RETRACTED ARTICLE: Secukinumab-induced paradoxical skin lesions, but successful treatment with tofacitinib in SAPHO syndrome: a case report

synovitis, acne, pustulosis, hyperostosis, and osteitis (sapHo) syndrome is a rare autoinflammatorydisorder without standardized therapy. IL-17 inhibitors have been effective in individual cases. However, some patients with sapHo may develop psoriasiform or eczematous lesions as a paradoxical side of treatment with biologics. We describe a patient with both secukinumab-induced paradoxical skin lesions and primary sapHo syndromefor whom tofacitinib treatment led to rapid remission. a 42-year-old man with sapHo developed paradoxical eczematous lesions after 3 weeks of secukinumab treatment. He then received tofacitinib treatment, which resulted in a rapid improvement in his skin lesions and osteoarticular pain. tofacitinib might be a good treatment option for patients with sapHo syndrome who exhibit secukinumab -induced paradoxicalskin lesions.


Introduction
synovitis, acne, pustulosis, hyperostosis, and osteitis (sapHo) syndrome is a rare autoinflammatory disorder with unknown pathogenesis [1].Nonsteroidal and anti-inflammatory drugs (NsaIDs) are often used as first-line drugs to control symptoms [2].tumor necrosis factor (tNF)-αantagonists have been extensively used for relieving osteoarticular pain and cutaneous lesions [3,4].IL-17 inhibitors have been effective in individual cases [5].However, some sapHo patients may develop paradoxical psoriasiform or eczematous lesions with anti-IL17 biologics.Here, we describe a sapHo patient with secukinumab-induced paradoxical eczematous lesions for whom tofacitinib treatment led to rapid remission.

Case report
a 42-year-old male patient presented with a 2-year history of recurrent swelling and pain at the left sternoclavicular joint, arthralgia in the left sacroiliac joint and palmoplantar pustulosis.Celecoxib (0.2 g po bi-diurnally) was prescribed to control his arthralgia.Mometasone furoate ointment was prescribed for the skin lesions.His condition worsened over the next month.His overall pain intensity score was 8 of 10 on aVisual analog scale (Vas).the patient exhibited erythematous macules containing tiny superficial pustules on the palms and soles (Figure 1).Laboratory tests revealed that his hypersensitive C-reactive protein (hCRp) level was 3.40 mg/L (reference range, 0-1.00 mg/L).erythrocytesedimentation rate, antinuclear antibody, rheumatoidfactor, and human leukocyte antigen-B27 tests were all normal.99m tc-methylenediphosphonatewhole-body bone scintigraphy examination shown the enhanced radionuclide uptake in left sternoclavicular joint, sternum, left first anterior rib, and left iliac crest (Figure 2).sacroiliac joint Ct showedserrated changes of bilateral sacroiliac joints and slightly rough articular surface (Figure 3).He was diagnosed with sapHo syndrome [1].secukinumab 300 mg weekly was prescribed, but 3 weeks later, new-onset eczematous plaques, pustules, exudate, and light yellow scabs sequentially appeared on the extensor surface of his lower limbs, palms, and soles (Figure 4).there was almost no change inarthralgia.at the 5th week secukinumab was suspended.Boric acid solution and fluticasone propionate ointment were applied.at the 7th week, tofacitinib (5 mg po bi-diurnally) was administered.the patient's rash subsided with treatment of tofacitinib after 1 month (Figure 5). the sternoclavicular joints and sacroiliac joint pain also improved.after 4 months of tofacitinib treatment, all skin lesions had resolved (Figure 6); the sternoclavicular joints and sacroiliac joint pain had decreased with Vas of 0.

Discussion
our sapHo patient developed a paradoxical eczematous rash after secukinumab injections.as switching to tofacitinib, skin lesions and osteoarticular pain improved gradually and remitted.While the pathogenesis of sapHo syndrome remains unclear and the treatment is not standardized, IL-17 may be involved.th17 cells are present in the peripheral blood of sapHo patients [6], and IL-17 can promote osteogenesis [7].Moreover, there is a complex p o l yg e n i c b a c k gro u n d to s a p H o. pro l i n e -d e r i n e-threonine-phosphatase-interacting protein 2 (pstpIp2), LpIN2 (Lipin 2) and NoD2 (nucleotide-binding oligomerization domain-containing protein 2) potentially involve in the sapHo [8].and some sapHo patients showed variants in Nicastrin (NCstN), NLRC4 and WDR1 [9].secukinumab blocks IL-17a and can be effective for sapHo [10][11][12][13][14].In a case series of three patients with sapHo syndrome treated with secukinumab, two patients had an improvement in palmonplantar pustulosis (ppp) but not in skeletal involvement [15].the third patient had ppp and musculoskeletal symptoms, did not improve, and had paradoxical psoriasiform lesions.the mechanism of the paradoxical skin lesions remains unclear.Inhibition of th17 cytokines could cause a shift toward a th2-dominated immune response [16].IL-17 inhibition may also downregulate the levels of antimicrobial peptides produced by keratinocytes [17].IL-22 may be a trigger of the spongiotic phenotype induced by anti-IL17a [18].Finally, IL-17a inhibition could induce overproduction of other isoforms of IL-17, which in turn trigger eczema [17].several risk alleles have equivalent risk profiles for psoriasis and atopic eczema [19].a single genetic variant can have multiple phenotypiccon sequences (pleiotropy), and patients possessing these particular alleles could beat greater risk of concurrently developing eczema under certain conditions.
JaKs are important intracellular signaling mediators.Blocking the JaKs can inhibit the function of a number of cytokines directly or indirectly, including γ-chaincytokines, IL-1, IL-6, IL-7, IL-12, IL-15, IL-17, IL-22, IL-23, and tNF-α.tofacitinib is a novel small-molecule inhibitor of JaKs.Four cases of successful sapHo treatment using tofacitinib have been reported since tofacitinib was launched in China in 2017 [20][21][22][23].In 2020, a retrospective analysis of theeffect of tofacitinib in 12 sapHo patients shown multidimensional improvement [24].tofacitinib was effective in sapHo patients with poor response to traditional agents and those unable to tolerate traditional drugs or biological agents [21,25].In our case, the patient's ppp, paradoxical lesions, and arthralgia improved rapidly after receiving tofacitinib.the JaK inhibitor tofacitinib may be a good option for sapHo patients, including those who had biologic-induced paradoxical skin lesions.

Figure 3 .
Figure 3. the computed tomography image showed changes of bilateral sacroiliac joints(red arrow).

Figure 4 .
Figure 4. Paradoxical rash on the extensor surface of his lower limbs, palms, and soles.