Opinion
EDITORIAL
Hidradenitis Suppurativa Current Progress and Future Questions Vanessa L. Pascoe, BA; Alexandra B. Kimball, MD, MPH
Hidradenitis suppurativa (HS) is a chronic, destructive, debilitating inflammatory skin disease characterized by recurrent, painful, deep-seated nodules and/or abscesses in intertriginous areas.1 It is also relatively common, with a reRelated article page 1273 ported prevalence as high as 1% to 4%.2,3 Nevertheless, HS has historically been an orphan disease, unclaimed by any specialty, owing, perhaps largely, to the treatment challenges it poses for physicians and the resulting nonadherence on the part of patients. Recently, however, there has been a surge in HS interest, as evidenced by the substantial increase in number of HS publications listed in PubMed, from around 30 in 2005 to approximately 100 in 2013. This increased activity highlights the possibility that more effective treatment for HS is at hand. Today, we have new therapies, new applications of existing therapies, and a growing understanding of the biology and genetics of both the disease and its spectrum of presentations. One obvious but important area of inquiry that derives from this recent progress is the examination of common HS comorbidities. It has long been established that patients with HS are more likely to be obese than the general population. There have also been fascinating syndromes described that include HS and that clearly demonstrate an important role of systemic inflammation. So, given our field’s highly successful exploration of associations of metabolic syndrome (MetS) and other comorbidities in psoriasis, an approach to evaluating HS is well established. There should be, however, some real differences between the HS and psoriasis populations. Psoriasis, at least in most of our studies of moderate to severe disease, affects men in their 40s. In contrast, HS is disease of younger women who, based on comparisons of moderate to severe cases in large clinical trials in both disease categories, may carry a higher obesity burden. These demographic differences alone should substantially affect the risk of myocardial infarction or other cardiovascular diseases across the 2 groups. As part of this ongoing line of inquiry, in the present issue of JAMA Dermatology, Miller et al4 report on HS and its association with MetS. Their cross-sectional analysis includes data from 32 hospitalized patients with HS, 326 population-based individuals with HS, and 14 851 population-based persons without HS in Denmark. The hospital cases were physician verified; the population cases were identified based on questionnaires; and the non-HS controls were from the general Danish population. Consistent with previous studies, the vast majority of patients with HS were women and were current or former smokers.5 jamadermatology.com
The authors define MetS according to a modified version of the National Cholesterol Education Program Adult Treatment Panel III criteria,6 which involves 4 key parameters: abdominal obesity, dyslipidemia, hypertension, and diabetes. They found a significant correlation in both the hospital and population HS groups with MetS, diabetes, general obesity, abdominal obesity, and low levels of high-density lipoprotein. The association between HS and hypertriglyceridemia was significant only for the population HS group, whereas the association between HS and hypertension was significant only for the hospital HS group. This finding is perhaps not surprising given the known obesity in the hospitalized population. When the authors adjusted for patient obesity or inflammatory load (measured by C-reactive protein [CRP] levels), the strength of the association between HS and MetS was reduced but remained significant. The median CRP level was higher in persons with HS (5.1 and 2.1 mg/L for the hospital and population groups, respectively) than in the non-HS population (1.4 mg/L). Interestingly, the association between HS and MetS or individual MetS parameters was not influenced by the degree of HS severity, with the exception of general obesity. This study has several strengths that distinguish it from others examining the association of HS and MetS. It evaluates both hospitalized and population-based patients with HS; it includes a large number of population-based cases and controls; and it analyzes the effects of possible confounding factors including inflammatory load (as measured by CRP level), physical activity, diet, and alcohol consumption. While activity level, diet, and alcohol consumption were not associated with HS, increased CRP level was associated with both HS and MetS. Two recent studies have similarly demonstrated a link between HS and MetS. In 2012, Sabat et al3 observed a significant correlation between HS and MetS in a hospital-based casecontrol study of 80 patients with HS. Similarly, earlier this year in a retrospective chart review, Gold et al7 found a higher prevalence of MetS in 366 patients with HS than in a control population of clinic patients. However, in contrast to the established association between higher obesity levels and worsening HS disease severity, neither study observed a correlation between HS severity and MetS.3,7 The association of HS with obesity is well established. However, this novel association between HS and MetS, of which obesity is but 1 component, highlights the potential risks of MetS and raises intriguing questions: What level of systemic inflammation do patients with HS experience? Is this inflammation a cause or an effect of the disease, and how much of it JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a New York University User on 05/19/2015
