantar Both
6 14 61
12 27 61
NA NA NA
5 21 69
NA NA NA
NA NA NA
NA NA NA
NA NA NA
0 36 64
NA NA 73
32 21 47
15 18 67
11 13 56
13 27 60
DM ¼ diabetes mellitus; NA ¼ not available; SAPHO ¼ synovitis, acne, pustulosis, hyperostosis, osteitis. Adapted from Br J Dermatol,1 with permission.
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Associated disorders (%) SAPHO syndrome Thyroid disease Hyperthyroidism Hypothyroidism Gluten sensitivity Type 2 DM
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a prevalence of 8%. Michaelsson et al11 reported a prevalence of gluten sensitivity in patients with PPP of 30%, whereas the prevalence in the present study was 1%. The prevalence of type 2 DM in patients with PPP has been reported to be as high as 25% in a study by Hagforsen et al,12 but it was 10% herein. Thus, in the present study, these disorders were found less frequently than previously reported in the literature. These findings are corroborated by a recent cross-sectional study of 102 patients with PPP that also found a low frequency of associated SAPHO syndrome (1%) and celiac disease (1%).24 Treatment of PPP is often challenging. Topical corticosteroids used under occlusion, oral psoraleneUV-A, and acitretin have shown benefit in treating PPP.13 Most patients in the present study (n¼194, 90%) were treated with topical corticosteroids. None of the systemic therapies used in this cohort were uniformly effective in treating PPP. The present findings are especially relevant for general practitioners and internal medicine subspecialists for several reasons. The high frequency of smoking history among patients with PPP in this cohort reinforces the importance of counseling these patients on smoking cessation. Thoroughly reviewing medication lists for common culprits such as TNF-a inhibitors7 in patients suspected of having PPP is also paramount, particularly given the widespread use of TNF-a inhibitors for the treatment of a variety of commonly encountered conditions, including rheumatoid arthritis and inflammatory bowel disease. Palmoplantar pustulosis can be associated with rare but important autoinflammatory syndromes such as SAPHO syndrome, thus potentially serving as a key diagnostic clue for general practitioners and subspecialists who are evaluating patients with complex and undiagnosed multisystem systemic disease. Furthermore, the present study found a lower frequency of associated systemic diseases among patients with PPP than previously reported. These findings suggest that patients with PPP may not need to be routinely screened for systemic disorders, although additional studies are necessary to further elucidate the association between PPP and thyroid disease, gluten sensitivity, and type 2 DM. It is also important to manage patient Mayo Clin Proc. n XXX 2017;nn(n):1-8 www.mayoclinicproceedings.org
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expectations and discuss the challenging nature of treatment of PPP. Finally, knowledge of the clinical features of PPP can aid its prompt recognition and can guard against misdiagnosing it as a condition that is more commonly seen in the primary care setting, such as tinea pedis or dyshidrotic eczema. This study is limited by its retrospective design. As such, findings from this study should be interpreted cautiously and may not be generalizable to other populations. In particular, because data regarding comorbidities were not collected in a standardized manner, the study may have underestimated the frequency of association of systemic disorders with PPP. Furthermore, there was a lack of uniform treatment and follow-up data on patients in this cohort. Larger, welldesigned studies are warranted to make conclusive recommendations for patients with PPP.
CONCLUSION To our knowledge, this cohort represents one of the largest single-center series of PPP in the literature and, thus, provides useful clinical information for providers who care for patients with PPP. Specifically, we found that an association of PPP with systemic disorders (eg, thyroid disease, gluten sensitivity, and type 2 DM) was less frequent than previously reported. Similar to previous studies, an association between PPP and smoking was also observed; approximately threefourths of patients in this study were current or former smokers. Treatment regimens in this cohort varied considerably. Overall, approximately a fourth of patients with PPP in this study cohort required treatment with oral medications to manage their disease. Further studies are needed to elucidate consistently effective treatment regimens for PPP. ACKNOWLEDGMENTS This study’s contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. Dr Olazagasti and Ms Ma contributed equally to this work.
