Continuing Education Activity

Acne fulminans is a severe variant of inflammatory acne, predominantly identified in adolescent males. This condition is characterized by a sudden development of painful nodules and plaques that can advance to suppurative, ulcerative, and hemorrhagic lesions. Acne fulminans may present as only dermatological symptoms or alongside systemic manifestations, such as fever, malaise, arthralgia, myalgia, bone pain, osteolytic lesions, and erythema nodosum. When initiating treatment in patients with severe acne, high doses of isotretinoin may trigger acne fulminans. The condition is typically resistant to the usual acne antibiotics. The recommended treatment for acne fulminans is a combination of corticosteroids and isotretinoin. The lesions may result in severe scarring and subsequent negative psychological impacts on the affected patients. Prevention, early recognition, and prompt treatment significantly reduce the risk of scarring. This activity reviews the etiology, epidemiology, evaluation, and management of acne fulminans, highlighting the importance of a well-coordinated interprofessional team in delivering comprehensive care to these patients.

Objectives:

• Identify the clinical signs and symptoms of acne fulminans, including systemic manifestations.

• Assess the appropriate diagnostic workup necessary for evaluating acne fulminans.

• Implement evidence-based treatment protocols for patients with acne fulminans.

• Collaborate with other healthcare professionals to improve evaluation, management, and counseling for patients with acne fulminans.
  

Introduction

Acne fulminans, also known as acne maligna, is a rare skin disorder characterized by an acute, painful, ulcerative, and hemorrhagic clinical form of acne. This condition may or may not be associated with systemic symptoms, such as fever and polyarthritis. In some cases, the condition can also lead to bone lesions and laboratory abnormalities. Acne fulminans is often confused with acne conglobata. This condition is typically resistant to the usual acne antibiotics.[1][2][3] The term acne fulminans was introduced by Plewig and Kligman in 1975, highlighting its abrupt onset and severity. Traditionally, acne fulminans has been categorized into two types based on systemic involvement—acne fulminans and acne fulminans sine fulminans, the latter indicating the absence of systemic involvement. Recently, 4 clinical variations have been identified— acne fulminans with systemic symptoms, acne fulminans without systemic symptoms, isotretinoin-induced acne fulminans with systemic symptoms, and isotretinoin-induced acne fulminans without systemic symptoms.[4]

Etiology

As acne fulminans is a rare skin disorder, its etiology remains poorly understood. When initiating treatment in patients with severe acne, high doses of isotretinoin may trigger acne fulminans. In addition, elevated levels of testosterone may play a role in the development of the condition. Anabolic steroids are known to increase levels of sebum and the density of Propionibacterium acnes. Bodybuilders who use anabolic steroids can develop the condition rapidly. The belief is that the density of P acnes or related antigens triggers the immune system, leading to acne fulminans. Others believe that the condition may be autoimmune-mediated, as circulating immune complexes have been observed in some patients with acne fulminans.[5][6] In rare cases, reports have indicated that antibiotics, such as lymecycline and pristinamycin, can induce acne fulminans.[7]

Acne fulminans has a genetic component, but its inheritance is unclear. This condition has been observed in both identical and non-identical siblings. The skin disorder may be associated with several syndromes, including synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO) syndrome; pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome; and pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) syndrome. However, acne conglobata is more commonly associated with these syndromes compared to acne fulminans.[8]

Epidemiology

Acne fulminans constitutes less than 1% of the total acne cases. A recent narrative review identified 212 cases of acne fulminans in case reports and studies published in English and Spanish between 1977 and 2021.[9] However, it is likely to occur much more frequently in clinical practice, despite the modest number of cases reported.[7] The disorder typically affects young males, primarily those of White ethnicity, between the ages of 13 and 22. Most of these males have a prior history of acne. Acne fulminans is primarily encountered in Caucasian male adolescents (aged 13-22), around 2 years after the initial development of acne vulgaris. The disorder is less prevalent among females and individuals of East Asian descent.[4]

Pathophysiology

Although the pathogenesis of acne fulminans remains elusive, numerous hypotheses have been proposed, including genetic susceptibility, altered immune response, iatrogenic causes, hormonal changes, and viral infections as potential causative or precipitating factors.

