Identification of a Homozygous PSTPIP1 Mutation in a Patient with a PAPA-Like Syndrome Responding to Canakinumab Treatment

OBSERVATION Identification of a Homozygous PSTPIP1 Mutation in a Patient With a PAPA-Like Syndrome Responding to Canakinumab Treatment

Alexandra Geusau, MD; Nadine Mothes-Luksch, MD; Hesam Nahavandi, MD; Winfried F. Pickl, MD; Carol A. Wise, MD; Zahra Pourpak, MD; Elisabeth Ponweiser; Leopold Eckhart, PhD; Raute Sunder-Plassmann, MD

Background: Pyogenic sterile arthritis, pyoderma gan- previously reported heterozygous polymorphism. Het- grenosum, and acne (PAPA) syndrome (OMIM 604416) erozygous changes were identified in both of the is a rare autosomal dominant inherited autoinflamma- patient’s parents and in 7 other family members, all of tory syndrome characterized by pyogenic sterile arthri- whom were asymptomatic. The patient was treated tis and less frequently accompanied by pyoderma gan- with canakinumab, a human anti–interleukin 1␤ grenosum and acne. It is associated with dominant monoclonal antibody, which led to rapid remission of missense mutations in the proline-serine-threonine phos- the symptoms. phatase–interacting protein 1 gene (PSTPIP1) located on chromosome 15. The patient was diagnosed as having Conclusions: To our knowledge, this is the first re- features of a PAPA-like syndrome in which cutaneous ported case of the resolution of dermatological symp- manifestations, such as pyoderma gangrenosum and acne toms associated with a PAPA-like syndrome using fulminans, predominated. canakinumab treatment. Further study of the p.Gly258Ala variant is warranted to determine whether this muta- Observations: Sequencing of the PSTPIP1 gene was per- tion has a role in causing an apparently recessive cuta- formed in the patient and his extended family. The patient’s DNA analysis revealed a homozygous nucleotide neous syndrome resembling PAPA syndrome. exchange c.773GϾCinthePSTPIP1 gene, leading to the substitution of glycine 258 by alanine (p.Gly258Ala), a JAMA Dermatol. 2013;149(2):209-215

EREDITARY AUTOINFLAM- lecular alterations should be undertaken matory disorders are a if the genetic defect is unknown. In the pa- heterogeneous group of tient described herein, genetic analysis sug- Author Affiliations: Division of rare diseases that do not gests the existence of a novel syndrome re- Author Aff Immunology, Allergy, and necessarily affect every sembling pyogenic sterile arthritis, Immunolog Infectious Diseases, Department memberH of a family carrying the disease- pyoderma gangrenosum (PG), and acne Infectious D of Dermatology (Drs Geusau causing mutation. The establishment of the (PAPA) syndrome (OMIM 604416) with of Dermato and Mothes-Luksch), Institute correct diagnosis may be difficult be- a recessive inheritance pattern and a dra- and Mothes of Immunology (Dr Pickl), cause the clinical presentation often mim- matic treatment response to canakinumab, of Immuno Department of Laboratory ics infection.1 For many syndromes, the a human anti–IL-1␤ monoclonal anti- Departmen Medicine (Ms Ponweiser and Medicine (M Dr Sunder-Plassmann), and genetic basis has not yet been character- body. Dr Sunder- Research Division of Biology ized, and research is ongoing to elicit the Research D and Pathobiology of the Skin, pathogenesis of these immune-mediated REPORT OF A CASE and Pathob Department of Dermatology diseases. Interleukin 1 (IL-1) and inflam- Departmen (Dr Eckhart), Medical masome activation have a pivotal role in (Dr Eckhar University of Vienna, and the perpetuation of inflammation and may A 22-year-old Iranian man was admitted University Medical Department, Hanusch Medical De Hospital (Dr Nahavandi), serve as a target for therapy. Even in the to the Department of Dermatology, Medi- Hospital (D Vienna, Austria; Sarah M. and absence of an identified genetic altera- cal University of Vienna, Vienna, Aus- Vienna, Au Charles E. Seay Center for tion, patients exhibiting clinical symp- tria, in poor clinical condition in the au- Charles E. Musculoskeletal Research, toms compatible with an autoinflamma- tumn of 2006. He had a fever and was Musculosk Texas Scottish Rite Hospital for tory condition should be considered for experiencing painful acne distributed pre- Texas Scott Children, Dallas (Dr Wise); and this new generation of therapeutics that dominantly on the trunk (Figure 1A), as Children, D Immunology, Asthma, and Immunolog Allergy Research Institute, block IL-1. In addition, if a phenotype is well as extensive serpiginous ulcers on his Allergy Res Tehran University of Medical indicative of one of these diseases, the left upper and lower leg with violaceous Tehran Uni Sciences, Tehran, Iran threshold for genetic analysis should be undermined borders covered with fibrin- Sciences, Te (Dr Pourpak). low, and efforts to elucidate possible mo- ous material, a condition indicative of PG (Dr Pourpa

