Rheumatology

The PAPA Spectrum and Related Diseases

At a Glance

PAPA syndrome belongs to the PSTPIP1-associated autoinflammatory disease spectrum. PAMI, PASH, PAPASH, PASS, and familial Mediterranean fever can look similar, but their symptoms, gene changes, and blood-test patterns differ, so specialists match the diagnosis and treatment to the full picture.

PAPA syndrome is part of a broader family of conditions known as PSTPIP1-Associated Autoinflammatory Diseases (PAAD) ^[1]. Because the PSTPIP1 gene plays such a central role in how the immune system handles inflammation, different mutations in this same gene can lead to a variety of overlapping symptoms. Understanding where your diagnosis fits on this spectrum can help your doctors tailor your treatment more effectively.

The PAAD Spectrum

While PAPA is the most well-known condition in this group, researchers have identified several other syndromes that share similar features but have key differences in how they affect the body.

PAMI Syndrome

PAMI syndrome (PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome) is a distinct condition with some shared features of PAPA ^[2]. While it includes the joint and skin issues seen in PAPA, it also typically involves:

Blood Count Issues: Patients often have chronic neutropenia (low white blood cells) and anemia (low red blood cells) ^[3].
Organ Enlargement: It is common to see an enlarged spleen (splenomegaly) or liver (hepatomegaly) ^[3]^[2].
Growth Challenges: Children with PAMI may experience slower growth or shorter stature compared to their peers ^[3].
High Zinc Levels: A unique feature of PAMI is extremely high levels of zinc and a protein called calprotectin in the blood. Elevated zinc or calprotectin is supportive of the diagnosis in the right context, rather than diagnostic on its own ^[2]^[3].

The PASH Spectrum: Adding Hidradenitis Suppurativa

Some patients have symptoms that overlap with a condition called hidradenitis suppurativa (HS)—painful, recurring lumps and abscesses in areas like the armpits or groin ^[4]. This has led to the naming of several “acronym” syndromes in the medical literature:

PASH: Includes Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis (but notably no arthritis) ^[4].
PAPASH: Includes Pyogenic Arthritis, Pyoderma gangrenosum, Acne, and Suppurative Hidradenitis ^[5].
PASS: Includes the features of PASH plus Spondylarthritis (inflammation that affects the spine and pelvic joints) ^[6].

These conditions are genetically complex; while some patients have PSTPIP1 mutations, others may have variations in different immune-related genes, suggesting that many different “glitches” can lead to this specific pattern of skin and joint inflammation ^[7]^[8].

Differentiating PAPA from Other Fever Syndromes

Because PAPA syndrome causes recurrent flares and fevers, it is sometimes confused with other “periodic fever syndromes,” most notably Familial Mediterranean Fever (FMF) ^[9]. However, the two conditions behave very differently:

Feature	PAPA Syndrome	Familial Mediterranean Fever (FMF)
Primary Symptoms	Long-lasting joint swelling and severe skin ulcers ^[10].	Short, self-limiting fevers (1–3 days) ^[9].
Pain Location	Intense pain in large joints (knees, elbows) ^[1].	Sharp pain in the abdomen or chest (serositis) ^[11].
Skin Issues	Deep ulcers (PG) and cystic acne ^[12].	Occasional “erysipelas-like” red rash on the lower legs ^[13].
Genetic Cause	Mutations in the PSTPIP1 gene ^[14].	Mutations in the MEFV gene ^[9].

Why “Clinical Overlap” Matters

It is common for a patient to not fit perfectly into one “box.” For example, some people have the PSTPIP1 mutation but only ever develop acne, while others have severe arthritis but never develop skin ulcers ^[10]^[15].

Doctors call this variable expression ^[1]. It means that the same genetic mutation can look different in different people, even within the same family. Because these conditions are rare and complex, treatment selection is not identical across this spectrum. Therapies for PAMI and PAPA are based largely on specialist experience and small case reports, and the best approach for one patient may not be appropriate for another ^[16]^[17]. Always work with a specialist who understands rare autoinflammatory diseases to determine the safest and most effective plan for your specific symptoms.

Common questions in this guide

What is the relationship between PAPA syndrome and the PAAD spectrum?

PAPA syndrome is one condition within the broader PSTPIP1-associated autoinflammatory disease spectrum, often abbreviated PAAD. Changes in the same gene can produce overlapping combinations of fever, joint inflammation, acne, and skin ulcers, so people may not fit one syndrome perfectly.

How can PAMI syndrome be distinguished from PAPA syndrome?

