Dermatology Online Journal

Hidradenitis suppurativa resulting in systemic amyloid A amyloidosis: A case report and review of the literature
Sasha D Girouard BA¹, Rodney H Falk MD², Helmut G Rennke MD³, Joseph F Merola MD⁴
Dermatology Online Journal 18 (1): 2

1. Harvard Medical School, Boston, Massachusetts
2. Cardiac Amyloidosis Program, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
3. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
4. Departments of Dermatology and Medicine (Division of Rheumatology), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

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Abstract

Hidradenitis suppurativa is a chronic, inflammatory disease of the follicular epithelium that presents as tender, subcutaneous nodules in an intertriginous distribution with sinus tract formation. Most commonly, hidradenitis suppurativa results in local complications, such as scarring and infection. However, systemic complications, such as anemia and arthropathies, have also been described. Herein, we report an unusual case of systemic amyloid A secondary to hidradenitis suppurativa. We describe a 39-year-old man with a long history of recurrent, tender, erythematous nodules in the axillary and anogenital regions, resulting in abscesses, sinus tract formation, and large areas of scarring. After 21 years of cutaneous disease with concurrent elevated systemic inflammatory markers, the patient was noted to have significant proteinuria. A kidney biopsy and immunostaining revealed deposits of amyloid A. Echocardiogram and electrocardiogram showed ventricular and atrial wall thickening with an appearance consistent with cardiac amyloid deposition. Systemic amyloid A amyloidosis is a serious, but rare, complication of chronic inflammatory disorders, including hidradenitis suppurativa, with potential multi-organ involvement including renal and cardiac manifestations. Amyloid A amyloidosis should be suspected in patients with chronic inflammatory cutaneous diseases who present with renal abnormalities, especially proteinuria or the nephrotic syndrome.

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Introduction

Originally described as a disorder of the apocrine gland, hidradenitis suppurativa (HS) is now recognized to be a chronic, recurrent inflammatory disease of the follicular epithelium that presents with tender subcutaneous nodules that coalesce or rupture to form abscesses and sinus tracts. HS often presents around puberty and most commonly affects intertriginous areas, such as the axillary, inguinal, perianal, perineal, and inframammary regions. The prevalence of HS is estimated to be between 1 percent to 4 percent; it predominantly affects women and is associated with smoking and body mass index [1]. Pathologically, HS develops from follicular hyperkeratosis, which leads to occlusion and possible secondary apocrine gland involvement, ultimately resulting in follicular rupture with subsequent inflammation, fibrosis, scarring, and secondary infection [2]; the specific instigating factor remains a matter of debate. Established disease may be quite refractory to treatment. However, therapeutic options include topical and systemic antibiotics, isotretinoin, antiandrogens, immunosuppressive therapy including intralesional and oral corticosteroids, and TNF-alpha antagonists. Procedural therapies including carbon dioxide laser ablation, radiotherapy, and surgical excision/debridement of areas of involvement are also commonly employed. HS has been associated with a number of complications including scarring, contractures, fistulization, infection, lymphedema, anemia, arthropathy, and squamous cell carcinoma; there is an increased risk in the overall incidence of malignancy [3, 4]. Here, we report an unusual case of severe refractory HS resulting in amyloid A (AA) amyloidosis.

Case report

A 39-year-old male presented with recurrent painful nodules, abscesses, and fistulas in the axillary and anogenital regions and laboratory findings of persistent proteinuria. His cutaneous disease first developed at age 18 with a tender, fluctuant nodule on the posterior neck and later progressed to painful, draining nodules on his chest, axillae, anogenital region, thighs, and low back. He was diagnosed with HS, and had no additional features of the follicular occlusion tetrad. Since its initial presentation his skin disease had never completely cleared, despite attempted treatment with isotretinoin, multiple oral antibiotics, intralesional steroids, excision and debridement, and laser therapy.

In 2001 he was enrolled in a trial of infliximab for recalcitrant HS and experienced improvement in his skin lesions after about one month of treatment. This treatment was terminated at the trial’s end. He developed a major flare between 2001 and 2002, accompanied by an unintended 60-pound weight loss over a 4-6 month period and supraventricular tachycardia, which was managed with ablation and a beta-blocker. He continued to develop new skin lesions and in 2003 he presented with leukocytosis (29 K/μL) and normocytic anemia (Hgb 6-7 g/dL), with low reticulocyte index, negative hemolysis labs, and normal iron studies. Because he did not respond to erythropoietin injections, a bone marrow biopsy was performed, but showed no evidence of malignancy or infiltration. Soon after, his skin disease flared severely and he was treated with extensive debridement of the thighs, axillae, and umbilicus with skin grafting. Following surgery, his leukocytosis normalized and anemia improved. Over the next year, he was treated with four major debridements and intermittent courses of antibiotics (tetracycline class and anti-MRSA agents, including linezolid and clindamycin), with some improvement of his skin disease. In 2008, significant proteinuria (3+) was identified during work-up for possible renal stones, and confirmed with a urine collection study (24-hour urine total protein of 5 g/24 hrs).

