Plasma cell pododermatitis is a rare and poorly understood feline dermatosis that should not be overlooked during consultations, particularly due to the pain and therefore lameness it can cause. An overview of the latest knowledge, both in terms of etiopathogenesis, diagnosis, and the most recent treatments and published protocols.
Introduction and Nosological Framework
1.1. Definition and Nomenclature
Feline plasma cell pododermatitis (FPP) constitutes a rare inflammatory dermatosis characterized by massive infiltration of mature plasma cells in the dermis of the cat’s footpads. This entity, colloquially referred to by the English term pillow foot due to the swollen and soft appearance of affected pads, occupies a unique place in the veterinary dermatological landscape (Miller 2013). The disease is distinguished by its exclusive tropism for paw tissue, with no exact equivalent in dogs or humans, although pathophysiological parallels can be drawn with certain human cutaneous plasma cell proliferations. Nosologically, FPP belongs to the group of feline plasma cell dermatoses, a spectrum that includes chronic plasma cell stomatitis and, more controversially, certain forms of extra-paw plasma cell dermatitis (Gross 2005). The infiltrate is composed of more than 90% well-differentiated plasma cells expressing the CD138 marker (syndecan-1), which formally distinguishes it from plasma cell neoplasias such as extramedullary plasmacytoma, where the Ki-67 proliferation index typically exceeds 20% (Mauldin 2016).
Classic appearance of feline plasma cell pododermatitis
1.2. Historical Milestones and Evolution of Knowledge
The first clinicopathological descriptions of FPP date back to the late 1970s, when Gruffydd-Jones, Orr, and Lucke published in 1980 a series of five cats presenting with swelling and ulceration of the footpads associated with dense dermal plasma cell infiltration (Gruffydd-Jones 1980). This foundational publication established the basic morphological criteria that still guide recognition of the condition. During the following decade, Taylor and Schmeitzel reported in 1990 two cases complicated by chronic hemorrhages in the footpads, highlighting the evolutionary potential of the disease toward deep ulceration and vascular fragility (Taylor 1990). The advent of serological testing for feline immunodeficiency virus (FIV) in the 1990s made it possible to highlight a statistical association between retroviroses and FPP, a link explored in several retrospective series showing FIV seroprevalence ranging from 20 to 62% in affected cats, compared to 2 to 4% in the general feline population (Guaguère 2004; Dias Pereira 2003). The retrospective study by Guaguère and colleagues, covering 26 cases, constitutes to date one of the largest published cohorts and has contributed to refining the understanding of the epidemiological profile and therapeutic response (Guaguère 2004). The introduction of doxycycline as first-line treatment in the early 2000s represented a therapeutic turning point, offering an alternative to long-term corticosteroid therapy with a complete response rate approaching 50 to 65% according to series (Bettenay 2003).
Epidemiology
2.1. Prevalence and Incidence Data
FPP remains an uncommon condition whose exact prevalence is difficult to establish, partly due to probable underdiagnosis related to spontaneous resolution of certain benign forms. Available data, from veterinary dermatology referral centers, place its frequency between 0.5 and 1.5% of all feline dermatological consultations (Miller 2013). In the series by Dias Pereira and Faustino, analyzing 8 cases diagnosed over a seven-year period in a Portuguese university center, annual incidence is estimated at approximately 1.1 cases per 1,000 feline consultations (Dias Pereira 2003). This relative rarity does not exclude underestimated prevalence in general practice, since early non-ulcerated stages frequently go unnoticed. No significant geographic variation has been reported, with cases documented on all continents, from Europe to North America, including Asia and Australia (Hnilica 2017). The sporadic nature of the disease, without temporal or spatial clustering phenomena, argues against a direct transmissible infectious etiology and points more toward an individual dysimmune pathogenesis.
2.2. Demographic Risk Factors: Breed, Age, and Sex
Unlike many feline dermatoses for which genetic determinism has been identified—for example the PNPLA1 gene in Golden Retriever ichthyosis or the KRT10 gene in epidermolytic ichthyosis—no clear breed predisposition has been demonstrated for FPP (Miller 2013). The majority of reported cases involve domestic shorthair cats, which reflects the predominance of this population in veterinary consultations rather than specific genetic susceptibility. Guaguère’s cohort included 23 European cats out of 26 (88.5%), with the remaining three being respectively a Persian, a Siamese, and a Chartreux (Guaguère 2004). Analysis of the Dias Pereira series confirms this absence of breed predisposition, with distribution proportional to the reference population (Dias Pereira 2003).
