Palisaded neutrophilic granulomatous dermatitis in a patient with HLA-B27–negative axial spondyloarthritis: a case report and literature review Špela Šuler Baglama1 ✉, Boštjan Luzar2, Metka Koren Krajnc3, Katarina Trčko1 ¹Department of Dermatology and Venereal Diseases, Maribor University Medical Centre, Maribor, Slovenia. 2Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. 3Department of Rheumatology, Maribor University Medical Centre, Maribor, Slovenia. S2 2022;31 Suppl:S2-S6 doi: 10.15570/actaapa.2022.s2 Introduction Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare histopathologic pattern belonging to a group of cutaneous granu- lomatous eruptions and neutrophilic dermatoses (1, 2). Although patients of all ages may be affected, PNGD most commonly de- velops in the 5th decade of life (mean age 47.3 years) and shows a female predominance (female:male = 3:1) (3). PNGD can be triggered by various systemic conditions (1). Here we present an interesting case of PNGD triggered by a relapse of HLA-B27–nega- tive axial spondyloarthritis (axSpA) in an adult male. To the best of our knowledge, this causal relationship is reported for the first time. The case report is followed by a review of the literature on PNGD and a presentation of the characteristics of the main dif- ferential diagnoses. Case report A 49-year-old male was referred to the dermatology department because of multiple asymptomatic bump-like changes above the elbows and knees of 6 months’ duration that appeared few weeks after a relapse of HLA-B27–negative axSpA, which the patient has had since 2012. AxSpA had successfully been treated with adali- mumab until 2014, which was then discontinued at the patient’s request. The patient did not have any checkups with rheumatolo- gists and did not receive any treatment in the meantime. However, a few months before the referral, the patient’s condition wors- ened with the onset of fatigue, unintentional loss of 18 kg over a 2-month period, and severe low back pain, causing awakening in the middle of the night and morning stiffness. Moreover, periph- eral arthritis with pain in the joints of the shoulder girdle, knees, and hands also developed, along with an episode of acute scleri- tis in the right eye. The patient denied other systemic symptoms. On physical examination there were multiple violaceous papules with a firm consistency and slightly hyperkeratotic surface locat- ed above the elbows and knees (Fig. 1). No other abnormalities were noticed except reduced spine mobility. An H&E stain of a biopsy specimen from a papule on the right el- bow revealed the presence of palisading granulomas surrounding neutrophilic debris, mucin, and collagen throughout the dermis, also extending into the subcutaneous fat. In addition, transepi- dermal elimination of granulomas was also present (Fig. 2). Based on clinical and histopathological features, a diagnosis of PNGD was made. Despite the apparent causal relationship between ax- SpA and PNGD, and in particular due to a history of weight loss, extensive investigations to exclude other potential triggers for PNGD followed. All laboratory results—including complete blood count, biochemistry, urinalysis, lactate dehydrogenase, angioten- sin convertase enzyme, rheumatoid factor, anti-nuclear antibody, extractable nuclear antigen, anti-dsDNA, C and P anti-neutrophil cytoplasmic antibody, complement C3 and C4, tumor markers, hematests, quantiferon test, serum protein electrophoresis, and serology for hepatitis B and C virus—were completely normal, negative, or nonreactive, except for mildly elevated leukocytes, C- reactive protein, and erythrocyte sedimentation rate. Abdominal ul- trasound and chest X-ray were without pathological abnormalities. Abstract Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare histopathological pattern belonging to a group of cutaneous granulomatous eruptions that typically manifests with asymptomatic skin-colored, erythematous, or violaceous papules or nod- ules. PNGD can be triggered by various systemic conditions, including medications and autoimmune and autoinflammatory disor- ders, as well as malignancies; for example, lymphoproliferative disorders. Therefore, in patients with PNGD an extended diagnos- tic workup is mandatory as well as follow-up in the case of idiopathic PNGD. To the best of our knowledge, this is the first reported case in the literature of PNGD causally related to a relapse of HLA-B27–negative axial spondyloarthritis. Keywords: palisaded neutrophilic granulomatous dermatitis, granulomatous dermatitis, neutrophilic dermatoses, axial