INTRODUCTION
PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum and Acne) is a rare autoinflammatory disease which is inherited in an autosomal dominant fashion through mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. These mutations produce a hyperphosphorylated PSTPIP1 protein and alter its involvement in the activation of the “inflammasome” involved in the production of interleukin-1β (IL-1β). Excessive production of IL-1β is a clear molecular characteristic of PAPA syndrome (1).
Autoinflammatory disease is similar to autoimmune diseases in its clinical characteristics, but they differ in the pathophysiological mechanism of the disease. In autoimmune diseases, antibodies are created against certain antigens in the body, and in autoinflammatory diseases, antibodies are not created, but in the field of genetic mutation, hyperphosphorylated proteins are produced that change its action in the activation of inflammasomes that are involved in the production of IL-1β. The autoinflammatory response occurs in several ways: unregulated production of cytokines by the inflammasome, intracellular stress, damage to regulatory pathways, increased NF-kappaB signalling, ubiquitination disorder, alteration of the interferon pathway, and complement activation. The emergence of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have enabled a better understanding of the basic innate immune pathways and pathogenetic mechanisms, thus creating new perspectives in targeted therapies. (2)
Two mutations were found in a protein called CD2-binding protein 1 (CD2BP1). This protein is part of the inflammatory pathway associated with other autoinflammatory syndromes such as: Familial Mediterranean fever (FMF), mevalonate kinase deficiency (hyperimmunoglobulin-D syndrome, HIDS), periodic fever syndrome, Muckle-Wells syndrome (MWS), multisystem inflammatory disease in neonates and familial cold autoinflammatory syndrome (FCAS). The exact mechanism of the manner in which the mutated gene causes the disease has not yet been established. (3)
In some cases, a person inherits a pathogenic variant from the parent who has the genetic disease. In other cases, the disease occurs due to a new pathogenic variant (de novo) in the causative gene and there is no family history of the disease. A child of a person with an autosomal dominant disease has a 50% (1 in 2) chance of inheriting the variant and the disease. Typically, children who inherit a dominant variant will have the disease, but they may be more or less affected than their parents. Sometimes a person can have a pathogenic variant of an autosomal dominant disease and show no signs or symptoms of the disease. (4)
CD2BP1, also known as proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1), is highly expressed in neutrophils. PSTPIP1 can form interactions with pyrin, a protein mutated in FMF. Mutations in PAPA syndrome result in hyperphosphorylation of the PSTPIP1 protein and change its participation in the activation of the “inflammasome”. This gene mutation places PAPA syndrome in the same pathogenic pathway as FMF. (5, 6)
These mutations were found both in PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne) and in similar syndromes such as PASH (pyoderma gangrenosum, acne and hidradenitis suppurativa) or PAPASH (pyogenic arthritis, acne, pyoderma gangrenosum and hidradenitis suppurativa). (6)
The characteristic form of PAPA syndrome is the classic triad that includes florid and painful flares of recurrent sterile arthritis, pyoderma gangrenosum and severe cystic acne, although only 25% of patients will have all three manifestations. (5)
Sterile pyogenic arthritis begins in the first decade of life, affects one joint and is progressively destructive in nature. It most often affects the ankles, knees, elbows and wrists. Exploratory joint surgery in PAPA syndrome shows non-specific inflammation of the joint and hypertrophic synovitis with marked synovial thickening and a high number of leukocytes found in joint fluid aspiration. (7)
Pyoderma gangrenosum lesions are less common, although they are an important feature of PAPA syndrome. Initially, they are characterised by small superficial erythematous violaceous papules, which develop into sterile pustules and aggressive ulcerative skin lesions mainly visible on the extremities. Biopsy of pyoderma gangrenosum skin lesions shows a predominance of neutrophilic inflammatory infiltrate in the dermis.