• Genetic and hereditary factors may play a significant role in some patients. For example, acne fulminans has been observed in monozygotic twins and siblings with the same human leukocyte antigen (HLA)-B27. Furthermore, the HLAcw6 gene has been implicated in the condition.[10] A genetically predisposed deficiency in the phagocytic activity of polymorphonuclear leukocytes against Cutibacterium acnes (previously P acnes) in certain patients has been proposed as a contributing factor to the acute exacerbation observed at the onset of systemic isotretinoin treatment.[11]

• A generalized type III or IV hypersensitivity reaction to C acnes antigens has also been suggested; however, quantitative or qualitative immunoglobulin assays have not yielded any indications, and no specific circulating immune complex has been identified.[4] The role of an autoimmune reaction is supported by several factors observed in the patients, including the prompt clinical improvement that occurs after systemic corticosteroid administration, the increase in γ-globulins, and the reduction in C3 complement levels. In addition, the hypothesis of a common denominator in both disorders, potentially represented by an exaggerated autoimmune response, is supported by the association of acne fulminans with SAPHO syndrome, as described in certain reports. This connection may involve the release of certain cytokines, such as tumor necrosis factor-alpha (TNF-α), in genetically predisposed subjects, which is induced by C acnes.[12]

• The systemic use of isotretinoin, and infrequently doxycycline, erythromycin, lymecycline, oxytetracycline, methylprednisolone, or interferon-α-2a, has been documented as a probable triggering factor. Isotretinoin has been proposed to elicit a significant immune response in acne fulminans against the C acnes antigens that are abundantly produced due to the deterioration and rupture of the pilosebaceous duct epithelium. The elevation of neutrophil chemotaxis or interleukin-1ß production, along with increased angiogenic activity that fosters excessive granulation tissue development, may constitute additional potential triggering variables.[3] High dosages of androgens are also deemed responsible for the development of acne fulminans. The elevated prevalence noted in young individuals with hereditary genetic syndromes marked by abnormal growth, such as Klinefelter, Marfan, or Kallmann syndrome, or in bodybuilders seeking to enhance muscle mass has been associated with the consumption of substantial quantities of testosterone or anabolic-androgenic steroids, including testosterone enanthate, trenbolone acetate, drostanolone propionate, and methandrostenolone.[13] Androgens may function by enlarging sebaceous glands, augmenting sebum production, and elevating C acnes density. These processes collectively contribute to an overactivation of the inflammasome, which increases interleukin-1 beta (IL-1β) and TNF-α levels, promotes Th17 cell development, and hinders polymorphonuclear leukocytes.[4]

• The documented emergence of certain cases of acne fulminans following measles infection indicates that, in certain instances, infections caused by paramyxovirus morbillivirus may trigger the condition. This association is possibly due to the production of inflammatory cytokines.[14]

Histopathology

In the initial stages, skin biopsy reveals a dermal abscess characterized by dense granulocytic infiltration, sporadic histiocytic cells, and destruction of the follicular wall and sebaceous glands. Subsequently, typical observations include hemorrhagic necrosis in the epidermis and dense mixed cellular infiltration accompanied by hyalinization of thrombotic blood vessels in the dermis.[15] Bone biopsies may reveal inflammatory neutrophilic and mononuclear infiltrates accompanied by granulation tissue, resembling osteomyelitis.

History and Physical

Acne fulminans typically has a sudden onset, and the lesions are often ulcerative in nature. Patients may complain of fever and joint pain. These patients typically provide a history that the conventional antibiotics used for treating acne did not work. Most patients mention that they did have acne in the past. Acne fulminans is similar to acne conglobata with numerous inflammatory nodules on the trunk. The nodules are often painful to touch, ulcerative, hemorrhagic, and covered with crusts. Unlike acne conglobata, there are cysts and acutely inflamed lesions, but polyporous comedones are absent. Painful splenomegaly and erythema nodosum may be associated with systemic symptoms. Aseptic osteolytic lesions can impact the clavicle, sternum, and long bones of the extremities. The inflammatory arthralgia typically affects multiple joints, typically the knees, hips, and pelvis. Pain primarily manifests in major joints, including the iliac, iliosacral, and knees.[4] Patients with acne fulminans who have systemic symptoms may have a stooped posture due to bone and joint pain.