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Abbreviations and Acronyms: CR = complete response; DM = diabetes mellitus; NA = not available; NR = no response; PPP = palmoplantar pustulosis; PR = partial response; SAPHO = synovitis, acne, pustulosis, hyperostosis, and osteitis; TNF = tumor necrosis factor Grant Support: This study was supported in part by Clinical and Translational Science Award grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health. Correspondence: Address to David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
REFERENCES 1. Brunasso AM, Puntoni M, Aberer W, et al. Clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study. Br J Dermatol. 2013;168(6):1243-1251. 2. Wetter DA. Palmoplantar pustulosis. CMAJ. 2013;185(11):982. 3. Brunasso AM, Massone C. Can we really separate palmoplantar pustulosis from psoriasis? J Eur Acad Dermatol Venereol. 2010; 24(5):619-621. 4. Mrowietz U, van de Kerkhof PC. Management of palmoplantar pustulosis: do we need to change? Br J Dermatol. 2011;164(5): 942-946. 5. Saez-Rodriguez M, Noda-Cabrera A, Alvarez-Tejera S, et al. The role of psychological factors in palmoplantar pustulosis. J Eur Acad Dermatol Venereol. 2002;16(4):325-327. 6. Akiyama T, Seishima M, Watanabe H, Nakatani A, Mori S, Kitajima Y. The relationships of onset and exacerbation of pustulosis palmaris et plantaris to smoking and focal infections. J Dermatol. 1995;22(12):930-934. 7. Shmidt E, Wetter DA, Ferguson SB, Pittelkow MR. Psoriasis and palmoplantar pustulosis associated with tumor necrosis factora inhibitors: the Mayo Clinic experience, 1998 to 2010. J Am Acad Dermatol. 2012;67:e179-e185. 8. Kundu BK, Naik AK, Bhargava S, Srivastava D. Diagnosing the SAPHO syndrome: a report of three cases and review of literature. Clin Rheumatol. 2013;32(8):1237-1243. 9. Rosen K, Lindstedt G, Mobacken H, Nystrom E. Thyroid function in patients with pustulosis palmoplantaris. J Am Acad Dermatol. 1988;19(6):1009-1016. 10. Gimenez-Garcia R, Sanchez-Ramon S, Cuellar-Olmedo LA. Palmoplantar pustulosis: a clinicoepidemiological study: the relationship between tobacco use and thyroid function. J Eur Acad Dermatol Venereol. 2003;17(3):276-279.
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11. Michaelsson G, Kristjansson G, Pihl Lundin I, Hagforsen E. Palmoplantar pustulosis and gluten sensitivity: a study of serum antibodies against gliadin and tissue transglutaminase, the duodenal mucosa and effects of gluten-free diet. Br J Dermatol. 2007;156(4):659-666. 12. Hagforsen E, Michaelsson K, Lundgren E, et al. Women with palmoplantar pustulosis have disturbed calcium homeostasis and a high prevalence of diabetes mellitus and psychiatric disorders: a case-control study. Acta Derm Venereol. 2005; 85(3):225-232. 13. Marsland AM, Chalmers RJ, Hollis S, et al. Interventions for chronic palmoplantar pustulosis. Cochrane Database Syst Rev. 2006;(1):CD001433. 14. From the Centers for Disease Control and Prevention: annual smoking attributable mortality, years of potential life lost and economic costs: United States, 1995-1999. JAMA. 2002; 287(18):2355-2356. 15. Enfors W, Molin L. Pustulosis palmaris et plantaris: a follow-up study of a ten-year material. Acta Derm Venereol. 1971;51(4): 289-294. 16. Hellgren L, Mobacken H. Pustulosis palmaris et plantaris: prevalence, clinical observations and prognosis. Acta Derm Venereol. 1971;51(4):284-288. 17. Burden AD, Kemmett D. The spectrum of nail involvement in palmoplantar pustulosis. Br J Dermatol. 1996; 134(6):1079-1082. 18. Eriksson MO, Hagforsen E, Lundin IP, Michaelsson G. Palmoplantar pustulosis: a clinical and immunohistological study. Br J Dermatol. 1998;138(3):390-398. 19. Hagforsen E, Awder M, Lefvert AK, et al. Palmoplantar pustulosis: an autoimmune disease precipitated by smoking? Acta Derm Venereol. 2002;82(5):341-346. 20. Asumalahti K, Ameen M, Suomela S, et al. Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J Invest Dermatol. 2003;120(4):627-632. 21. Miot HA, Miot LD, Lopes PS, Haddad GR, Marques SA. Association between palmoplantar pustulosis and cigarette smoking in Brazil: a case-control study. J Eur Acad Dermatol Venereol. 2009;23(10):1173-1177. 22. Adisen E, Tekin O, Gulekon A, Gurer MA. A retrospective analysis of treatment responses of palmoplantar psoriasis in 114 patients. J Eur Acad Dermatol Venereol. 2009;23(7):814-819. 23. Trattner H, Blüml S, Steiner I, Plut U, Radakovic S, Tanew A. Quality of life and comorbidities in palmoplantar pustulosis: a cross sectional study on 102 patients [published online March 2, 2017]. J Eur Acad Dermatol Venereol. http://dx.doi.org/10. 1111/jdv.14187. 24. Yiannias JA, Winkelmann RK, Connolly SM. Contact sensitivities in palmarplantar pustulosis (acropustulosis). Contact Dermatitis. 1998;39(3):108-111.
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