Always another worry for patients with hidradenitis suppurativa: Amyloid A amyloidosis

By Warren R. Heymann, MD, FAAD
March 27, 2024
Vol. 6, No. 13

My introduction to hidradenitis suppurativa (HS) was as a first-year dermatology resident on the inpatient dermatology service at Van Etten Hospital in the Bronx, caring for a most unfortunate woman with HS; she had secondarily infected pyoderma gangrenosum with a repugnant odor and a fungating anal squamous cell carcinoma (SCC) tracking up her spinal cord. Had this patient been my initial exposure to dermatology, you would not be reading this editorial, as I would have chosen internal medicine. Aside from SCC and systemic infections, amyloid A amyloidosis (AA, aka secondary AA amyloidosis, SAA) is a rare, but potentially life-threatening complication. This commentary will focus on HS and AA.

One of the titans of 20th-century dermatology, Sam Moschella (who passed away in 2022 at age 101 years), was the first to describe renal disease due to SAA in severe HS in a 37-year-old man also afflicted with acne conglobate and dissecting cellulitis. (1)

According to Papa and Lachman, AA is a rare systemic complication that can develop in any long-term inflammatory disorder by the pathogenic extracellular deposition of misfolded protein in a confirmation rich in beta-pleated sheets. “In AA amyloid, the fibrils are derived from serum amyloid A (SAA) protein, an acute-phase reactant synthetized largely by hepatocytes under the transcriptional regulation of proinflammatory cytokines [particularly TNF-a, IL-1 and IL-6]. In Western countries, the low incidence of chronic infections and improving treatments for autoimmune diseases have resulted in a falling incidence of AA amyloidosis, which is now less common than primary, amyloid light-chain (AL), or wild-type transthyretin (previously known as senile) amyloidosis. The kidney is the major involved organ, with proteinuria as first clinical manifestation. The extent of renal damage defines the patient prognosis, and renal biopsy is the commonest diagnostic investigation. Targeted anti-inflammatory treatment aimed at promoting a sustained and complete normalization of circulating SAA levels prevents progressive amyloid deposition and protects renal function, avoiding the need for renal replacement therapy. Novel therapies aimed at promoting clearance of existing amyloid deposits may be an effective treatment approach in the near future.” Rarely, AA may adversely affect the GI tract, heart, nerves, lungs, and thyroid gland. (2) AA of the gastrointestinal tract has been reported in HS. (3)

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HS is a chronic relapsing auto-inflammatory skin disease of the follicular epithelium, manifesting as recurrent and painful nodules and abscesses that may drain, potentially resolving with disfiguring scars and sinus tracts. Evidence suggests a vital role of proinflammatory cytokines, such as interleukin (IL)-1, IL-10, IL-17, and TNF-α in HS. Kridin et al evaluated 4417 patients with HS compared to 22,085 healthy controls (HC). The prevalence of amyloidosis was increased in patients with HS compared with the HC group [n = 7 (0.2%) vs. n = 2 (0.0%), respectively; OR = 17.5; 95% CI 3.6–84.4; P < 0.001]. In a multivariate analysis, HS was still associated with amyloidosis (OR = 11.2; 95% CI 1.3–94.5; P = 0.03). Their literature review identified 9 additional patients who developed AA during their course of HS, with 44.4% eventually having renal failure. Favorable outcomes were reported in patients managed by TNF-α inhibitors. (4) An intriguing hypothesis in response to this article was presented by Ilgen et al who noted that of the 17 reported cases of AA associated with HS, 11 were from either Turkey or Israel, questioning the possibility of whether screening for the MEFV mutations of the pyrin inflammasome (in Familial Mediterranean Fever) should be performed in patients with HS. (5)

Helvaci et al reported 8 HS cases complicated by AA. Six patients were male. The median age was 44 years, and the median disease duration before the amyloidosis diagnosis was 15.5 years. In a mean follow-up of 18 ± 6 months, the authors achieved favorable renal responses in 4 of the 8 cases (50 %) treated with either infliximab, adalimumab, or anakinra. All patients had a dermatologic response, with 4 complete and 4 partial remissions. The authors concluded, “We propose screening of severe HS cases with microalbuminuria/proteinuria and establishing a low threshold for kidney biopsy to achieve the goal of early diagnosis.” (6)