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C D

AAGGCT G AAGGCT G C C

co het co het G/C G/C

AAGGGCT AAGGGCT

co wt co wt AAGCCTG G G

co hom C Index Patient

Figure 1. Patient at the time when the pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA)–like syndrome was diagnosed. A and B, Shown are acne fulminans on the back (A) and pyoderma gangrenosum on the left upper leg (B) of the patient. Note the atrophic scar on the left lower leg. C, The pedigree of the patient (solid square) is shown; dots within circles (female relatives) or squares (male relatives) indicate heterozygous asymptomatic carriers of the p.Gly258Ala mutation. The patient carries a homozygous mutation. As expected, both parents carry a mutant allele, which they inherited from their mothers, who are sisters (both heterozygous for p.Gly258Ala). All the remaining heterozygous individuals are siblings of the patient’s mother. Results from the sequencing analysis of PSTPIP1 and from the c.773GϾC genotyping for the patient, his siblings, and his parents are shown. co indicates control; het, heterozygous individual; hom, individual carrying the mutant variant homozygously; and wt, individual carrying the wild-type variant. D, Erythematous painful patches are seen at the application site of anakinra, a recombinant human interleukin 1 receptor antagonist.

(Figure 1B). Inspection of his oral cavity revealed aph- cell count to ϫ109/L, multiply by 0.001). The differen- thous lesions on the buccal mucosa; candidiasis was pres- tial white blood cell count demonstrated neutrophilia of ent. Extended atrophic scars on the legs, buttocks, and 86% (reference range, 50%-75%) and relative lympho- back of the patient had originated from prior episodes penia of 7% (reference range, 25%-40%) (to convert neu- of painful ulcers. The patient exhibited no inflamma- trophilia and lymphopenia fractions to proportion of 1.0, tory arthritis, joint mutilation, or clinical symptoms of multiply by 0.01). inflammatory bowel disease, such as abdominal pain, Initially, serum immunoglobulin analysis revealed an cramping, or diarrhea. At his initial admission in 2006, elevated serum IgA level of 1080 mg/dL (reference range, a blood workup showed a highly elevated C-reactive pro- 70-500 mg/dL), a normal IgG level of 1010 mg/dL (ref- tein level of 24 mg/dL (reference range, Ͻ1 mg/dL), a erence range, 700-1600 mg/dL), and a normal IgM level white blood cell count of 22 000/␮L (reference range, of 47 mg/dL (reference range, 40-280 mg/dL) (to con- 4000-10 000/␮L), and moderate hypochromic micro- vert IgA level and IgM level to milligrams per liter, mul- cytic anemia (to convert C-reactive protein level to nano- tiply by 10; to convert IgG level to grams per liter, mul- moles per liter, multiply by 9.524; to convert white blood tiply by 0.01). Antinuclear antibodies and rheumatoid