spondy- loarthritis Acta Dermatovenerologica Alpina, Pannonica et Adriatica Acta Dermatovenerol APA Received: 20 December 2021 | Returned for modification: 1 February 2022 | Accepted: 13 February 2022 ✉ Corresponding author: spela.baglama@gmail.com Figure 1 | (a) Typical clinical presentation of palisaded neutrophilic granuloma- tous dermatitis with multiple firm violaceous papules over the elbows with slightly hyperkeratotic surface; (b) note the yellowish discoloration when the le- sion is stretched (the same is visible on diascopy). S3 Acta Dermatovenerol APA | 2022;31 Suppl:S2-S6 PNGD triggered by axial spondyloarthritis Magnetic resonance imaging of the sacroiliac joints showed sub- chondral sclerosis with slight bone marrow edema. Topical betamethasone was initiated for PNGD. The patient was also referred to a rheumatologist, who prescribed nonsteroi- dal anti-inflammatory drugs (NSAIDs), which did not have a sat- isfactory effect. Therefore, treatment with a biological drug from the group of tumor necrosis factor (TNF)-α inhibitors was indi- cated. Unfortunately, therapy was again refused by the patient. As a result, peroral methylprednisolone with gradual tapering was initiated. The doses were as follows: 16 mg a day for 2 weeks, followed by a reduction of 4 mg every 3 weeks. However, this ta- pering scheme was unsuccessful because the low back pain was under control only when the patient had been taking 16 mg of methylprednisolone per day, and so the patient never tried to re- duce the dose below 12 mg daily. Moreover, at follow-up 3 months after the introduction of methylprednisolone, the inflammatory parameters increased slightly with additional signs of synovitis of the metacarpophalangeal and proximal interphalangeal joints of the right hand with dactylitis of the middle fingers as well as epicondylitis of the left elbow. The patient again had an episode of scleritis. There were still some firm violaceous papules on the elbows, whereas on the knees they regressed with residual post- inflammatory macules. Due to the progression of HLA-B27–nega- tive axSpA, at the time of writing the patient finally agreed to re- treatment with a biological drug. Discussion and literature review Many other names have been used in the literature for PNGD, thus creating much unnecessary confusion. These names include rheumatoid papules, eosinophilic granulomatosis with polyangiitis (Churg–Strauss granuloma), and cutaneous extravascular necrotiz- ing granuloma (1). The pathogenesis of PNGD has not been completely elucidated. However, based on underlying systemic diseases with an immuno- reactive nature and leukocytoclastic vasculitis sometimes present in early lesions, it is considered to be caused by the deposition of immune complexes in dermal vessels followed by complement activation, chronic inflammation, fibrosis, and granulomatous in- filtrate (1, 4). Clinically, PNGD typically manifests with multiple asympto- matic or rarely tender skin-colored, erythematous, or violaceous papules or nodules that may coalesce into plaques or annular configurations (5). They are located on the extensor extremities, especially the elbows, whereas disseminated lesions or lesions on the trunk, buttocks, and head are rare. Other morphologies re- ported are urticarial, linear, ulcerated, and necrotic (5–7). Differential diagnosis of PNGD on clinical grounds is shown in Table 1 and includes frictional lichenoid dermatitis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), erythema elevatum et diutinum, and particularly some other cutaneous non-infec- tious granulomatous skin diseases, including granuloma annu- lare, cutaneous sarcoidosis, rheumatoid nodules, interstitial gran- ulomatous dermatitis (IGD), and interstitial granulomatous drug reaction (IGDR). However, considerable overlap exists between clinical features and the histological picture in PNGD, IGD, and IGDR, suggesting a possible relationship between the three condi- tions. Therefore, the unifying term reactive granulomatous derma- titis has been proposed to encompass PNGD, IGD, and IGDR (1). The diagnosis of PNGD is based on clinicopathological correla- tion. Histologic features of PNGD are diverse, depending on the stage of the lesions. Early forms are characterized by neutrophilic infiltrate, leukocytoclastic vasculitis, and collagen degeneration. As the lesions evolve, interstitial and/or palisaded granuloma- tous infiltrates surrounding leukocytoclastic debris and collagen degeneration can be seen, which was also evident in the patient presented (1). To aid in diagnosis, lesions typically become