1263
Opinion Editorial
is independent of the obesity? What will be the downstream consequences of such prolonged systemic inflammation? Interestingly, when inflammatory marker levels have been evaluated in patients with HS, they have often been higher than those observed in patients with psoriasis, suggesting that the inflammatory burden of HS may be substantial. While Miller et al4 discovered higher median CRP levels in patients with HS than in controls, Grant et al8 observed baseline elevations in erythrocyte sedimentation rate and CRP levels in patients with HS. Furthermore, both values decreased with infliximab treatment. Another study found an association between CRP levels and HS disease severity: mean high-sensitivity CRP values were almost 4 times higher in patients with high-severity HS than in those with medium-severity disease.9 Adding further credence to the theory that patients with HS have substantial systemic burden, the disease has been associated with various systemic inflammatory conditions in addition to MetS. A recent systemic review of the literature demonstrated that HS was associated with diseases including Crohn disease (CD), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), pyoderma gangrenosum, PASH syndrome (pyoderma gangrenosum, acne, and suppurative hidradenitis), Adamantiades-Behçet disease, spondyloarthropathy, Dowling-Degos disease, and KID syndrome (keratitis-ichthyosis deafness).10 Such associations have led to the supposition that HS may belong to a group of autoinflammatory diseases characterized by recurrent noninfectious inflammatory episodes, the absence of auto-antibodies and antigen-specific T cells, and the presence of neutrophilic infiltrates.10 Crohn disease is the most well studied and widely reported systemic inflammatory disease associated with HS in this group. Case-series estimates of the co-occurrence range from 16% in patients with inflammatory bowel disease (CD and ulcerative colitis) to 38% in patients with CD alone.10 Furthermore, both HS and CD have shown clinical response to antiARTICLE INFORMATION Author Affiliations: Department of Dermatology, Massachusetts General Hospital, Boston (Pascoe, Kimball); Johns Hopkins University School of Medicine, Baltimore, Maryland (Pascoe); Department of Dermatology, Harvard Medical School, Boston, Massachusetts (Kimball). Corresponding Author: Alexandra B. Kimball, MD, MPH, Clinical Unit for Research Trials and Outcomes in Skin, Department of Dermatology, Massachusetts General Hospital, 50 Staniford St, Ste 240, Boston, MA 02114 ([email protected]). Published Online: September 17, 2014. doi:10.1001/jamadermatol.2014.1871. Conflict of Interest Disclosures: None reported. REFERENCES 1. Revuz J. Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2009;23(9):985-998. 2. Jemec GB, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol. 1996;35(2, pt 1):191-194.
1264
inflammatory treatment with anti–tumor necrosis factor (TNF) therapy.11 SAPHO syndrome, an inflammatory condition, has also been linked to HS in a handful of case reports.12 One thing that remains to be determined is the chronological relationship between obesity, systemic inflammation, and HS. The lack of correlation between HS disease severity and MetS thus far is important in sorting out these relationships, although of note, severity scoring in HS is undergoing substantial evolution at present. Moreover, one study observed no difference in metabolic alterations between patients with HS who had undergone surgical intervention to reduce disease burden and those who had not.3 Thus, it is possible that MetS may be an early or even primary event, rather than a secondary one, in patients with HS. These unanswered questions highlight the need to delineate the consequences of long-term systemic inflammation in patients with HS. These patients tend to be female. They also tend to be young: Sabat et al3 discovered that 40% of patients with HS who were younger than 35 years also had MetS compared with none of their respective age- and sex-matched controls. In this younger patient population, the downstream effects of chronic inflammation may manifest differently over the course of a lifetime. Physicians who treat patients with HS must be aware that, regardless of age or disease severity, these patients may have substantial underlying metabolic derangements that should be assessed. Additionally, this knowledge of systemic inflammation and the possibility that MetS and/or its components may be partly responsible for HS development can inform future HS treatment directions. Metformin has recently been reported as an effective treatment for HS13; similarly, treatment of psoriasis with TNF inhibitors appears to improve some of the cardiovascular markers and outcomes.14 Perhaps similar interventions targeting components of MetS will be important in helping to relieve HS symptoms and associated risks through reducing systemic inflammation.
3. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One. 2012;7(2):e31810. 4. Miller IM, Ellervik C, Vinding GR, et al. Association of metabolic syndrome and hidradenitis suppurativa [published online September 17, 2014]. JAMA Dermatol. 10.1001/jamadermatol.2014.1165. 5. Schrader AM, Deckers IE, van der Zee HH, Boer J, Prens EP. Hidradenitis suppurativa. J Am Acad Dermatol. 2014;71(3):460-467. 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497. 7. Gold DA, Reeder VJ, Mahan MG, Hamzavi IH. The prevalence of metabolic syndrome in patients with hidradenitis suppurativa. J Am Acad Dermatol. 2014;70(4):699-703. 8. Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with
moderate to severe hidradenitis suppurativa. J Am Acad Dermatol. 2010;62(2):205-217. 9. Crowley JJ, Mekkes JR, Zouboulis CC, et al. Association of hidradenitis suppurativa disease severity with increased risk for systemic comorbidities. Br J Dermatol. 2014;32(4):97-108. 10. Dessinioti C, Katsambas A, Antoniou C. Hidradenitis suppurativa (acne inversa) as a systemic disease. Clin Dermatol. 2014;32(3):397-408. 11. van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease. Br J Dermatol. 2010;162(1):195-197. 12. Steinhoff JP, Cilursu A, Falasca GF, Guzman L, Reginato AJ. A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome. J Clin Rheumatol. 2002;8(1):13-22. 13. Verdolini R, Clayton N, Smith A, Alwash N, Mannello B. Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol. 2013;27(9):1101-1108. 14. Hugh J, Van Voorhees AS, Nijhawan RI, et al. From the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2014;70(1):168-177.
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a New York University User on 05/19/2015
jamadermatology.com
EDITORIAL
Hidradenitis Suppurativa Current Progress and Future Questions Vanessa L. Pascoe, BA; Alexandra B. Kimball, MD, MPH
Hidradenitis suppurativa (HS) is a chronic, destructive, debilitating inflammatory skin disease characterized by recurrent, painful, deep-seated nodules and/or abscesses in intertriginous areas.1 It is also relatively common, with a reRelated article page 1273 ported prevalence as high as 1% to 4%.2,3 Nevertheless, HS has historically been an orphan disease, unclaimed by any specialty, owing, perhaps largely, to the treatment challenges it poses for physicians and the resulting nonadherence on the part of patients. Recently, however, there has been a surge in HS interest, as evidenced by the substantial increase in number of HS publications listed in PubMed, from around 30 in 2005 to approximately 100 in 2013. This increased activity highlights the possibility that more effective treatment for HS is at hand. Today, we have new therapies, new applications of existing therapies, and a growing understanding of the biology and genetics of both the disease and its spectrum of presentations. One obvious but important area of inquiry that derives from this recent progress is the examination of common HS comorbidities. It has long been established that patients with HS are more likely to be obese than the general population. There have also been fascinating syndromes described that include HS and that clearly demonstrate an important role of systemic inflammation. So, given our field’s highly successful exploration of associations of metabolic syndrome (MetS) and other comorbidities in psoriasis, an approach to evaluating HS is well established. There should be, however, some real differences between the HS and psoriasis populations. Psoriasis, at least in most of our studies of moderate to severe disease, affects men in their 40s. In contrast, HS is disease of younger women who, based on comparisons of moderate to severe cases in large clinical trials in both disease categories, may carry a higher obesity burden. These demographic differences alone should substantially affect the risk of myocardial infarction or other cardiovascular diseases across the 2 groups. As part of this ongoing line of inquiry, in the present issue of JAMA Dermatology, Miller et al4 report on HS and its association with MetS. Their cross-sectional analysis includes data from 32 hospitalized patients with HS, 326 population-based individuals with HS, and 14 851 population-based persons without HS in Denmark. The hospital cases were physician verified; the population cases were identified based on questionnaires; and the non-HS controls were from the general Danish population. Consistent with previous studies, the vast majority of patients with HS were women and were current or former smokers.5 jamadermatology.com