Most patients develop acne, usually a form of nodulocystic acne, which generally appears after puberty and persists into adulthood. Nodulocystic acne can cause scarring if left untreated. Some characteristics of this syndrome include the decrease of arthritis intensity over time followed by the exacerbation of the skin manifestations. (6-8)
Fever, fatigue, oral ulceration, proteinuria, haematuria and keratitis have also been described in patients with PAPA syndrome. (7, 8)
In addition to the clinical signs of the disease, genetic testing and evidence of the presence of a mutation on the chromosome 15 of the PSTPIP1/CD2BP1 gene is necessary to confirm the diagnosis, and this is the basis for confirming the diagnosis of PAPA syndrome. (4, 7, 8)
Considering the small number of described cases of PAPA syndrome in the world, the therapeutic approach to these patients is still insufficiently researched. Non-steroidal anti-inflammatory drugs did not show a significant effect, except for pain relief. Systemic corticosteroids, some DMARDs (Disease Modifying Antirheumatic Drugs) have shown their effectiveness in treatment, and recently biological drugs have become the drugs of choice, primarily TNF-alpha inhibitors (Tumour Necrosis Factor Alpha) and interleukin-1 inhibitors. Topical or intralesional corticosteroids are considered the first line of local therapy and can be applied to the active border of the ulcer. Topical calcineurin inhibitors such as topical tacrolimus are considered first-line therapy and have been used to treat pyoderma gangrenosum in several cases. (9-11)
CASE REPORT
In the case of our patient, who is now 25 years old, the first symptoms of the disease appeared in the second year of life with elevated body temperature and swelling and pain in the knees. The family history was negative for autoimmune diseases. This patient’s disease was originally thought of as infectious arthritis and he was treated for a year with different antibiotics administered orally and parenterally, with non-steroidal anti-inflammatory drugs, but this did not yield and significant results. When the patient reached the age of three, a diagnosis of juvenile idiopathic arthritis was made, and methotrexate was introduced into the therapy. Until the age of seven, the patient intermittently experienced the phases of exacerbation and remission of the disease. Exacerbations of symptoms occurred spontaneously and could not be linked to changes in lifestyle or exposure to environmental factors. In terms of clinical symptoms, swelling of the knees, elbows and ankles were the ones that occurred during that period. On several occasions, the patient’s joints were punctured, and intra-articular glucocorticoids were administered during therapy, which led to a short-term improvement in the patient’s condition. The disease was accompanied by increased inflammatory reactants, leukocytosis with a predominance of neutrophil granulocytes and anaemia. Immunological tests, including rheumatic tests and antinuclear antibodies, were negative. The HLA-B27 locus was not present. At the age of 10, the patient was introduced to etanercept therapy, which was administered to him during the course of one year, but no significant therapeutic response was achieved during this time. During that period, the patient started to notice the appearance of skin changes, and following that a skin biopsy was performed, which showed an inflammatory neutrophilic infiltrate, but the pathologist did not make a specific diagnosis at that time. The skin changes worsened over time. At the age of 12, the patient developed acne, which was attributed to puberty. Methotrexate therapy was continued until the age of 12, when the patient’s doctors decided to include infliximab in the therapy due to exacerbation of the disease and inadequate therapeutic response. The patient experienced partial improvement and withdrawal of symptoms, but during the administration of the fifth dose of the drug, a severe allergic reaction in the form of angioedema developed, and the drug was discontinued. After the washout period, adalimumab was included in the therapy, which was administered to the patient during the course of the following two years. After that, the patient and his family changed their place of residence, and the treatment was continued in another clinical centre. During the first examination by a paediatric rheumatologist in our clinical centre, based on the clinical features and the course of the disease, PAPA syndrome was suspected, and a skin biopsy was requested once again, which, according to the pathologist’s description, corresponded to pyoderma gangrenosum and could be differentially diagnosed as PAPA syndrome. Figures 1, 2, 3 and 4 show some clinical and radiographic features of the patient, which are consistent with the diagnosis of PAPA syndrome: a deformed right elbow, with atrophic scars after surgery, narrowing of the intra-articular space visible on X-ray, joint remodelling and effusion, pyoderma gangrenosum on the volar side of the forearm and nodulocystic acne on the face.
Genetic testing was indicated, and the blood was sent for analysis to the Department of Genetics at the Paediatric Hospital “Bambino Gesu” in Italy, and the existence of a pathological mutation of the PSTPIP1 gene, heterozygous on chromosome 15, substitution E748G<C in exon 11, which is a known mutation for PAPA syndrome, was proven. Then the biological drug adalimumab, during the administration of which the patient did not achieve a complete remission of the disease, was replaced by an inhibitor of interleukin-1, the drug called anakinra. After a month and a half of using the aforementioned drug (1 x 100 mg SC), there was a significant improvement in the skin manifestations, but in the laboratory findings there was a sudden increase in the values of liver transaminases, aspartate aminotransferase (AST) 115 (ref. values in the range of 0–31 U/L), alanine aminotransferase (ALT) 204 (ref. value in the range of 0–36 U/L) and increased alkaline phosphatase (ALP) 235 (ref. value in the range of 0–100 U/L). For this reason, the administration of the mentioned biological drug was suspended. Given that the level of transaminases did not decrease even after discontinuing the medication, the patient was referred for gastroenterohepatological treatment, where acute hepatitis B was confirmed after performing clinical tests (HBV DNA PCR – 456,413 copies/ml). The patient was not previously vaccinated against hepatitis B, but the markers for hepatitis B and C were regularly controlled according to the protocol before the inclusion of DMARDs and biological therapy, which were negative in the earlier period. In addition to that, as part of the gastroenterohepatological treatment, an immunological treatment was performed to rule out the development of autoimmune hepatitis, which was negative (antimitochondrial antibodies, AMA: neg., anti-smooth muscle antibodies ASMA: neg., liver kidney microsome type 1 antibodies, LKM1: neg., anti-liver cytosol 1 autoantibody, LC1: neg., anti-soluble-liver-antigen autoantibodies, anti-SLA: neg). In the following period, according to the recommendation of the gastroenterologist, all immunosuppressive therapy was discontinued and the antiviral drug Entacavir was included in the therapy, in a dose of 0.5 mg per day. During this period, the patient turned 18 and was referred to an adult rheumatologist for the continuation of his treatment. Several years of struggle with ailments for which we had no possibility of adequate treatment due to active hepatitis B followed. NSAIDs meant to be administered orally and parenterally, topical NSAIDs for joint pain and glucocorticoid creams for skin changes were prescribed.