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©2013 American Medical Association. All rights reserved. Downloaded From: http://archderm.jamanetwork.com/ by a Florida Atlantic University User on 02/23/2016 factors were negative, as was serologic testing for hepa- dures. The 15 exons, exon-intron boundaries, 5' untrans- titis A, B, and C and human immunodeficiency virus. Im- lated region, and 3' untranslated region of PSTPIP1 were munophenotyping of whole blood cells was performed amplified by polymerase chain reaction and were se- as previously reported.2,3 Increased CD64 of 31% (refer- quenced using the primers listed in the eTable (http: ence value, 20%) and elevated CD16 of 86% (reference //www.jamaderm.com). In our patient, we identified a value, Ͻ10%) expression indicated activation of granu- homozygous c.773GϾC p.Gly258Ala substitution in exon locytes and monocytes, respectively. The CD4/CD8 ra- 11 (rs34240327). Subsequently, we developed a muta- tio was normal (1.52), with reduced numbers of CD4ϩ genically separated–polymerase chain reaction protocol (380/␮L) and CD8ϩ (250/␮L) T cells, indicating dys- for the screening of the patient’s relatives using the fol- regulation within the T-cell compartment. lowing primers: CD2BP1 forward wild type: 5'-CGG CTG For lymphocyte proliferation assays, peripheral blood ACG CTG GGA GG-3', CD2BP1 forward mutant: 5'- mononuclear cells (PBMCs) (ϫ105 per well) were incu- GAG GAA GTG AAT CTG ACG CTA GAA GC-3', and bated with staphylococcal superantigen A (10 ng/mL), CD2BP1 reverse: 5'-GCT CTT GGC CTG GAT-3' (TIB staphylococcal superantigen B (20 ng/mL), phytohemag- MOLBIOL Gmbh). The 23 family members were geno- glutinin (12.5 ␮g/mL), or phorbol myristate acetate (10Ϫ7 typed for the p.Gly258Ala variant (Figure 1C), and the mol/L) (all from Sigma Chemicals) or with soluble CD3 mutagenically separated–polymerase chain reaction re- monoclonal antibody (2 ␮g/mL; Ortho) or plain me- sults in the patient’s sisters and parents were confirmed dium in 96-well round-bottom tissue culture plates for by sequencing exon 11. The c.773GϾC mutation was pres- 72 hours. Tetanus toxoid (10 limes flocculation per well) ent in a heterozygous form in 9 of the patient’s relatives and purified protein derivative (2 ␮g/mL) (both from Stat- analyzed. No other homozygous carrier of the p.Gly258Ala ens Serum Institute) and medium only were incubated variant was detected. with PBMCs for 6 days. Subsequently, cells were pulsed The patient’s relatives were clinically investigated, and with [methyl-3H] thymidine (1 ␮Ci per well) for an- their medical histories were recorded by a specialist using other 18 hours and were processed as previously de- a questionnaire provided by us. This included questions scribed.3,4 Although the patient’s PBMCs reacted ro- pertaining to the individual’s relationship to the pa- bustly but significantly less than control PBMCs to tient, his or her medical history, and the current clinical phytohemagglutinin (34 vs 113 kilo counts per minute status, with a particular focus on symptoms possibly re- [kcpm]),weak proliferation was observed on stimula- lated to PAPA syndrome. Two of 9 family members car- tion with staphylococcal superantigen A (24 vs 91 kcpm) rying the mutant allele heterozygously exhibit active ac- and staphylococcal superantigen B (5 vs 43 kcpm), the nelike lesions or acne-associated scars on the back. phorbol ester phorbol myristate acetate (12 vs 