yel- lowish on diascopy (8). PNGD is a reaction pattern that can occur a few years prior to diagnosis, concomitantly with or many years after numerous lymphoproliferative, autoimmune, and autoinflammatory diseas- es, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, chronic myelomonocytic leukemia, ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, systemic vasculitides (i.e., microscopic polyangiitis and granulomatosis with polyangiitis), and Behçet’s disease (4–7, 9–14). An associa- tion of PNGD with HLA-B27–negative axSpA has not been report- ed in the literature so far, making our case unique. There is only Figure 2 | Histology showing features of palisaded neutrophilic granulomatous dermatitis: (a, b) palisading granulomas surrounding neutrophilic debris, mu- cin, and collagen can be seen throughout the dermis and subcutaneous fat; (c) note transepidermal granuloma elimination (a–c, H&E, original magnification). S4 Acta Dermatovenerol APA | 2022;31 Suppl:S2-S6Š. Šuler Baglama et al. one similar case of a woman with ankylosing spondylitis, rheu- matoid arthritis, and a history of treatment with TNF-α inhibitors, which could also trigger PNGD as a paradoxical side effect (15–17). In addition to TNF-α inhibitors, PNGD can also be triggered by allopurinol and ledipasvir/sofosbuvir (18, 19). However, the last association of PNGD with antiviral drugs is questionable because the hepatitis C in that case report could also have been a cause of PNGD (19). Because of many possible triggers of PNGD, patients’ history, physical examination, extensive laboratory tests, and age- appropriate malignancy screening are mandatory to exclude any underlying disease. In the case of idiopathic PNGD, it is advised to follow-up a patient regularly (6). We excluded other potential PNGD triggers and confirmed a causal relationship with axSpA in our patient. Weight loss and mildly elevated inflammatory param- eters were thus caused by a relapse of axSpA. It is primarily important to treat the causative disease when PNGD manifests. However, PNGD-specific treatment options are dapsone and topical, intralesional, and systemic corticosteroids, whereas NSAIDs, methotrexate, cyclosporine, cyclophospha- mide, hydroxychloroquine, colchicine, and TNF-α inhibitors have been prescribed in the literature because of underlying diseases and have shown various success in remitting skin lesions. Regres- sion of skin changes is spontaneous in 20% (1). In a case series involving 52 patients with either PNGD (11.6%) or IGD (88.4%), cu- taneous lesions completely disappeared in 76.9% of patients, but it was not specified how many of these received treatment (20). However, in our case PNGD only partially regressed after systemic and local corticosteroid therapy. Moreover, axSpA progressed de- spite methylprednisolone treatment. Therefore, treatment with adalimumab was initiated. To conclude, PNGD is a rare granulomatous reaction pattern that can occur concomitantly with several systemic disorders that must be excluded during the patient’s diagnostic workup. Because PNGD can manifest before systemic disease occurrence, in the ab- sence of triggers, regular patient monitoring is recommended. References 1. Rosenbach M, English JC 3rd. 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S5 Acta Dermatovenerol APA | 2022;31 Suppl:S2-S6 PNGD triggered by axial spondyloarthritis Ta bl e 1 | D iff er en tia l d ia gn os is o f p al is ad ed n eu tro ph ili c g ra nu lo m at ou s de rm at iti s w ith re fe re nc es . 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Co nc om ita nt ly m ph o- pr ol ife ra tiv e di so rd er s Ho dg ki n’ s ly m ph om a, no n- Ho dg ki n’ s ly m ph om a, C M L Ly m ph om a, M DS , m ye lo dy sp la si a w ith le uk em ic pr og re ss io n, le uk em ia – Po ss ib le in di ss em in at ed fo rm – – M DS , A M L, C M L, m ul tip le m ye lo m a, ha iry ce ll le uk em ia , e tc .– Pa ra pr ot ei ne m ia s, ly m ph om a, m ul tip le m ye lo m a, M DS S6 Acta Dermatovenerol APA | 2022;31 Suppl:S2-S6Š. Šuler Baglama et al. AC E = an gi ot en si ne c on ve rta se e nz ym e, A CE i = a ng io te ns in e co nv er ta se e nz ym e in hi bi to rs , A D = at op ic d er m at iti s, A I = a ut oi m m un e, A M L = ac ut e m ye lo id le uk em ia , A NC A = an ti- ne ut ro ph il cy to pl as m ic a nt ib od y, a nt i-C CP = cy cl ic ci tru lli na te d pe pt id e an tib od y, a xS pA = a xi al s po nd yl oa rt hr iti s, B B = be ta a dr en er gi c b lo ck er s, C CB = ca lc iu m c ha nn el b lo ck er s, C M L = ch ro ni c m ye lo ge no us le uk em ia , C M V = cy to m eg al ov