Rheumatology Advance Access originally published online on March 9, 2006
Rheumatology 2006 45(9):1140-1143; doi:10.1093/rheumatology/kei178
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Peculiarities of PAPA syndrome
Rheumatology Department, Level 3, North Shore Hospital, Auckland, New Zealand.
Correspondence to: M. Corkill. E-mail: Michael.Corkill{at}waitematadhb.govt.nz
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Abstract |
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Objectives. To describe a family from New Zealand with the pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, an autoinflammatory, variably expressed, erosive destructive form of arthritis.
Methods. Information was gained through medical records and interviews of the affected patients and wider family. DNA sequencing was performed at Seay Center for Musculoskeletal Research Texas Scottish Rite Hospital for Children.
Results. Five patients were affected over three generations with an E250Q mutation found on the CD2BP1 gene on chromosome 15. Common features included a severe, pauciarticular-onset, destructive peripheral arthritis, beginning at ages 5, 5, 2, 3 and 1
years. This combination marked cervical ankylosis (in two members), micrognathia and a more severe phenotype is unique. A third-generation family member treated early with DMARDs is following a less severe course. The skin involvement was variable, all with degrees of acne from puberty, though only one patient displayed pyoderma gangrenosum. A clear pattern of the arthritis switching off in adolescence and the triggering of skin disease was observed.
Conclusions. Differing degrees of joint destruction, and cervical ankylosis in this family with the E250Q mutation demonstrate PAPA syndrome's variable expression. Further understanding of this rare condition and its pathway may allow better targeting of treatments, not just for families with this specific syndrome but also for other, more common, forms of arthritis.
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Introduction |
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We report a New Zealand family series with the pyogenic arthritis, pyoderma gangrenosum (PG) and acne (PAPA) syndrome, an erosive destructive form of arthritis arising from two known mutations in the CD2 binding protein 1 (CD2BP1) gene on chromosome 15. This variably expressed syndrome, arising in our family from the E250Q mutation, displayed peculiarities of phenotype in our family. A clear transition in adolescence from inflammatory arthritis to skin disease is evident. Further understanding of this particular predilection may allow better targeting of treatments, not just for families with this specific syndrome but also for other more common forms of arthritis.
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Case report |
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We care for four affected members of a family in New Zealand (Fig. 1a). The ages and clinical features of the affected family members are shown in Table 1. All developed an asymmetrical destructive inflammatory polyarthropathy between 18 months and 5 yr of age. In each case a single memorable monoarticular traumatic event appeared to trigger recurrent, highly neutrophilic synovial inflammatory episodes (Fig. 1d). Cultures of drained fluid were sterile, and serum rheumatoid factor and antinuclear antibodies were negative. The inflammatory component of the joint disease fluctuated, with variable periods of inactivity and eventual remission around the late teens. Non-axial joints, particularly the knee, elbow, shoulder and hands, were most severely affected. Contributing to the characteristic appearance of this family is micrognathia, and two family members had cervical spine ankylosis (Fig. 1c). Acne was severe in the two women and mild in the two eldest males, and is developing currently in the youngest member. Definite PG has occurred in only one member. DNA from two family members (II-1 and III-1) was sent to Seay Center for Musculoskeletal Research Texas Scottish Rite Hospital for Children. A G964C point mutation in exon 11 predictive of the E250Q mutation was found.
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The earliest affected family member (I-1), born in 1918, died aged 67 from a myocardial infarction. After jumping from a truck at the age of 5 yr, his legs were in casts for prolonged periods, until he had bilateral knee arthrodesis. Jaw and cervical spine disease made operations difficult and later in his life he was troubled by chronic leg ulcers (not confirmed as PG) and psoriasis. Medical treatment comprised aspirin alone.
Persistent right knee inflammation after a fall from a bicycle at age 5 yr spread in the eldest affected sister (II-1) from a monoarticular fashion to a polyarticular distribution over the subsequent 3 yr. From near complete immobility at age 8 yr, she has largely been in remission since the age of 13. Treatment comprised NSAID, glucocorticoid injections and rigorous physiotherapy at a young age. Despite her postinflammatory joint deformity and the development of secondary hip osteoarthritis requiring replacement at age 56, she continues to work as a local social worker. Her skin has been affected by rosacea with a prominent pustular component.
The younger sister (II-2) alone has been affected by PG, with recurrent lesions around operative wounds and central line sites. This complicated her bilateral hip joint replacements, though earlier arthrodeses of her knees and right elbow performed in childhood were not affected. She remembers joint complaints progressing after a fall when she was 2 yr old and flares settling by age 10. NSAIDs, including high-dose aspirin and later prednisolone, for her PG have been the mainstay of treatment. Like her father, she developed complete cervical ankylosis (Fig. 1c). She also suffered from idiopathic hepatitis following her second hip joint replacement.
The older male of the affected third generation (III-1) displayed the most aggressive disease, with rapid widespread joint destruction (Fig. 1b). Seven joint replacements and a right wrist fusion before the age of 30 have improved his disability such that he currently lives alone unaided. He initially had prominent pyogenic arthritis, sometimes openly discharging, which required recurrent drainage, but he has had no inflammatory flares since age 22. At the time of the inflammatory disease process, gold and d-penicillamine were used with poor effect. Intra-articular glucocorticoid was beneficial for disease control.
The youngest member (III-2) has a slightly different phenotype or has yet to fully express the one common to the rest of the affected members of his family. He has a milder peripheral polyarthropathy. Early treatment with sulphasalazine and leflunomide has resulted in currently ongoing disease remission at age 17, though the possibility of spontaneous remission remains. A speech dyspraxia and a learning impairment compound his joint disability.