81 kcpm), Degenerative joint disease is reported in one of the older and soluble CD3 monoclonal antibody (6 vs 19 kcpm). heterozygous individuals. No symptoms compatible with Moreover, in contrast to the control individual, signifi- PAPA syndrome were found in the remaining carriers. cantly reduced recall responses to tetanus toxoid (4 vs Initially, when the patient was severely ill, high dos- 27 kcpm) and purified protein derivative (2 vs 78 kcpm) ages of oral methylprednisolone (2 mg/kg/d) had led to were observed in the patient. Oxidative burst of neutro- a significant improvement in his condition and a de- phils was normal on phorbol myristate acetate stimula- crease in inflammatory variables. The clinical response tion and was reduced on N-formyl-methionyl-leucyl- was delayed, and it took weeks until the skin lesions im- phenylalanine stimulation. Phagocytosis of opsonized proved and the corticosteroid dosage could be slowly Escherichia coli particles was normal. reduced. In the following 3 years, the patient’s skin con- The patient reported that he had been experiencing dition was kept stable with a weekly dose of methylpred- skin ulcers and acne lesions since age 14 years. From early nisolone (approximately 60 mg), with occasional skin childhood, he had had recurrent episodes of arthralgia, flares of varied intensity, infrequently accompanied by painful joints, and fever that did not respond to the ad- respiratory tract infections requiring higher dosages and ministration of high-dose antibiotics on the occasion of hospitalizations. To avoid long-term adverse effects of sys- repeated hospitalizations. The patient is the eldest of 3 temic corticosteroid use, alternative treatment options siblings, with his younger sister also occasionally expe- were considered. The administration of anakinra, a re- riencing acnelike lesions. The patient and his sisters are combinant human IL-1 receptor antagonist (100 mg/d descendants of a consanguineous marriage (ie, his mother subcutaneously), resulted in intolerable adverse effects and father are double first cousins) (Figure 1C). The medi- at the injection site (Figure 1D) within a few days, too cal history and the coincidence of cystic acne and PG were short a period to determine a therapeutic effect. Finally, indicative of PAPA syndrome, which belongs to the fam- a few weeks later, treatment with canakinumab (150 mg ily of autoinflammatory disorders and is caused by mu- subcutaneously), a human anti–IL-1␤ monoclonal anti- tations in the proline-serine-threonine phosphatase– body, was initiated, to be applied every 8 weeks.7 Con- interacting protein 1 gene (PSTPIP1) located on comitantly, the patient was prophylactically prescribed chromosome 15, encoding a protein also known as CD2- isoniazid because of a positive tuberculosis test result binding protein 1 (CD2BP1).5,6 (QuantiFERON; Cellestis), without evidence of active tu- We performed sequence analysis of the PSTPIP1 gene berculosis. Six days before the first injection of in our patient. Four milliliters of blood was drawn from canakinumab, the patient had been advised to discon- the patient after obtaining his informed consent for DNA tinue any other therapy, which promptly led to exacer- analysis. In addition, DNA was isolated from 23 family bation of his skin lesions (Figure 2A) and to a signifi- members living in Iran, according to standard proce- cant increase in serum C-reactive protein and serum

