Panniculitis is an umbrella term for a group of different inflammatory conditions found in the subcutaneous fat of the skin – and a rare result for ZZ individuals and other severely deficient phenotypes. Panniculitis may first appear as raised red spots. But when the spots become deep ulcers in the skin with tissue breakdown it is known as necrotizing panniculitis. This characteristic helps to distinguish it from other forms of panniculitis and its association with Alpha-1 Antitrypsin Deficiency.

In the 1920’s Frederick Parkes Weber and Henry Asbury-Christian separately reported cases of subcutaneous nodules and deterioration of the subcutaneous fat. They both described this as panniculitis. The discovery of Alpha-1 Antitrypsin Deficiency was in 1963. Ten years after the discovery of Alpha-1, the first case associating the two conditions was reported. Since this first finding, there have been 120 reported cases of Alpha-1-related panniculitis.

The workup for a panniculitis diagnosis recommends Alpha-1 testing, but because there is no diagnostic algorithm endorsed by any dermatological society, it is hard to know the true prevalence. Testing is also highly dependent upon the healthcare provider’s knowledge of Alpha-1 Antitrypsin Deficiency.

The age for pulmonary Alpha-1 diagnosis is usually between 40 and 50 years, though liver disease can occur in up to 30% of infants, children, and adults with the ZZ-genotype. The median age of diagnosis for panniculitis associated with the Alpha-1 ZZ-genotype is around 36 years. Based on case studies, this age is usually too young for individuals to have experienced significant pulmonary manifestations as fewer than a third of this age group have a diagnosis of lung disease. This realization suggests that the association between Alpha-1 Antitrypsin Deficiency and panniculitis is underdiagnosed in those that have yet to show lung or liver disease.

There is no clear cause for an outbreak of panniculitis. Ulceration, tender nodules, and sometimes lesions with discharge define these outbreaks. The distribution is not in any certain areas of the body, therefore there is no suggested classical presentation. A panniculitis outbreak is typically gradual. The intermittent episodes may develop into a systemic inflammatory condition leading to pleural effusions, thrombosis, or interstitial fluid build-up. If these conditions are untreated, they may lead to death.

Evidence shows that misfolded alpha-1 proteins in liver cells polymerize (join with other misfolded alpha-1 proteins over and over). Polymers inside the liver cell may get out of the liver cell, while other Z-alpha-1 antitrypsin in the blood may polymerize in the bloodstream. Then, the polymers go through the lungs and heart via the bloodstream where they land in fat tissues. When they get into fat tissues (and other places) these polymers bring neutrophils into the fat tissue and into the lungs. The neutrophils cause redness, pain, inflammation, and fat destruction. Fat destruction is called necrotizing panniculitis.

Panniculitis occurs equally in men and women. The National Heart, Lung, and Blood Institute (NHLBI) Registry of Individuals reported severely deficient and in SZ phenotypes in Alpha-1-related panniculitis. The treatment is the same for all severely deficiency phenotypes with necrotizing panniculitis. Since several skin conditions can lead to symptoms and signs similar to panniculitis, the diagnosis of panniculitis depends on a positive skin biopsy.

The rarity of Alpha-1-related panniculitis means a lack of affordable and effective therapies. The off-label use of IV-infused alpha-1 antitrypsin augmentation therapy shows efficacy as a single drug treatment and as a rescue therapy, although it usually requires higher doses than those used in treating Alpha-1 lung disease. Unfortunately, the off-label status and the requirement for higher doses can often lead to insurance denial, although multiple studies have demonstrated efficacy. Augmentation therapy is not available in all countries and, therefore, plasma exchange is a choice to consider. The evidence for efficacy of this therapy in Alpha-1-related panniculitis is not strong, but it may be an alternative. Antibiotics, chemotherapeutic agents, and Dapsone have also displayed varying levels of effectiveness in non-Alpha-1 panniculitis, so they may have some efficacy if augmentation therapy is not available. Recent studies show treatment with the immunosuppressant Anakinra for panniculitis outside of Alpha-1 Antitrypsin Deficiency has proven effective.

The true prevalence of Alpha-1-related panniculitis is still unknown, as diagnosis depends on awareness of the various presentations of diseases related to Alpha-1 Antitrypsin Deficiency, which is lacking even among pulmonologists. Recognizing that panniculitis is an Alpha-1 manifestation is crucial to managing accessibility to effective therapies.

References:

Alessandro N. Franciosi, James Ralph, Naoimh J. O’Farrell, Colm Buckley, Christian Gulmann, Marina O’Kane, Tomás P. Carroll, Noel G. McElvaney, Alpha-1 antitrypsin deficiency–associated panniculitis, Journal of the American Academy of Dermatology, 2021 https://doi.org/10.1016/j.jaad.2021.01.074

Gross, B., Grebe, M., Wencker, M., Stoller, J. K., Bjursten, L. M., & Janciauskiene, S. (2009). New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy. Dermatology (Basel, Switzerland), 218(4), 370–375. https://doi.org/10.1159/000202982

Panniculitis. (n.d.). Alpha -1 Foundation. Retrieved February 14, 2022, from https://www.alpha1.org/newly-diagnosed/learning-about-alpha-1/panniculitis