Evaluation

As the disorder may be associated with systemic symptoms, the diagnostic workup should include the following:

• Complete blood cell count: This test may reveal an elevated white blood cell count with a large percentage of neutrophils, anemia from chronic disease, and a leukemic-type reaction.

• There may be an increase in the erythrocyte sedimentation rate and C-reactive proteins.

• Liver function test

• Human chorionic gonadotrophin (blood or urine) in female patients

• Occasionally, hypoalbuminemia or an increase in alpha- or gamma-globulins occurs.

• Urinalysis may occasionally reveal microscopic hematuria, proteinuria, and other urinary abnormalities.

• An elevation in serum alkaline phosphatase levels indicates the existence of osteolytic lesions.

• Circulating immune complexes have been identified in patients associated with erythema nodosum.

• Bacterial cultures obtained from blood, joint fluid, and skin are often sterile.[16]

• Because of bone and joint pain, imaging studies are often performed. In the early stage, X-rays only show reactive changes. About 50% of patients demonstrate lytic lesions on a plain film X-ray, and the bone scan may show multiple areas of increased uptake. The lesions are destructive and often resemble acute osteomyelitis. Cultures of these bony lesions are often negative. Technetium-99 bone scintigraphy can show many areas of higher uptake. These areas are typically found in 70% of cases at the mid-shaft of the humerus, the median half of the clavicle, the acromion, and the mid-sternum.[17]

Treatment / Management

Acne fulminans does not respond to the traditional antibiotics used to treat the typical form of acne. Even when these agents are used, the response is slow and incomplete. The recommended treatment for acne fulminans involves a combination of corticosteroids and isotretinoin. Oral corticosteroids should be started first at high doses (0.5-1 mg/kg/d) for at least 2 weeks (at least 4 weeks if systemic symptoms) until lesions heal. Isotretinoin therapy can then be initiated at an initial dose of 0.1 mg/kg/d in combination with corticosteroids for 4 weeks. If no flare occurs during this period, the isotretinoin dose is maintained for an additional four weeks, whereas corticosteroid doses are gradually tapered. Increasing isotretinoin doses should then progressively reach a minimum dose of 120 mg/kg.[18][19][20][13] More severe cases can require hospitalization.[7] If prednisone cannot be discontinued from therapy and patients are on a high dose for over 2 to 3 months, or if steroids are contraindicated, steroid-sparing agents should be considered. In patients who remain adherent, relapses are rare. If a relapse does occur, a repeat cumulative dose of isotretinoin at 150 mg/kg is the recommendation. The treatment with isotretinoin lasts for many months, as the initial dose is low.

Other treatments include:

• In instances where corticosteroids or isotretinoin are contraindicated, or in cases of acne fulminans associated with erythema nodosum or ulcerative colitis, sulfones, particularly diaminodiphenylsulfone (dapsone), may be administered, relying upon negative serological results for glucose-6-phosphate dehydrogenase deficiency in males. Dapsone may be administered as monotherapy (often 50-75 mg/d, occasionally 100-200 mg/d) for a duration of up to 12 months or in conjunction with prednisolone or isotretinoin.[21]

• Immunosuppressive drugs have been used in combination therapy with systemic prednisone or isotretinoin in some instances. In cases of acne fulminans with pyoderma gangrenosum-like ulcerations, cyclosporine A at 5 mg/kg/d has been used in conjunction with prednisolone (10-40 mg/d).[22] In individuals with acne fulminans who experience significant and recurrent skeletal involvement, such as bilateral osteomyelitis, after weaning corticosteroids, the administration of methotrexate at 15 mg weekly with folic acid supplementation for up to 12 months may be advised.[23] The use of azathioprine as a steroid-sparing treatment at 1 to 3 mg/kg/d for 8 months has been proposed in cases of acne fulminans with circulating immune complexes and leukemoid reaction.[24]

• Anecdotal evidence indicates that acne fulminans, which is unresponsive to conventional therapies or linked to significant osteoarticular involvement—such as bilateral acute sacroiliitis, hip synovitis, or SAPHO syndrome—has shown promising outcomes with the use of recombinant IL-1 receptor antagonists, such as anakinra, or TNF-α inhibitors, such as infliximab and adalimumab.[25]