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C 14 450 C-reactive protein Serum amyloid A 400 12

350 Serum Amyloid A Level, mg/dL 10 300

8 250

6 200

150 4

C-Reactive Protein Level, mg/dL 100 2 50

0 0

–80 –60 –40 –20 0 20 40 60 80 100 120 140 160 180 200 220 240 260 Day

Figure 2. Patient after cessation of systemic corticosteroids. A, Before treatment with canakinumab, the patient had dense folliculitis in the neck and face area. B, During treatment with canakinumab, complete remission is seen at the same sites after 9 months and 3 injections of canakinumab. C, Response patterns to canakinumab injections (150 mg subcutaneously) in the C-reactive protein (CRP) and serum amyloid A (SAA) levels are shown in the patient over time. The arrows indicate the canakinumab injections every 8 weeks (at days 57, 110, 167, and 223). At day 0 (6 days before the first injection of canakinumab), the CRP and SAA levels increased significantly. Note that the normal levels of CRP and SAA are less than 1 mg/dL and 0 to 6.4 mg/L, respectively (to convert C-reactive protein level to nanomoles per liter, multiply by 9.524). Within a few days after the first injection, the CRP and SAA levels dropped, accompanied by significant clinical improvement. Subsequently, the curves seem to follow a decrescendo pattern associated with the injections.