PAMI can share PAPA’s joint and skin problems but more often includes persistent neutropenia or anemia, an enlarged spleen or liver, and poor growth or short stature. Very high blood zinc or calprotectin can support PAMI when the symptoms fit, but neither result proves the diagnosis by itself.

What is the difference between PAPA syndrome and familial Mediterranean fever?

PAPA is linked to PSTPIP1 changes and commonly features prolonged joint swelling, large-joint pain, skin ulcers, or cystic acne. Familial Mediterranean fever is usually linked to MEFV changes and causes shorter fever attacks, often with abdominal or chest pain; a specialist may use the symptom pattern and genetic testing to tell them apart.

Do painful armpit or groin lumps mean I have PASH or PAPASH?

Recurrent painful lumps or abscesses in skin folds may indicate hidradenitis suppurativa, which can occur in PASH- or PAPASH-like patterns. PASH includes pyoderma gangrenosum, acne, and hidradenitis without arthritis, while PAPASH also includes pyogenic arthritis; one symptom alone cannot establish either diagnosis.

Can people with the same PSTPIP1 mutation have different symptoms?

Yes. This is called variable expression: one person may mainly have acne, while another may have severe arthritis or skin ulcers, even within the same family. Doctors therefore assess the full symptom history rather than relying on the gene result alone.

Which blood tests can help evaluate the PAPA spectrum?

A complete blood count can look for neutropenia or anemia, and zinc and calprotectin levels may support PAMI when the symptoms fit. These tests are not diagnostic on their own, so clinicians combine them with the examination, symptom pattern, and genetic testing.

How is treatment chosen when symptoms overlap several syndromes?

Treatment is individualized according to the dominant problems, such as joint inflammation, skin ulcers, acne, hidradenitis, or recurrent fever. Because evidence for PAPA and PAMI therapies is limited, a specialist in rare autoinflammatory disease should weigh the clinical findings and available treatment experience.

Get notified when new evidence is published on PAPA syndrome.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

References (17)

1
Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature.
Martinez-Rios C, Jariwala MP, Highmore K, et al.
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2
Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
Holzinger D, Fassl SK, de Jager W, et al.
The Journal of allergy and clinical immunology 2015; (136(5)):1337-45.
PMID: 26025129
3
PSTPIP1-Associated Myeloid-Related Proteinemia Inflammatory (PAMI) Syndrome: A Systematic Review.
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PMID: 37628706
4
Ancient friends, revisited: Systematic review and case report of pyoderma gangrenosum-associated autoinflammatory syndromes.
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PMID: 33305249
5
Pyoderma Gangrenosum, Acne, and Hidradenitis Suppurativa Syndrome: A Case Report and Literature Review.
Huang J, Tsang LS, Shi W, Li J
Frontiers in medicine 2022; (9()):856786 doi:10.3389/fmed.2022.856786.
PMID: 35402426
6
PASS Syndrome: An IL-1-Driven Autoinflammatory Disease.
Leuenberger M, Berner J, Di Lucca J, et al.
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PMID: 26919742
7
Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation.
Marzano AV, Borghi A, Meroni PL, Cugno M
The British journal of dermatology 2016; (175(5)):882-891 doi:10.1111/bjd.14691.
PMID: 27106250
8
Whole-Exome Sequencing in 10 Unrelated Patients with Syndromic Hidradenitis Suppurativa: A Preliminary Step for a Genotype-Phenotype Correlation.
Marzano AV, Genovese G, Moltrasio C, et al.
Dermatology (Basel, Switzerland) 2022; (238(5)):860-869 doi:10.1159/000521263.
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9
[Familial Mediterranean fever].
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10
Case Report: Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne: A Single-Center Experience and Literature Review.
Wang Y, Wu N, Yu K, Shen M
Frontiers in immunology 2021; (12()):735851 doi:10.3389/fimmu.2021.735851.
PMID: 34745107
11
FMF is not always "fever": from clinical presentation to "treat to target".
Maggio MC, Corsello G
Italian journal of pediatrics 2020; (46(1)):7 doi:10.1186/s13052-019-0766-z.
PMID: 31941537
12
PAPA Syndrome: Challenges in Achieving Long-Term Remission.
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13
Not easy-peasy to diagnose: familial Mediterranean fever unaccompanied by fever.
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14
Interrupting an IFN-γ-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne.
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15
Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases.
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16
Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome.
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17
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This page is for informational purposes only and does not constitute medical advice. A specialist should interpret your symptoms, genetic results, and blood tests when evaluating PAPA or a related syndrome.