• Ustekinumab, an IL-12/23 inhibitor, and apremilast, a phosphodiesterase-4 inhibitor, have been used to treat acne fulminans.[26][27]

• Colchicine has been documented as effective as a steroid-sparing medication in 12 patients with acne fulminans when used in conjunction with a low dosage of isotretinoin.[28]

• Tetracyclines may potentially be regarded as a therapeutic option. The highest recommended doses include doxycycline 100 mg twice daily, minocycline 100 mg twice daily, or oxytetracycline 500 mg 4 times daily.[16] Another tetracycline worthy of consideration is sarecycline. Caution must be taken when concomitant isotretinoin is administered to avoid pseudotumor cerebri.[29]

• Topical medications should not be advised as the sole therapeutic choice due to their limited and variable efficacy. Topical high-potency corticosteroids, applied on ulcerative nodules twice daily for 7 to 10 days, may reduce inflammation. Additional supplementary topical therapies encompass washing with antibacterial agents and antiseptic lotions. Surgical debridement and regular warm compresses using 20% to 40% urea solutions are recommended before applying topical treatments to prevent crusting. For mild atrophic scarring, topical tretinoin cream is recommended at concentrations of 0.05%  to 0.1% on a nightly basis. For moderate-to-severe atrophic scarring, topical tretinoin 0.1% cream is recommended, combined with over-the-counter glycolic acid for 3 months. A 2015 study reported that 32 out of 35 patients (91%) showed improvement in scarring, as assessed by a qualitative scarring grading system, after 12 weeks of treatment with tretinoin 0.025% and glycolic acid 12%.[30]

• Intralesional steroids may be used for hypertrophic scarring. For pronounced atrophic scarring, in-office interventions are often more effective than topical treatments. Depending on the depth and type of scars, options include chemical reconstruction of skin scars using trichloroacetic acid (TCA CROSS), ablative lasers (fractional and non-fractional), non-ablative fractional resurfacing, punch grafting, and microneedling.[31]

• A pulsed dye laser is a non-ablative laser that can be safely administered with minimal downtime alongside isotretinoin therapy and should, hence, be considered for scarring. Although it has shown moderate effectiveness, adverse effects and pain remain significant concerns. Because the lesions are large, multiple treatments are required, and scarring and hypopigmentation are common complications.

• Photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) involves the application of red light at 635 nm with an irradiance of 100 mw/cm² for 20 min following a 3-h occlusion with 20% ALA on all affected regions, administered over a 5-week treatment period. This therapy has been combined with systemic isotretinoin at a dosage of 20 mg daily for 3 months to reduce follicular obstruction and hyperkeratosis.[32]

Finally, the treatment of these patients requires collaboration between a dermatologist and an internist. Retinoids are teratogenic, so women of childbearing age should exercise great caution when using them. A registry of all patients who receive retinoids exists. All women who receive therapy with isotretinoin should avoid getting pregnant for at least 1 month after discontinuing the drug.

Differential Diagnosis

The differential diagnoses for acne fulminans include the following:

• Acne conglobata: Acne conglobata is an uncommon and severe type of acne, predominantly affecting young men with a mean age of 20 to 25 years. This condition initially manifests as distinct follicular pustules, which then progress persistently into deep burrowing abscesses, painful nodules, and many polyporous comedones. Unlike acne fulminans, acne conglobata develops gradually and is not associated with systemic symptoms. Acne fulminans may occasionally be mistaken for acne conglobata. Although acne fulminans and acne conglobata are both severe forms of inflammatory acne characterized by painful, oozing, and hemorrhagic nodulocystic lesions, they can be distinguished by their clinical features. Acne conglobata is chronic and defined by the presence of polyporous comedones, whereas acne fulminans presents acutely and lacks this comedonal feature.