amyloid A levels (Figure 2C). He reported sickness, with- inflammatory variables decreased. Additional injections out fever or arthralgia. Within a few days following the were administered according to the given schedule, and first injection, his skin improved significantly, and the he remained well for the following 9 months, with a com-

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©2013 American Medical Association. All rights reserved. Downloaded From: http://archderm.jamanetwork.com/ by a Florida Atlantic University User on 02/23/2016 plete clearance of the acne lesions (Figure 2B). We ob- revealed a lower response compared with the control, served slight flares of acne at the end of 8 weeks, occa- without recall responses to tetanus toxoid and purified sionally accompanied by a moderate increase in C-reactive protein derivative. In addition, the patient was initially protein and serum amyloid A levels, corresponding to a seen with very low B-lymphocyte numbers and with el- decline in the drug level. The course of the C-reactive evated serum IgA levels; their relevance to the clinical protein and serum amyloid A curves during the 9-month manifestation is unclear. Cortesio et al16 reported sig- observation period followed a decrescendo pattern. nificantly impaired chemotaxis in macrophages from 2 patients with PAPA syndrome, whereas T-cell migra- COMMENT tion was not compromised. Hypogammaglobulinemia and elevated tumor necrosis factor (TNF) serum levels, which were unrelated to The coexistence of severe and unusual episodic arthritis the pathologic findings in our patient, have previously in addition to ulcerative skin lesions and cystic acne clus- been reported in a patient with PAPA syndrome who im- tered in a few families was originally termed familial re- proved after substitution of immunoglobulins.17 Cyto- current arthritis. In 1997, this syndromic triad was named kine production by PBMCs was studied in 2 patients with PAPA syndrome.8 So far, 34 affected individuals from 5 PAPA syndrome and showed that these patients pro- families (2 in the United States, 1 in Italy, 1 in the Neth- duced more inflammatory cytokines on lipopolysaccha- erlands, and 1 in New Zealand) have been described ride stimulation, in particular IL-1␤ and IL-1␣.11 The find- worldwide.5,8-12 Pyogenic sterile arthritis resulting in joint ing that elevated IL-1 levels lead to lymphopenia had mutilation is reportedly the most common clinical rep- already been observed in the 1990s, when laboratory ani- resentation. However, PAPA syndrome manifestations mals were infused with a series of purified acute-phase vary among family members carrying the mutation and proteins in an attempt to better understand the patho- can lack the clinical characteristics such as PG or a late mechanisms involved in sepsis.18 One of the mecha- onset in life.11 So far, 4 genetic variations in PSTPIP1 nisms accounting for this phenomenon might be a cen- (p.Ala230Thr, p.Glu250Gln, p.Glu250Lys, and tral nervous system mode of action of IL-1␤, leading to p.Asp266Asn) have been described that lead to this rare stimulation of both the sympathetic nervous system and autoinflammatory disorder with autosomal dominant in- the hypothalamic-pituitary axis.19 That catecholamines heritance, primarily affecting the joints and skin5,8,13,14 have the tendency to suppress T-lymphocyte activation (http://fmf.igh.cnrs.fr/ISSAID/infevers/search.php?n by lectins, such as concanavalin A, is well estab- =5). In contrast to the previously reported PSTPIP1 mu- lished20,21 and might involve signaling via ␤-adrenergic tations that cause autosomal dominant inherited PAPA receptors involving the p38 mitogen–activated protein syndrome, we present evidence that a homozygous kinase pathway.22,23 Besides the antiproliferative effects, PSTPIP1 mutation (c.773GϾC and p.Gly258Ala) may catecholamines might also favor T-cell apoptosis by in- define a novel form of a recessively inherited PAPA-like creasing T-cell Fas ligand levels, potentially explaining syndrome. the clinically evident states of lymphopenia observed in To estimate the functional significance of the our patient.22 p.Gly258Ala mutation, we determined the degree of evo- Considering the clinical presentation of the patient and lutionary conservation of the Gly258 residue by com- his relatives, the effect of p.Gly258Ala seems to be less parative analysis of PSTPIP sequences derived from the pronounced than or different from other mutations caus- Ensembl genome database (http://www.ensembl.org/). ing PAPA syndrome. In 7 of 9 heterozygous relatives, the Gly258 was found to be conserved, with a single excep- amount of intact PSTPIP1 protein seems to be sufficient tion, among all mammals investigated (eFigure). By con- to compensate for the variant protein to prevent the de- trast, Gly258 was not conserved in nonmammalian ver- velopment of PAPA-like syndrome. However, 2 of his tebrates (eFigure). Remarkably, none of the species mother’s siblings carrying this mutation had a history of investigated had an alanine residue at the amino acid po- acne, with one of them seen with active acne lesions on sition corresponding to Gly258. Together, these find- the back. Until now, the p.Gly258Ala substitution had ings indicated an important role of Gly258 in maintain- been described as a polymorphism (rs34240327) being the structural integrity of PSTPIP1 or in facilitating cause it was detected in heterozygous form with an al- intermolecular interactions of PSTPIP1 in mammals. Pre- lelic frequency of 1.4% (no homozygous p.258Ala car- viously, Nesterovitch et al15 identified a heterozygous riers) in a collective of apparently healthy individuals p.Gly258Ala mutation in 1 of 14 patients with PG and (http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi suggested an effect of the mutation on the multimeriza- ?rs=34240327). If only the altered protein is present in tion of the PSTPIP1 protein or its interaction with homozygous carriers of p.Gly258Ala, the dysregulation PTPN12. However, this hypothesis has not yet been tested of proinflammatory pathways leads to a novel pheno- experimentally. Further investigations are required to un- type of PAPA syndrome that mainly affects the skin (ie, ravel the molecular pathogenic mechanism of the PST- ulceration and acne fulminans); joint involvement is mild, PIP1 p.Gly258Ala mutation. without mutilation. Notably, Nesterovitch et al15 re- Immunological investigations during the first epi- cently described a patient with PG carrying a heterozy- sode of our patient’s disease course documented at our gous p.Gly258Ala mutation and having a history of mild clinic revealed reduced numbers of CD4ϩ and CD8ϩ T arthralgia and acne. In light of the minor effect of this cells, indicating dysregulation within the T-cell com- variant on our patient’s heterozygous relatives, we specu- partment. Proliferative responses to mitogens of PBMCs late that the individual described by Nesterovitch et al