The authors define MetS according to a modified version of the National Cholesterol Education Program Adult Treatment Panel III criteria,6 which involves 4 key parameters: abdominal obesity, dyslipidemia, hypertension, and diabetes. They found a significant correlation in both the hospital and population HS groups with MetS, diabetes, general obesity, abdominal obesity, and low levels of high-density lipoprotein. The association between HS and hypertriglyceridemia was significant only for the population HS group, whereas the association between HS and hypertension was significant only for the hospital HS group. This finding is perhaps not surprising given the known obesity in the hospitalized population. When the authors adjusted for patient obesity or inflammatory load (measured by C-reactive protein [CRP] levels), the strength of the association between HS and MetS was reduced but remained significant. The median CRP level was higher in persons with HS (5.1 and 2.1 mg/L for the hospital and population groups, respectively) than in the non-HS population (1.4 mg/L). Interestingly, the association between HS and MetS or individual MetS parameters was not influenced by the degree of HS severity, with the exception of general obesity. This study has several strengths that distinguish it from others examining the association of HS and MetS. It evaluates both hospitalized and population-based patients with HS; it includes a large number of population-based cases and controls; and it analyzes the effects of possible confounding factors including inflammatory load (as measured by CRP level), physical activity, diet, and alcohol consumption. While activity level, diet, and alcohol consumption were not associated with HS, increased CRP level was associated with both HS and MetS. Two recent studies have similarly demonstrated a link between HS and MetS. In 2012, Sabat et al3 observed a significant correlation between HS and MetS in a hospital-based casecontrol study of 80 patients with HS. Similarly, earlier this year in a retrospective chart review, Gold et al7 found a higher prevalence of MetS in 366 patients with HS than in a control population of clinic patients. However, in contrast to the established association between higher obesity levels and worsening HS disease severity, neither study observed a correlation between HS severity and MetS.3,7 The association of HS with obesity is well established. However, this novel association between HS and MetS, of which obesity is but 1 component, highlights the potential risks of MetS and raises intriguing questions: What level of systemic inflammation do patients with HS experience? Is this inflammation a cause or an effect of the disease, and how much of it JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a New York University User on 05/19/2015
1263
Opinion Editorial
is independent of the obesity? What will be the downstream consequences of such prolonged systemic inflammation? Interestingly, when inflammatory marker levels have been evaluated in patients with HS, they have often been higher than those observed in patients with psoriasis, suggesting that the inflammatory burden of HS may be substantial. While Miller et al4 discovered higher median CRP levels in patients with HS than in controls, Grant et al8 observed baseline elevations in erythrocyte sedimentation rate and CRP levels in patients with HS. Furthermore, both values decreased with infliximab treatment. Another study found an association between CRP levels and HS disease severity: mean high-sensitivity CRP values were almost 4 times higher in patients with high-severity HS than in those with medium-severity disease.9 Adding further credence to the theory that patients with HS have substantial systemic burden, the disease has been associated with various systemic inflammatory conditions in addition to MetS. A recent systemic review of the literature demonstrated that HS was associated with diseases including Crohn disease (CD), SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), pyoderma gangrenosum, PASH syndrome (pyoderma gangrenosum, acne, and suppurative hidradenitis), Adamantiades-Behçet disease, spondyloarthropathy, Dowling-Degos disease, and KID syndrome (keratitis-ichthyosis deafness).10 Such associations have led to the supposition that HS may belong to a group of autoinflammatory diseases characterized by recurrent noninfectious inflammatory episodes, the absence of auto-antibodies and antigen-specific T cells, and the presence of neutrophilic infiltrates.10 Crohn disease is the most well studied and widely reported systemic inflammatory disease associated with HS in this group. Case-series estimates of the co-occurrence range from 16% in patients with inflammatory bowel disease (CD and ulcerative colitis) to 38% in patients with CD alone.10 Furthermore, both HS and CD have shown clinical response to antiARTICLE INFORMATION Author Affiliations: Department of Dermatology, Massachusetts General Hospital, Boston (Pascoe, Kimball); Johns Hopkins University School of Medicine, Baltimore, Maryland (Pascoe); Department of Dermatology, Harvard Medical School, Boston, Massachusetts (Kimball). Corresponding Author: Alexandra B. Kimball, MD, MPH, Clinical Unit for Research Trials and Outcomes in Skin, Department of Dermatology, Massachusetts General Hospital, 50 Staniford St, Ste 240, Boston, MA 02114 ([email protected]). Published Online: September 17, 2014. doi:10.1001/jamadermatol.2014.1871. Conflict of Interest Disclosures: None reported. REFERENCES 1. Revuz J. Hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2009;23(9):985-998. 2. Jemec GB, Heidenheim M, Nielsen NH. The prevalence of hidradenitis suppurativa and its potential precursor lesions. J Am Acad Dermatol. 1996;35(2, pt 1):191-194.