As previously mentioned, the cornerstone of managing AA is controlling the driving inflammatory disease, which diminishes SAA production, and may even result in the regression of amyloid deposition. (4) An example is a 40-year-old woman with severe, recalcitrant Hurley stage III HS complicated by renal, cardiac, and neurological AA, demonstrating improved skin and neuropathy with secukinumab. (7)

Proteinuria is the first clinical manifestation in almost 95% of patients with AA, whereas 50% present with nephrotic syndrome. (2) MacMahon et al report the case of a 61-year-old man with Crohn disease, stage III HS, acute renal failure (due to AA and tubulointerstitial nephritis), treated with adalimumab, who succumbed to aspiration pneumonia. The authors proposed a low threshold for screening chronic HS for AA with a simple dipstick urinalysis. (8)

Fortunately, AA due to HS is rare. Regardless, if the disorder is severe enough to warrant biological therapy, why not check a urinalysis when you are ruling out latent tuberculosis?

Point to Remember: For patients with chronic, severe hidradenitis suppurativa, a simple urinalysis can screen for renal amyloidosis, the most common manifestation of amyloid A amyloidosis.

Our expert’s viewpoint

Robert Micheletti, MD, FAAD
Associate Professor of Dermatology and Medicine at the University of Pennsylvania
Chief of Hospital Dermatology
Chief of Dermatology at Pennsylvania Hospital

Always another worry, indeed….Anyone who has cared for a patient with severe hidradenitis suppurativa (HS) can vouch for the severity of the skin disease. However, HS is much more than skin deep. Like rheumatoid arthritis or chronic HIV-infection, HS is a systemic inflammatory condition which increases the risk of numerous other important disease states. Experts recommend screening for no fewer than 19 associated conditions in those with HS, including debilitating skin diseases like dissecting cellulitis and pyoderma gangrenosum; psychiatric conditions like depression and substance abuse; metabolic disorders like diabetes mellitus and cardiovascular disease; and other inflammatory autoimmune processes like spondyloarthritis and inflammatory bowel disease. (9) Add to this ever-expanding literature systemic amyloidosis, a rare, direct complication of systemic inflammation, and the subject of this week’s “Insights and Inquiries.”

In agreeing with all of the excellent points raised above, I would only add the following perspective: For a chronic condition with such significant quality-of-life impact and so many important medical comorbidities, HS is vastly underdiagnosed and undertreated. A prospective multinational survey found that the average delay from symptom onset to HS diagnosis is 10.2 years. (10) Further, in a cross-sectional analysis, only 1.8% of patients with HS received a prescription for a TNF-inhibitor (adalimumab or infliximab), (11) despite approximately 33% of patients having moderate or severe HS, for whom biologic therapy is recommended according to evidence-based guidelines. (12) With such an alarming number of patients having longstanding, undertreated disease, the 15.5 years median HS disease duration before amyloidosis diagnosis is not far off for many…

Last, I concur with the recommendation to screen patients with chronic, severe HS for proteinuria with a simple urinalysis — for AA amyloidosis, sure, but also for chronic kidney disease associated with more mundane conditions like hypertension and diabetes, which are also independently associated with HS and together account for two-thirds of cases of chronic kidney disease. (13) As arguably the most important front-line clinicians for patients with hidradenitis, dermatologists must become acquainted with important comorbid conditions and support screening efforts and comprehensive care strategies wherever possible.

1. Moschella SL. Hidradenitis suppurativa. Complications resulting in death. JAMA. 1966 Oct 3;198(1):201-3. doi: 10.1001/jama.198.1.201. PMID: 5953172.

2. Papa R, Lachmann HJ. Secondary, AA, Amyloidosis. Rheum Dis Clin North Am. 2018 Nov;44(4):585-603. doi: 10.1016/j.rdc.2018.06.004. Epub 2018 Sep 7. PMID: 30274625.

3. Kochi S, Esaki M, Kurahara K. Secondary gastrointestinal amyloid A amyloidosis possibly caused by hidradenitis suppurativa. Dig Endosc. 2018 Sep;30(5):681. doi: 10.1111/den.13219. Epub 2018 Aug 8. PMID: 29933503.