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©2013 American Medical Association. All rights reserved. Downloaded From: http://archderm.jamanetwork.com/ by a Florida Atlantic University User on 02/23/2016 was also experiencing a PAPA-like syndrome. There- rity of the data and the accuracy of the data analysis. Study fore, the heterozygous p.Gly258Ala mutation could rep- concept and design: Geusau and Sunder-Plassmann. Ac- resent the basis for a variant PAPA syndrome that be- quisition of data: Geusau, Mothes-Luksch, Nahavandi, comes clinically manifest only in the presence of genetic Pickl, Wise, Pourpak, Ponweiser, and Sunder- modifiers (such as a second p.Gly258Ala allele in our pa- Plassmann. Analysis and interpretation of data: Geusau, tient). Another potential trigger might be microbial patho- Pickl, Ponweiser, and Sunder-Plassmann. Drafting of the gens that lead to the activation of proinflammatory cy- manuscript: Geusau, Wise, Eckhart, and Sunder- tokines via lipopolysaccharides, initiating an Plassmann. Critical revision of the manuscript for impor- immunological response and an increase in cytokine pro- tant intellectual content: Geusau, Wise, Eckhart, and Sun- duction, which in turn leads to disease flares. Our pa- der-Plassmann. tient’s medical history bears this out; the symptoms were Conflict of Interest Disclosures: None reported. exacerbated when he contracted an additional infec- Additional Contributions: Ebrahim Radinia, MD, and tion. The required extra trigger factor may also be the Leyla Sedighipour, MD, assisted with the study, Mah- reason why in oligosymptomatic patients PAPA syn- dokht Mossalaei and Petra Jurkowitsch provided tech- drome can remain undiagnosed for a long time. nical help, and Tina Breckwoldt, PhD, revised the manu- The ex vivo experiments performed in 2 patients with script. PAPA syndrome revealed an increase in the secretion of Online-Only Material: An eTable and eFigure are avail- inflammatory cytokines by PBMCs (ie, IL-1␣, IL-1␤, and able at http://www.jamaderm.com. TNF) on lipopolysaccharide stimulation.11 These data provided by Schellevis et al11 and the present understand- ing about the pathogenesis of PAPA syndrome offer new REFERENCES treatment options in patients with this condition. For in- stance, subcutaneous injection of the IL-1 receptor an- 1. Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. tagonist anakinra resulted in significant improve- J Allergy Clin Immunol. 2009;124(6):1141-1151. 11,24 ment. Another option includes therapies targeting 2. Greinix HT, Pohlreich D, Kouba M, et al. 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Proc Natl Acad Sci U S A. 2003;100(23):13501-13506. Accepted for Publication: August 17, 2012. 14. Smith EJ, Allantaz F, Bennett L, et al. Clinical, molecular, and genetic characteristics of PAPA syndrome: a review. Curr Genomics. 2010;11(7):519-527. Correspondence: Alexandra Geusau, MD, Division of 15. Nesterovitch AB, Hoffman MD, Simon M, Petukhov PA, Tharp MD, Glant TT. Immunology, Allergy, and Infectious Diseases, Depart- Mutations in the PSTPIP1 gene and aberrant splicing variants in patients with ment of Dermatology, Medical University of Vienna, pyoderma gangrenosum. Clin Exp Dermatol. 2011;36(8):889-895. Waehringer Guertel 18-20, 1090 Vienna, Austria 16. Cortesio CL, Wernimont SA, Kastner DL, Cooper KM, Huttenlocher A. Impaired podosome formation and invasive migration of macrophages from patients with ([email protected]). a PSTPIP1 mutation and PAPA syndrome. 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©2013 American Medical Association. All rights reserved. Downloaded From: http://archderm.jamanetwork.com/ by a Florida Atlantic University User on 02/23/2016 and acne syndrome (PAPA syndrome) associated with hypogammaglobu- activation by catecholamines: evidence for a non-classical mechanism of cat- linemia and elevated serum tumor necrosis factor-␣ levels. J Clin Rheumatol. echolamine action. Immunology. 1995;85(4):544-549. 2002;8(5):273-275. 22. Lajevic MD, Suleiman S, Cohen RL, Chambers DA. Activation of p38 mitogen- 18. Hawes AS, Fischer E, Marano MA, et al. Comparison of peripheral blood leuko- activated protein kinase by norepinephrine in T-lineage cells. Immunology. 2011; cyte kinetics after live Escherichia coli, endotoxin, or interleukin-1 alpha admin- 132(2):197-208. istration: studies using a novel interleukin-1 receptor antagonist. Ann Surg. 1993; 23. LaJevic MD, Koduvayur SP, Caffrey V, Cohen RL, Chambers DA. Thy-1 mRNA 218(1):79-90. destabilization by norepinephrine a 3' UTR cAMP responsive decay element and ␤ 19. Woiciechowsky C, Scho¨ning B, Daberkow N, et al. Brain IL-1 increases neu- involves RNA binding proteins. Brain Behav Immun. 2010;24(7):1078-1088. trophil and decreases lymphocyte counts through stimulation of neuroimmune 24. Dierselhuis MP, Frenkel J, Wulffraat NM, Boelens JJ. Anakinra for flares of pyo- pathways. Neurobiol Dis. 1999;6(3):200-208. genic arthritis in PAPA syndrome. Rheumatology (Oxford). 2005;44(3):406- 20. Bergquist J, Tarkowski A, Ekman R, Ewing A. Discovery of endogenous catechol- 408. amines in lymphocytes and evidence for catecholamine regulation of lympho- 25. Stichweh DS, Punaro M, Pascual V. Dramatic improvement of pyoderma gan- cyte function via an autocrine loop. Proc Natl Acad Sci U S A. 1994;91(26): 12912-12916. grenosum with infliximab in a patient with PAPA syndrome. Pediatr Dermatol. 21. Cook-Mills JM, Cohen RL, Perlman RL, Chambers DA. Inhibition of lymphocyte 2005;22(3):262-265.