At the time of presentation, the patient was taking atenolol, allopurinol, omeprazole, propoxyphene, zolpidem, iron, and clonazepam as needed. On review of systems, he complained of subjective recurrent fevers, chills, unintended weight loss, diarrhea, anorexia, malaise, two-pillow orthopnea, increasing dyspnea on exertion, bilateral lower extremity edema, low back pain, and asymmetric chronic recurrent joint pain involving his wrists, ankles, and knees. He was physically debilitated from the severity of his skin disease. He lived with his wife and acknowledged a remote smoking history, but denied alcohol or drug use. His family history was significant for psoriasis and rheumatoid arthritis, but there was no family history of HS, inflammatory bowel disease, recurrent febrile illness, or other autoimmune diseases.

Figure 1
Figure 1. Hypertrophic scarring and hyperpigmentation in the anogenital region after a 21-year history of widespread recurrent tender, erythematous nodules, abscesses, and sinus tract formation status-post numerous medical interventions and surgical debridements

On examination, his blood pressure was 110/78 mmHg and his heart rate was 110 beats per minute. His temperature was 37.4°C and body weight was 75.3 kg. Our patient’s general appearance was thin and cachectic. Skin exam showed marked cribriform scarring of the posterior neck and bilateral axillae with scattered erythematous fluctuant subcutaneous nodules, sinus tracts, scarring, and hyperpigmentation on the buttocks, groin, and inner thighs, bilaterally, with malodorous discharge (Figure 1). Additionally, physical exam was notable for hyperdynamic apical impulse, a systolic flow murmur that increased with the Valsalva maneuver, hepatomegaly and marked splenomegaly, 1+ bilateral lower extremity edema to knees, and moderate bilateral knee effusions with no erythema, warmth, or tenderness, but with normal range of motion.

Laboratory findings included hyperkalemia (6.1 mmol/L; normal 3.4-5.0 mmol/L), azotemia (39 mg/dL; normal 6-23 mg/dL), elevated creatinine (1.95 mg/dL; normal 0.50-1.20 mg/dL), and low-normal albumin (3.5g/dL; normal 3.5-5.2 g/dL). He had a normocytic anemia (Hgb 9.5 g/dL; normal 13.5-18.0 g/dL), and leukocytosis (15.2 K/µL; normal 4-10 K/µL) with increased neutrophils (86.2%; normal 48-76%) and decreased lymphocytes (7.3%; normal 0.8-4.1%). Serum renin was low normal at 0.4 ng/ml/hr (normal supine range 0.2-1.6 ng/ml/hr) with a low serum aldosterone (2.5 ng/dl; normal 4.0-31 ng/dl) and an elevated plasma cortisol, suggesting hyporeninemic hypoaldosteronism. Inflammatory studies were notable for an elevated ESR (119 mm/hr) and CRP (152.2 mg/L), with no evidence of monoclonal gammopathy on SPEP, UPEP, immunofixation or serum free light chain assay. Coagulation studies were notable for mildly increased PT-INR (1.3) and PTT (37.5 sec). He had markedly elevated NT-proBNP (2494 pg/mL), with normal CK and troponin levels. According to records from an outside hospital, he was anti-nuclear antibody, rheumatoid factor, and anti-citrullinated peptide antibody negative and had not been exposed to hepatitis B or C.

Figure 2	Figure 3
Figure 2. This light microscopy image shows a glomerulus with moderate expansion of the mesangial areas by homogenous matrix (short arrows). A similar amorphous material also infiltrates the walls of small arteries and arterioles (long arrows). (PAS stain, Original magnification 400x). Figure 3A. PAS stain showing infiltration of the walls of the small arteries of the kidney cortex by amorphous, acellular material. 3B. Congo red stain revealing orange-red deposits in the vascular walls, which exhibit characteristic green birefringence under polarized light 3C and 3D. The material infiltrating the vascular walls is reactive for protein A by direct immunofluorescence microscopy. (Original magnification 400x).