iru s, C RP = C -re ac tiv e pr ot ei n, D M = de rm at om yo si tis , E SR = e ry th ro cy te s ed im en ta tio n ra te , F = fe m al e, G I = g as tro in te st in al in fe ct io n, G -C SF = g ra nu lo cy te c ol on y- st im ul at in g fa ct or , H B = he pa tit is B , H C = he pa tit is C , H IV = h um an im m un od efi ci en cy v iru s, IB D = in fla m m at or y bo w el d is ea se , I FN = in te rfe ro n, Ig = im m un og lo bu lin , M = m al e, M DS = m ye lo dy sp la st ic s yn dr om e, M S = m ul tip le s cl er os is , N SA ID = n on -s te ro id al a nt i-i nf la m m at or y dr ug , P G = py od er m a ga ng re no su m , R A = rh eu m at oi d ar th rit is , R F = rh eu m at oi d fa ct or , R TI = re sp ira to ry tr ac t i nf ec tio n, S CL E = su ba cu te cu ta ne ou s l up us e ry th em at os us , S LE = sy st em ic lu pu s e ry th em at os us , T B = tu be rc ul os is , T M P- SM X = tri m et ho pr im /s ul fa m et ho xa zo le , TN F = tu m or n ec ro si s fa ct or , U C = ul ce ro us co lit is , U V = ul tra vi ol et , U TI = u ro ge ni ta l t ra ct in fe ct io n, V ZV = va ric el la zo st er vi ru s. Ta bl e 1 | C on tin ue d. Pa lis ad ed ne ut ro ph ili c gr an ul om at ou s de rm at iti s (1 ) In te rs tit ia l gr an ul om at ou s de rm at iti s (1 ) In te rs tit ia l gr an ul om at ou s dr ug re ac tio n (1 ) Gr an ul om a an nu la re (8 ) Rh eu m at oi d no du le s (8 ) Cu ta ne ou s sa rc oi do si s (2 1) Sw ee t’s s yn dr om e or a cu te fe br ile ne ut ro ph ili c de rm at os is (2 2) Fr ic tio na l lic he no id de rm at iti s (2 3) Er yt he m a el ev at um et d iu tin um (2 4) Co nc om ita nt so lid o rg an m al ig na nc ie s – Un co m m on (b re as t, en do m et ria l, lu ng , es op ha ge al ) – Po ss ib le in di ss em in at ed fo rm – – Br ea st , p ro st at e, o ra l, ce rv ic al , g as tri c, lu ng ca nc er , m el an om a, e tc .– Lu ng , b re as t Co nc om ita nt in fe ct io ns HC Pu lm on ar y co cc id io m yc os is , B . bu rg do rfe ri in fe ct io n – VZ V – – RT I, GI , n on - tu be rc ul os is m yc ob ac te ria , H IV , T B, UT I, HC , H B, V ZV , C M V, ba ct er ia l e nd oc ar di tis – HI V, T B, H B, H C, st re pt oc oc ca l in fe ct io n, ra re ly ot he rs Ot he r po ss ib le un de rly in g tri gg er s – Di ab et es , pu lm on ar y si lic os is – Di ab et es , dy sl ip id em ia – – Pr eg na nc y, tr au m a, ra di at io n th er ap y M ay b e a m in or m or ph ol og ic va ria nt o f A D, b ut po ss ib ly n ot ; UV li gh t Di ab et es Dr ug -in du ce d va ria nt TN F- α in hi bi to rs , al lo pu rin ol , le di pa sv ir/ so fo sb uv ir TN F- α in hi bi to rs , fu ro se m id e, A CE i CC B, B B, lip id -lo w er in g ag en ts , A CE i, br om ph en ira m in e, ra ni tid in e, bu pr op io n, fu ro se m id e, tra st uz um ab , th al id om id e, al lo pu rin ol Va cc in es , al lo pu rin ol , to pi ra m at e, g ol d, TN F- α in hi bi to rs , IF N- α – – G- CS F, az at hi op rin e, al l-t ra ns re tin oi d ac id , h yd ra la zi ne , bo rte zo m ib , T M P- SM X, te tra cy cl in es , N SA ID , va cc in at io n, e tc . – – Hi st ol og y Ea rly le si on s: ne ut ro ph ili c in fil tra te , le uk oc yt oc la st ic va sc ul iti s, an d co lla ge n de ge ne ra tio n; o ld er le si on s: in te rs tit ia l an d/ or p al is ad ed gr an ul om at ou s in fil tra te s su rro un di ng co lla ge n de ge ne ra tio n In te rs tit ia l hi st io cy te s su rro un di ng fo ci of d eg en er at ed co lla ge n th at ca n le ad to cl eft in g na m ed “ flo at in g si gn ”, th e hi st io cy te s m ay fo rm s m al l gr an ul om as , va sc ul iti s is a bs en t, m uc in is g en er al ly ab se nt In te rfa ce d er m at iti s, di ffu se in te rs tit ia l hi st io cy te s w ith gr an ul om as , su rro un di ng fo ci of d eg en er at ed co lla ge n, p ro m in en t tis su e eo si no ph ili a In te rs tit ia l an d pa lis ad ed gr an ul om at ou s in fil tra te , ne cr ob io si s, m uc in de po si tio n Pa lis ad ed gr an ul om as w ith ce nt ra l m as si ve ne cr os is w ith fi br in de po si ts Sp ec ifi c m an ife st at io ns : na ke d or s ar co id al n on - ca se ou s gr an ul om as , co m m on ly m ul tin uc le at ed gi an t c el ls w ith in gr an ul om as ; no n- sp ec ifi c: re ac tiv e pr oc es s Di ffu se d er m al ne ut ro ph ili c in fil tra te , u su al ly w ith s up er fic ia l de rm al e de m a, so m et im es a ls o va sc ul iti s No ns pe ci fic pe riv as cu la r ly m ph oc yt ic in fil tra te Ea rly le si on s: le uk oc yt oc la st ic va sc ul iti s; la te le si on s: pe riv as cu la r fib ro si s, ex tra ce llu la r l ip id de po si ts