1264
inflammatory treatment with anti–tumor necrosis factor (TNF) therapy.11 SAPHO syndrome, an inflammatory condition, has also been linked to HS in a handful of case reports.12 One thing that remains to be determined is the chronological relationship between obesity, systemic inflammation, and HS. The lack of correlation between HS disease severity and MetS thus far is important in sorting out these relationships, although of note, severity scoring in HS is undergoing substantial evolution at present. Moreover, one study observed no difference in metabolic alterations between patients with HS who had undergone surgical intervention to reduce disease burden and those who had not.3 Thus, it is possible that MetS may be an early or even primary event, rather than a secondary one, in patients with HS. These unanswered questions highlight the need to delineate the consequences of long-term systemic inflammation in patients with HS. These patients tend to be female. They also tend to be young: Sabat et al3 discovered that 40% of patients with HS who were younger than 35 years also had MetS compared with none of their respective age- and sex-matched controls. In this younger patient population, the downstream effects of chronic inflammation may manifest differently over the course of a lifetime. Physicians who treat patients with HS must be aware that, regardless of age or disease severity, these patients may have substantial underlying metabolic derangements that should be assessed. Additionally, this knowledge of systemic inflammation and the possibility that MetS and/or its components may be partly responsible for HS development can inform future HS treatment directions. Metformin has recently been reported as an effective treatment for HS13; similarly, treatment of psoriasis with TNF inhibitors appears to improve some of the cardiovascular markers and outcomes.14 Perhaps similar interventions targeting components of MetS will be important in helping to relieve HS symptoms and associated risks through reducing systemic inflammation.
3. Sabat R, Chanwangpong A, Schneider-Burrus S, et al. Increased prevalence of metabolic syndrome in patients with acne inversa. PLoS One. 2012;7(2):e31810. 4. Miller IM, Ellervik C, Vinding GR, et al. Association of metabolic syndrome and hidradenitis suppurativa [published online September 17, 2014]. JAMA Dermatol. 10.1001/jamadermatol.2014.1165. 5. Schrader AM, Deckers IE, van der Zee HH, Boer J, Prens EP. Hidradenitis suppurativa. J Am Acad Dermatol. 2014;71(3):460-467. 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497. 7. Gold DA, Reeder VJ, Mahan MG, Hamzavi IH. The prevalence of metabolic syndrome in patients with hidradenitis suppurativa. J Am Acad Dermatol. 2014;70(4):699-703. 8. Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with
moderate to severe hidradenitis suppurativa. J Am Acad Dermatol. 2010;62(2):205-217. 9. Crowley JJ, Mekkes JR, Zouboulis CC, et al. Association of hidradenitis suppurativa disease severity with increased risk for systemic comorbidities. Br J Dermatol. 2014;32(4):97-108. 10. Dessinioti C, Katsambas A, Antoniou C. Hidradenitis suppurativa (acne inversa) as a systemic disease. Clin Dermatol. 2014;32(3):397-408. 11. van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease. Br J Dermatol. 2010;162(1):195-197. 12. Steinhoff JP, Cilursu A, Falasca GF, Guzman L, Reginato AJ. A study of musculoskeletal manifestations in 12 patients with SAPHO syndrome. J Clin Rheumatol. 2002;8(1):13-22. 13. Verdolini R, Clayton N, Smith A, Alwash N, Mannello B. Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol. 2013;27(9):1101-1108. 14. Hugh J, Van Voorhees AS, Nijhawan RI, et al. From the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2014;70(1):168-177.
JAMA Dermatology December 2014 Volume 150, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a New York University User on 05/19/2015
jamadermatology.com