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Discussion |
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When considered in the light of the other reported PAPA families, this case report raises several important points regarding the expression and progression of this syndrome.
The lineage described by Lindor et al. [1] displayed the features first called PAPA syndrome, and these were inherited in an autosomal dominant fashion. As in our patients, it was variably expressed, with onset of joint disease between 1 and 16 yr of age and acne beginning at puberty. The clinical syndrome in the second described kindred [2] also displayed a dominantly inherited pyogenic arthritis primarily involving the knees, elbows and ankles. Prominent cutaneous findings included acne and lesions in the proband, consistent with PG. Both these families shared with our cases the occurrence of skin and joint flares after mild physical trauma, which may correlate with the postulated pathogenesis involving increased inflammatory sensitivity.
Our series has a few notable differences. The initial two series describe a pauciarticular arthritis of predominantly non-axial joints. Our cases also had a predominantly non-axial distribution, though polyarticular and more aggressive. In addition they had a distinctive small jaw, and the first two affected family members developed severe cervical spine disease (Fig. 1c). Acne was of variable severity and PG was confirmed in only one family member. No cases of type 1 diabetes were seen, as has been documented in two families [1, 3]. A mutation in A230T has been seen in two other reported [1, 3] cases and a small number of unreported cases. The E250Q identified in our family has been seen only in the unrelated family described by Wise et al. [2].
It is now clear that mutations of single genes involved in the control of inflammation can cause a disease localizing to the synovium. Genome-wide linkage scans localized a candidate region to 15q22-24 by Wise et al. [2], and again within this region on 15q in the second family [4]. Subsequent positional cloning identified two missense mutations within the CD2BP1 gene of these families [5]. Further consolidating its disruption in the inflammatory pathway, the familial Mediterranean fever (FMF) protein pyrin was demonstrated to bind CD2BP1 [6]. It is postulated that the increased pyrin binding seen with the PAPA mutations may alter inflammatory susceptibility. This may involve recruitment of caspase-1 and subsequent effects on apoptosis pathways or on NF
B or IL-1 production [7]. Through pyrin, PAPA aligns itself with the other autoinflammatory disorders FMF, hyper-IgD and periodic fever syndrome, familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease [8].
It is puzzling why synovial inflammation, as the major manifestation of this genetic disorder, appears to switch to skin inflammation at the time of puberty both in males and females. Low levels of testosterone have been associated with rheumatoid arthritis [9], and testosterone has been shown to dampen the inflammatory response [10]. Perhaps the increase in testosterone, even though more pronounced in boys, plays a role in this discriminatory activity.
Improved understanding of the pathogenetic pathways raises the possibility of directed therapy. Prior to it becoming clear that these were episodes of sterile inflammation, continued accumulation of pyogenic material would occur until surgical drainage was performed. PAPA syndrome has been reported to be generally responsive to glucocorticoid intra-articularly and orally, as in our family [1–3]. Though glucocorticoids have a blanket immune suppressant effect, inhibition of NFB may represent a specific point of effect in this pathway. Consistent with the proposed pathogenesis, excess IL-1ß levels have been noted [6], and increased levels may contribute to TNF production [3], raising the possibility that an IL-1 receptor antagonist may have therapeutic effect. Shoham et al. [6] reported promising preliminary responses in two patients with anakinra. Success in treating other autoinflammatory syndromes (MWS and FCAS) with anakinra would also support its use here [11, 12]. Recent reports of PAPA flares treated successfully with a week only of anakinra suggest a novel method of administration [13]. Consistent with an increased cytokine response, TNF levels after lipopolysaccharide stimulation are higher in PAPA subjects than controls [3]. Sustained remission was seen in one patient with steroid-resistant disease treated with 25 mg twice weekly of the TNF inhibitor etanercept [3]. The youngest member of our family received DMARDs early in the course of his disease, which so far appears to have prevented full expression his family's phenotype. Reduced joint flares occurred while on initial treatment with sulphasalazine, and a rash necessitated discontinuation. Subsequent leflunomide treatment has induced a 20-month disease remission at age 15. Beyond leflunomide's inhibition of pyrimidine synthesis, a more specific effect on the postulated PAPA pathway is not clear.
Increasing recognition of the peculiarities of expression of this syndrome and further elucidation of its pathogenesis will aid in the directed use of treatment trials. Further clarification of the downstream effects of the pyrin interaction will allow both increased treatment options and linkage to other inflammatory conditions.
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Acknowledgements |
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I would like to thank Dr Wise and colleagues at Seay Center for Musculoskeletal Research Texas Scottish Rite Hospital for Children, for the DNA sequencing.
The authors have declared no conflicts of interest.
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References |
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- Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT. (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA Syndrome. Mayo Clin Proc 72:611–5.[Abstract]
- Wise CA, Bennett LB, Pascual V, Gillum JD, Bowcock AM. (2000) Localization of a gene for familial recurrent arthritis. Arthritis Rheum 43:2041–5.[CrossRef][Web of Science][Medline]
- Cortis E, De Benedetti F, Insalaco A, et al. (2004) Abnormal production of the tumour necrosis factor alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome. J Pediatr 145:851–5 Erratum in: J Pediatr 2005;146:193.[CrossRef][Web of Science][Medline]
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- Wise CA, Gillum JD, Seidman CE, et al. (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 11:961–9.
[Abstract/Free Full Text] - Shoham NG, Centola M, Mansfield E, et al. (2003) Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci USA 100:13501–6.
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- Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. (2004) Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50:607–12.[CrossRef][Web of Science][Medline]
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