Given his persistent proteinuria, a renal biopsy was performed. The biopsy revealed deposition of amyloid deposits predominantly in the small arteries and arterioles and to a lesser extent in the glomeruli (Figure 2). The deposits displayed apple green birefringence upon examination of Congo red-stained tissue under polarized light microscopy (Figure 3). By immunostaining the material was reactive for amyloid A and negative for kappa and lambda light chains, lysozyme, transthyretin, and fibrin-related antigens. In addition, advanced chronic changes of the parenchyma were visualized, including focal global glomerulosclerosis (73%) of glomeruli), focal tubular atrophy and interstitial fibrosis (60% of parenchyma), and moderately severe arterial and arteriolar sclerosis.

An echocardiogram was also performed and showed severe concentric left ventricular thickening, a hyperdynamic left ventricle, and left ventricular outflow tract obstruction. Right ventricular thickening with normal right ventricle function was observed. The appearance was consistent with amyloidosis.

The patient began treatment with adalimumab 40 mg SC once weekly, with marked improvement in his cutaneous disease, and fludrocortisone therapy normalized his chronically elevated potassium. Serum systemic inflammatory markers will be followed longitudinally with consideration for the addition of colchicine and other amyloid-directed therapies. The effect of treatment on renal and cardiac function has not yet been re-assessed, but our patient reports improvement in dyspnea and lower extremity edema. He is managed by a multi-disciplinary team including consultants in dermatology, nephrology, rheumatology, and cardiology.

Discussion

The differential diagnosis for chronic, recurrent painful nodules in an intertriginous distribution is listed in Table 1. Wherreas systemic inflammatory diseases, such as metastatic Crohn disease, can present with tender nodules, several infectious causes may manifest similarly. This case is most consistent with a diagnosis of HS given its characteristic onset at puberty, time course, distribution, and refractoriness to multiple treatment modalities.

Amyloid A amyloidosis is a rare complication of HS, which has been described in a limited number of case reports [5, 6, 7]. An early report by Moschella in 1966, details the case of a man who died from complications of HS, including amyloidosis and hypoalbuminemia [5]. More recently, Titze et al described a case of a 62-year-old man with a 25-year history of chronic HS, who developed AA amyloidosis diagnosed by colon biopsy, that presented with diarrhea, edema, bilateral pleural effusions, hypoalbuminemia, and proteinuria [6]. Another case reported a 39-year-old man with a 9-year history of relapsing HS, who presented with proteinuria and hypoalbuminemia. He was found to have AA amyloid deposits in a kidney biopsy without evidence of cardiac involvement on echocardiogram [7].

The pathogenesis of AA amyloidosis results from the overproduction of serum amyloid A, an acute-phase protein primarily produced in the liver. In chronic inflammatory states the protein fibrils deposit and accumulate in the extracellular matrix of tissues. Once deposited, this proteinaceous material does not elicit a significant inflammatory reaction, but interferes with the architecture and function of the surrounding cells. Diagnosis is made by tissue biopsy; the regular beta sheet structure of the deposits display a unique green birefringence by polarized light microscopy when stained with Congo red dye and immunohistology is used to identify the specific subunit protein.

Amyloid A amyloidosis is a multi-organ progressive disease that most commonly presents with kidney involvement, but may also affect the cardiovascular, musculoskeletal, and gastrointestinal systems. Kidney pathology may present as asymptomatic proteinuria or clinically apparent nephrotic syndrome and can progress to kidney failure. Cardiac involvement is rare and is usually asymptomatic [8]. When present, the echocardiographic appearance is identical to other forms of cardiac amyloidosis including on rare occasions, as in our case, the unusual manifestation of dynamic left ventricular outflow tract obstruction [9]. Arthropathy can result from amyloid deposits in joints and surrounding tissue and amyloid infiltration may lead to pseudohypertrophy of the muscles. In the skin, AA amyloidosis manifests as waxy thickening, easy bruising, and subcutaneous nodules or plaques. In the gastrointestinal system, AA amyloidosis can cause hepatosplenomegaly, bowel perforation, and GI hemorrhage, related to fragility and decreased distensibility of blood vessels from deposition of protein AA along the blood vessel wall. Additionally, amyloidosis has been associated with impaired coagulation and anemia. Mixed sensory and motor peripheral neuropathy and autonomic neuropathy have also been described, but are more common in primary amyloidosis.