4. Kridin K, Amber KT, Comaneshter D, Cohen AD. Amyloidosis in hidradenitis suppurativa: a cross-sectional study and review of the literature. Clin Exp Dermatol. 2020 Jul;45(5):565-571. doi: 10.1111/ced.14186. Epub 2020 Mar 25. PMID: 31989656.

5. İlgen U, Botsalı A, Vural S. Hidradenitis suppurativa and amyloidosis: a possible association with the pyrin inflammasome. Clin Exp Dermatol. 2021 Jul;46(5):949. doi: 10.1111/ced.14607. Epub 2021 Mar 17. PMID: 33577081.

6. Helvacı Ö, Güz G, Adışen E, Cevher SK, Güz G. Hidradenitis Suppurativa: a lesser-known cause of AA amyloidosis. Hippokratia. 2020 Jan-Mar;24(1):33-37. PMID: 33364737; PMCID: PMC7733359.

7. Tas-Aygar G, Gonul M, Ozcan I, Ayli MD, Ertoy-Baydar D. Secukinumab may be remedy for systemic amyloidosis findings secondary to hidradenitis suppurativa. Dermatol Ther. 2020 Nov;33(6):e14205. doi: 10.1111/dth.14205. Epub 2020 Sep 11. PMID: 32829493.

8. Mac Mahon J, Murray G, McCartney Y, Crowther S, Tobin AM, Molloy K. Systemic AA amyloidosis in hidradenitis suppurativa: Should we be screening? J Eur Acad Dermatol Venereol. 2023 May;37(5):e600-e601. doi: 10.1111/jdv.18807. Epub 2023 Jan 11. PMID: 36463423.

9. Garg A, Malviya N, Strunk A, Wright S, Alavi A, Alhusayen R, Alikhan A, Daveluy SD, Delorme I, Goldfarb N, Gulliver W, Hamzavi I, Jaleel T, Kimball AB, Kirby JS, Kirchhof MG, Lester J, Lev-Tov H, Lowes MA, Micheletti R, Orenstein LA, Piguet V, Sayed C, Tan J, Naik HB. Comorbidity screening in hidradenitis suppurativa: Evidence-based recommendations from the US and Canadian Hidradenitis Suppurativa Foundations. J Am Acad Dermatol. 2022 May;86(5):1092-1101.

10. Garg A, Neuren E, Cha D, Kirby JS, Ingram JR, Jemec GBE, Esmann S, Thorlacius L, Villumsen B, Marmol VD, Nassif A, Delage M, Tzellos T, Moseng D, Grimstad Ø, Naik H, Micheletti R, Guilbault S, Miller AP, Hamzavi I, van der Zee H, Prens E, Kappe N, Ardon C, Kirby B, Hughes R, Zouboulis CC, Nikolakis G, Bechara FG, Matusiak L, Szepietowski J, Glowaczewska A, Smith SD, Goldfarb N, Daveluy S, Avgoustou C, Giamarellos-Bourboulis E, Cohen S, Soliman Y, Brant EG, Akilov O, Sayed C, Tan J, Alavi A, Lowes MA, Pascual JC, Riad H, Fisher S, Cohen A, Paek SY, Resnik B, Ju Q, Wang L, Strunk A. Evaluating patients' unmet needs in hidradenitis suppurativa: Results from the Global Survey Of Impact and Healthcare Needs (VOICE) Project. J Am Acad Dermatol. 2020 Feb;82(2):366-376.

11. Orenstein LAV, Wright S, Strunk A, Garg A. Low prescription of tumor necrosis alpha inhibitors in hidradenitis suppurativa: A cross-sectional analysis. J Am Acad Dermatol. 2021 May;84(5):1399-1401.

12. Alikhan A, Sayed C, Alavi A, Alhusayen R, Brassard A, Burkhart C, Crowell K, Eisen DB, Gottlieb AB, Hamzavi I, Hazen PG, Jaleel T, Kimball AB, Kirby J, Lowes MA, Micheletti R, Miller A, Naik HB, Orgill D, Poulin Y. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part II: Topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019 Jul;81(1):91-101. doi: 10.1016/j.jaad.2019.02.068. Epub 2019 Mar 11.

13. Wang M, Li J, Li Y, Yao S, Zhao M, Wang C, Wu S, Xue H. The effects of hypertension and diabetes on new-onset chronic kidney disease: A prospective cohort study. J Clin Hypertens (Greenwich). 2020 Jan;22(1):39-46.

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