• Rosacea fulminans: Rosacea fulminans is a rare and severe type of rosacea that primarily affects women aged 15 to 46. The condition is marked by the abrupt emergence of inflammatory nodules, painful cysts, draining sinuses, abscesses, and edema, accompanied by red-cyanotic centrofacial erythema; comedones and extrafacial or systemic involvement are uncommon.[33]

• SAPHO syndrome: SAPHO syndrome is a chronic disease that is more frequently observed in women, with an average onset age of 32 years. Typically, acne in SAPHO syndrome is mild; nevertheless, in severe cases, it may be mistaken for acne fulminans. In contrast to acne fulminans, SAPHO syndrome may exhibit a prolonged interval between the emergence of cutaneous manifestations—such as acne and palmo-plantar pustulosis—and the onset of systemic manifestations, which encompass synovitis, hyperostosis, osteitis, fever, and weight loss.[16] The skeletal alterations identified in SAPHO syndrome, marked by osteitis and hyperostosis, are observed in any affected skeletal segments, regardless of the existence of associated cutaneous signs.

Prognosis

Recurrent cases of acne fulminans are extremely uncommon. Bone lesions generally resolve with treatment; however, persistent radiographic alterations, including sclerosis and hyperostosis, may persist. The acute inflammatory process can also lead to scarring and fibrosis.

Complications

Acne fulminans typically presents with highly inflammatory, painful lesions and nodules, most commonly affecting the back, chest, and face. These lesions may rapidly progress to ulcerative and suppurative forms, often accompanied by crusting hemorrhagic lesions. Over time, these lesions may lead to significant scarring (See Image. Acne Scarring on the Back). The majority of bone lesions associated with acne fulminans have been reported to resolve following treatment, with radiologic follow-up showing normal findings or slight sclerosis or thickening up to 15 years later.[34] Nevertheless, acne fulminans in pediatric patients has been rarely associated with chronic non-bacterial osteomyelitis, necessitating further evaluation by a rheumatologist.[35]

Deterrence and Patient Education

Patients should be instructed to contact their healthcare professionals promptly if their acne exacerbates during isotretinoin treatment. If the acne increases in size, number, or pain or starts to bleed, the patient requires re-evaluation. Certain patients may assume that acne must exacerbate before it ameliorates with isotretinoin treatment, thus resulting in their reluctance to pursue medical attention. Nonetheless, only a limited proportion of individuals undergoing isotretinoin treatment seems to experience an acne flare, which may occasionally be classified as acne fulminans. Early identification of the condition allows for treatment before progressing to a more severe disease state. In addition, because of the potential for scarring and post-inflammatory hyperpigmentation resulting from chronic erythema linked to acne fulminans, patients should be advised to apply non-comedogenic sunscreen daily, consider protective clothing, and practice sun avoidance. Educating patients about the elevated risk of scarring and strategies for prevention is essential for optimal outcomes.

Pearls and Other Issues

Currently, no standardized therapy exists for preventing the onset of acne fulminans. However, an initial dosage of isotretinoin ≤0.2 mg/kg/d has been shown to reduce acne exacerbation compared to 0.5 mg/kg/d.[36] Commencing with a reduced dosage may potentially diminish the risk of developing acne fulminans and should be contemplated when commencing isotretinoin therapy. Moreover, the concomitant use of isotretinoin medication with an antihistamine has been documented to diminish the incidence of isotretinoin-related acne exacerbations.[37] Consequently, integrating an antihistamine with conventional isotretinoin treatment may also potentially impede the onset of acne fulminans.

Enhancing Healthcare Team Outcomes

Acne fulminans is a serious systemic condition characterized by severely disfiguring skin lesions. Primary care providers and nurse practitioners should recognize this as a critical form of acne requiring a dermatologist referral. The majority of patients are affected negatively by poor cosmesis, which alters their quality of life and restricts them from participating in sports or social activities. Many patients may become withdrawn and socially isolated, highlighting the importance of offering psychosocial support. Mental health treatment and the use of antidepressants can be beneficial for these individuals. Suicidal ideation is prevalent in these patients, and close follow-up with a psychiatrist is highly recommended. The use of retinoids has not been shown to worsen the risk of depression or suicidal ideation.[15][38]

Clinicians, nurses, and pharmacists should educate patients on the disorder, including strategies to avoid triggering factors. Patients should be advised to keep their skin clean and dry, avoid smoking, and avoid applying unproven remedies such as oils and ointments. An interprofessional team approach, including clinicians, specialists, nurses with expertise in dermatology, and pharmacists, is essential to achieving the best outcomes.