Without effective treatment, AA amyloidosis can be fatal, with end stage kidney failure as a predominant cause of death. The mean survival from diagnosis is 133 months. Factors associated with poor prognosis include older age, a reduced serum albumin concentration, end-stage kidney failure at baseline, and elevated serum amyloid A concentration [10]. The cornerstone of management of AA amyloidosis is to control the underlying inflammatory disease. The treatment of HS may involve antibiotics, isotretinoin, antiandrogens, immunosuppression, carbon dioxide laser ablation, and surgical approaches. In the case reported herein, the patient responded well to repeated surgical debridement, although only as a temporizing measure. Significant benefit was achieved with the anti-TNF-α agents, infliximab and adalimumab. An additional case report documented an efficacious response to infliximab in a patient with AA amyloidosis secondary to HS [7] and several studies have demonstrated success with anti-TNF-α agents in the treatment of HS [11], although adverse effects such as infection and malignancy are of concern. A systematic review of the literature reported the anti-TNF-α agents, etanercept, infliximab, and adalimumab, may be effective in treatment of HS and produce minimal side effects. However, the study is limited by positive publication bias, a lack of standardized treatment regimens, and non-uniform reporting of outcomes [11]. Randomized, controlled trials are needed to more definitively evaluate the role of TNF-α inhibitors in the treatment of HS. Interestingly, elevated levels of TNF-α as well as IL-1 have been documented in patients with HS [12]. One case report describes successful treatment of HS with the IL-1 antagonist, anakinra [13].

Although the treatment of AA amyloidosis primarily involves controlling the underlying inflammatory disease, therapies aimed at reducing the deposition and stability of amyloid A are alternative approaches. Strategies to decrease the amyloid A protein load include anti-inflammatory/immunosuppressive therapy, anti-cytokine therapy, and innovative therapies with specific, small molecule inhibitors. Several case reports and case series have documented success in treating AA amyloidosis with cytotoxic and immunosuppressive agents, such as azathioprine, chlorambucil, methotrexate, and cyclophosphamide [14, 15, 16, 17]. Additionally, colchicine has been an effective treatment in patients with AA amyloidosis secondary to familial Mediterranean fever [18]. The chemical solvent, dimethylsulfoxide, has been shown to exhibit anti-amyloid activity in cases of AA amyloidosis secondary to rheumatoid arthritis or Crohn disease [19]. However, the efficacy of these modalities for HS-induced AA amyloidosis has not been studied. In addition to anti-inflammatory/immunosuppressive therapies, anti cytokine modalities, including TNF-α, IL-1β, and IL-6 blockade, have been shown to be effective in treatment of AA amyloidosis [20]. As previously mentioned, multiple case reports and case series have documented successful treatment of HS with TNF-α inhibitors [13] and one case report specifically details effective treatment of HS-induced AA amyloidosis [7]. Finally, experimental therapies that interfere with fibril formation are currently under development. For instance, eprosidate, a small sulfonated molecule designed to inhibit amyloid fibril polymerization and tissue deposition of fibrils by interfering with the glycosaminoglycan binding site on amyloid fibrils, was recently shown to slow progression of AA amyloid-related renal disease in a randomized controlled trial [21].

In summary, we have presented the case of a 39-year-old man with a twenty-one year history of hidradenitis suppurativa, diagnosed with AA amyloidosis after presenting with persistent proteinuria. The patient complained of constitutional symptoms, diarrhea, dyspnea, orthopnea, edema, and arthropathies and on exam, had tender, erythematous fluctuant nodules, predominantly in the genito-femoral region. Additional findings were tachycardia, hepatosplenomegaly, lower extremity edema, and moderate bilateral knee effusions. Laboratory findings were significant for azotemia, elevated creatinine, leukocytosis, normocytic anemia, elevated inflammatory markers, coagulation abnormalities, and an elevated NT-proBNP. Echocardiogram and electrocardiogram showed an infiltrative cardiomyopathy and the kidney biopsy confirmed a diagnosis of AA amyloidosis with evidence of chronic kidney injury. Based on the available literature, our patient has a poor prognosis, which can only be improved by more effectively controlling his HS. In the past, he responded to infliximab and surgical debridement; he currently has experienced improvement with adalimumab. Alternative therapies, such as oral retinoids, antibiotics, and carbon dioxide laser ablation, have not been helpful in controlling our patient’s HS.

In conclusion, although rare, patients with HS may develop systemic amyloidosis. The development of AA amyloidosis most commonly involves the kidneys and presents with proteinuria. Thus, it is important for clinicians to consider a diagnosis of amyloid in patients with HS and other chronic cutaneous inflammatory diseases, who present with renal or cardiac abnormalities. In certain cases, it may even be appropriate to periodically screen patients with chronic inflammatory cutaneous disease, such as HS, with urinalyses. Cardiac and musculoskeletal involvement as seen in our patient, is less common in AA amyloidosis. Finally, anti-TNF-α agents, such as infliximab and adalimumab, may be promising new therapies for HS and may prove to be particularly useful in patients with AA amyloidosis. However, prospective controlled trials are needed to evaluate the efficacy and safety of these treatments in patients with HS. By continuing to investigate the pathogenesis of HS, advances in treatment should eventually lead to earlier, more efficacious therapy for patients with HS and prevent potentially fatal complications such as AA amyloidosis.

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