Notable Notes

Skin Pores in Persian Medical Textbooks

“Skin pores” as an informal term is used for the outlet of “pi- ditions, such as opening, dilation, and porosity, and also losebaceous units and sweat-producing glands.” However, “tra- opposite conditions, such as obstruction, closure, tighten- ditional Persian medicine,” as one of the branches of comple- ing, and condensation, has also been considered, because mentary medicine with roots that go back earlier than 8000 they cause differences in the penetration of materials2,3 and, BC,1 has fully described “skin pores/pores” with the special directly or indirectly, mediate in the manifestation of some term of “masams.”2,3 This rich school of traditional medicine symptoms. Masams are also mainly considered in the diag- believes that masams play an important role in the appear- nosis and treatment of some diseases. Symptoms and dis- ance of some symptoms and diseases and uses them in the eases, such as alopecia, underweight disorder, infertility, and management of many disorders.2,3 some types of fever, are caused by “obstruction or tighten- Masams are very small natural pores or openings, espe- ing” of masams. Conversely, “dilation” of masams causes cially in the skin surface near the hair follicles,2 and also in diaphoresis, increase in body metabolism, and removal of other body organs (eg, the eyelids, eyes,3 stomach, uterus, pla- material from the body. Many disorders, such as diarrhea, centa, muscles, bones, joints2). Except for the eyelid’s ma- various fevers, hemorrhoids, skin eruptions, amenorrhea, sams, which are considered to be the same as skin masams, and obesity, also are treated according to these alternations they act as a pathway for exchange of materials in other body of masams.2,3 organs. These pores are divided into 2 groups, perceptible (vis- It is consequential that long ago, great Persian physi- ible) and imperceptible (conceptual or functional), and vari- cians, without having advanced and modern instruments ous functions are associated with them.2,3 and only by observation of signs and symptoms, realized Persian medicine believes that respiration is one of the that specific factors (macroscopic, microscopic, and nano- main responsibilities of skin and is performed basically by scopic pores) are associated with the transpiration of mate- masams.2 Masams are also known as entrance pathways of rials. They used the term “masams” for all these factors materials, such as wind, steam, and foreign substances, and (not only for pilosebaceous units and sweat glands) and cause differences in the effects of medications by their selec- diagnosed and treated many diseases almost perfectly with tive penetration. They also play an important role in the this method. excretion of waste materials by producing sweat, sebum, and hair.2,3 The production of sweat is also used as a main treat- Fatemeh Alizadeh, MD ment strategy for fevers.2 The role of masams in various con- Fatemeh Moradi, MD

Author Affiliations: Traditional Iranian Medicine Research Association, Student’s Scientific Research Center, Tehran Uni- versity of Medical Sciences, Tehran, Iran. Contact Dr Alizadeh at Traditional Iranian Medicine Research Association, Exceptional Talent Developmental Center of Teh- ran University of Medical Sciences, No. 56, Vesal Street, Keshavarz Boulevard, Tehran 1417633114, Iran (resadayamfaraj @yahoo.com).

1. Larijani B, Zahedi F. An introduction on medical ethics history in different era in Iran. DARU Suppl. 2006;(1):10-16. 2. Avicenna. Canon of Medicine (Al-Qanun Fit-Tib) [in Arabic]. Beirut, Lebanon: Al-Elmi Lel-Matbuat; 2005. 3. Arzani MA. Akbari’s Book of Medicine (Tibb-e Akbari) [in Persian]. Tehran, Iran: Studies of Medical History and Islamic and Complementary Medicine; 2008.

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