In 2019, the patient started using isotretinoin in a dose of 3 x 10 mg, which led to a short-term improvement in his condition with acne, but in the long term the drug did not show a significant therapeutic effect, and it was discontinued. After the negative result of the HBV PCR test, a glucocorticoid, methylprednisolone, was reintroduced into the patient’s therapy in a minimal dose: at first it was administered at a dose of 8 mg per day, then 4 mg per day, while leflunomide tablets were also included in the therapy in a dose of 20 mg per day. Over time, the joint manifestations went into partial remission, but the skin changes remained in the stage of relapse, significantly impairing the patient’s quality of life and increasing the tendency to develop secondary infections. The chronology of the drugs used, and the leading diagnoses are shown in a graphic representation in Figure 5. After three negative HBV DNA PCR tests and completed antiviral therapy, the patient was prepared for the inclusion of biological therapy with the drug called canakinumab, which we expect to show an adequate therapeutic effect.
DISCUSSION
PAPA syndrome is an extremely rare disease, and to confirm the diagnosis, we need genetic testing and confirmation of the presence of a pathological mutation on the chromosome 15 along with corresponding clinical features. The disease most often begins with arthritis, and in the initial phase, due to the presence of pus in the joint, a bacterial infection is suspected, and patients are wrongly treated with antibiotics along with possible punctures and drainage of the joints. Unnecessary use of antibiotics and joint puncture may cause psychological and physical trauma to a child who has been misdiagnosed for many years. If an autoimmune disease is suspected, most often such cases are diagnosed as juvenile idiopathic arthritis. The absence of skin changes in the first stage of the disease is the reason due to which the correct diagnosis is not made in time. With the appearance of skin changes, primarily pyoderma gangrenosum, PAPA syndrome can be suspected because acne itself is usually associated with puberty. All patients with elements of pyogenic sterile arthritis and the appearance of skin changes, whether it be acne or pyoderma gangrenosum, should undergo genetic testing. The presence of other skin changes such as hidradenitis suppurativa in addition to acne and arthritis should lead us in the direction of PASHA syndrome or another entity from the group of autoinflammatory diseases. If the diagnosis of PAPA syndrome is confirmed, considering how destructive this disease can be to the joints and the skin, the treatment should be started with drugs that have shown the best effectiveness so far, namely interleukin-1 inhibitors or TNF-alpha inhibitors. The application of the IL-1β inhibitor, anakinra, primarily has a good effect on calming the inflammatory process in the joint, and remissions of skin changes have been proven after its application in some cases. If anakinra does not give an adequate therapeutic response, which is also recorded in the literature, the use of canakinumab is recommended, which has shown a better therapeutic effect on skin changes. Maintaining skin hygiene also plays a huge role in the treatment. Sterile wound dressing is necessary, because wounds can be the site of infection, either bacterial or viral. Given that we excluded other mechanisms of disease transmission, we believe that skin defects in our patient are responsible for hepatitis B virus infection. The use of topical glucocorticoids in the form of creams can show a short-term effect, but due to the effect on the skin itself, long-term use should be avoided. In addition to that, the use of systemic glucocorticoids should be considered only in cases of acute disease. Changes on the visible parts of the skin, and disease exhaustion have a great psychological impact on the patient, and it is necessary to provide such patients with psychological support. Often, these patients decide against having children because they are aware that this is a genetic disease. Deformities that occur on large joints as part of this syndrome sometimes require surgical correction in order to maintain the functionality of the joint or endoprosthetic replacement. Considering the different cases described in the literature, each patient with this syndrome requires an individual approach and lifelong adjustment of therapy.
CONCLUSION
PAPA syndrome is a complex entity, which we should keep in mind in terms of differential diagnosis, because cases of this disease occur sporadically in our climate, and remain undiagnosed for a long time. The disease is of a chronic nature, and after the diagnosis, the applied therapy sometimes does not yield successful therapeutic results. Comorbidities that may appear complicate the situation and make the treatment of these patients more difficult.
Acknowledgments: The authors report no acknowledgments.
Funding: For this work authors did not receive any funding.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / LITERATURA
<jrn>10. Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44(3):406–8.PubMedhttps://doi.org/10.1093/rheumatology/keh479</jrn>
<jrn>11. Brenner M, Ruzicka T, Plewig G, Thomas P, Herzer P. Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol. 2009;161(5):1199–201.PubMedhttps://doi.org/10.1111/j.1365-2133.2009.09404.x</jrn>
Figure 1 Deformed right elbow with atrophic scars after surgery
Figure 2 X-ray of the elbow joint, with visible narrowing of the intra-articular space with joint remodelling and effusion
Figure 3 Pyoderma gangrenosum on the volar side of the forearm
Figure 4 Facial nodulocystic acne
Figure 5 Graphic representation of prescribed therapy and diagnoses since 1999 until 2023