Download A case report and review of the literature

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
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 multiorgan 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.
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.
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.
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
dings included hyperkalemia (6.1 mmol/L; normal 3.4-5.0 mmol/L), azotemia (39 mg/dL;
g/dL), elevated creatinine (1.95 mg/dL; normal 0.50-1.20 mg/dL), and low-normal albumin
mal 3.5-5.2 g/dL). He had a normocytic anemia (Hgb 9.5 g/dL; normal 13.5-18.0 g/dL), and
15.2 K/µL; normal 4-10 K/µL) with increased neutrophils (86.2%; normal 48-76%) and
phocytes (7.3%; normal 0.8-4.1%). Serum renin was low normal at 0.4 ng/ml/hr (normal
.2-1.6 ng/ml/hr) with a low serum aldosterone (2.5 ng/dl; normal 4.0-31 ng/dl) and an elevated
l, suggesting hyporeninemic hypoaldosteronism. Inflammatory studies were notable for an
119 mm/hr) and CRP (152.2 mg/L), with no evidence of monoclonal gammopathy on SPEP,
ofixation or serum free light chain assay. Coagulation studies were notable for mildly
NR (1.3) and PTT (37.5 sec). He had markedly elevated NT-proBNP (2494 pg/mL), with
d troponin levels. According to records from an outside hospital, he was anti-nuclear antibody,
tor, and anti-citrullinated peptide antibody negative and had not been exposed to hepatitis B or
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 fibrinrelated 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 HSinduced AA amyloidosis has not been studied. In addition to antiinflammatory/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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