Age at diagnosis varies considerably, ranging from 6 months to 14 years, with a median between 4 and 7 years according to studies (Gross 2005; Guaguère 2004). This wide age range suggests that the disease corresponds neither to a juvenile developmental condition nor to a strictly geriatric pathology, but that it can occur at any time in adult life depending on the convergence of individual immunological factors. Regarding sex, data remain contradictory. Some series report a slight predominance for males with a sex ratio of 1.4:1 in favor of males (Guaguère 2004), while others find no significant difference. Reproductive status (intact or neutered) does not appear to exert a determining influence, although most cats included in published studies are neutered, consistent with feline population management practices in industrialized countries. The absence of an identified genetic polymorphism associated with FPP contrasts with other feline immune dermatoses, such as the eosinophilic granuloma complex where polygenic genetic factors have been suspected, and reinforces the hypothesis of an acquired pathogenesis involving environmental or infectious cofactors.
Etiopathogenesis: A Multifactorial Immune Dysregulation
3.1. Arguments in Favor of a Dysimmune Origin
The etiology of FPP remains incompletely elucidated to date, but all clinical, biological, and histopathological data converge toward an immune-mediated pathogenesis. Several arguments support this hypothesis. The first is based on the very nature of the infiltrate, composed almost exclusively of mature polyclonal plasma cells, indicators of chronic and sustained antigenic activation of the B lymphocyte compartment. Immunohistochemical analysis reveals that these plasma cells express both kappa and lambda light chains of immunoglobulins in a physiological ratio of approximately 2:1, excluding a monoclonal neoplastic process (Gross 2005; Mauldin 2016). The second argument stems from polyclonal hypergammaglobulinemia documented in 50 to 63% of affected cats, indicating diffuse stimulation of the humoral immune system, without identified antigenic specificity (Guaguère 2004). Serum protein electrophoresis reveals elevation of gamma fractions without monoclonal peak, formally distinguishing this condition from multiple myeloma or secretory plasmacytoma. Finally, favorable response to immunomodulatory or immunosuppressive agents—doxycycline, glucocorticoids, cyclosporine—constitutes an indirect therapeutic argument in favor of a dysimmune mechanism (Bettenay 2003; Miller 2013).
Detection of antinuclear antibodies (ANA) in a non-negligible proportion of affected cats, estimated between 25 and 50% according to series, reinforces the autoimmune hypothesis, although the clinical significance of these ANA remains debated in feline medicine (Dias Pereira 2003). Their presence could reflect non-specific lymphocyte activation rather than true self-directed reactivity. Direct immunofluorescence analysis of footpad biopsies has demonstrated deposits of IgG, IgM, and complement C3 fraction at the dermo-epidermal junction and around dermal vessels in a majority of cases, a pattern suggestive of immune complex disease (Gross 2005). These deposits resemble those observed in feline systemic lupus erythematosus, suggesting a partially shared pathophysiological mechanism involving the classical complement pathway triggered by C1q fragment fixation to antigen-antibody complexes.
3.2. Involvement of Feline Immunodeficiency Virus and Retroviruses
The association between FPP and FIV infection constitutes one of the most discussed aspects of etiopathogenesis. Several retrospective studies report significantly higher FIV seroprevalence in cats with FPP than in the general population. In Guaguère’s series, 50% of the 26 tested cats were seropositive for FIV, a rate markedly higher than the expected prevalence of 2 to 4% in the European domestic feline population (Guaguère 2004). Dias Pereira and Faustino found a seroprevalence of 62.5% in their cohort of 8 cases (Dias Pereira 2003). FIV, a lentivirus of the Retroviridae family, causes profound dysregulation of adaptive immunity through progressive depletion of CD4+ T lymphocytes and chronic polyclonal activation of B lymphocytes. This phenomenon, mediated by direct stimulation of Toll-like receptor 7 (TLR7) by single-stranded viral RNA and aberrant secretion of IL-6, promotes plasma cell differentiation and non-specific immunoglobulin production (Hartmann 2012). Activation of the JAK1/STAT3 pathway downstream of the IL-6 receptor constitutes a key mechanism of this excessive plasmacytogenesis, with phosphorylated STAT3 transcription factor translocating to the nucleus to induce expression of BLIMP-1 (PRDM1), the master regulator of terminal B lymphocyte differentiation into plasma cells (Nutt 2015).
Association with feline leukemia virus (FeLV) is less well documented, with seroprevalence rates oscillating between 0 and 20% according to cohorts, figures that do not always differ significantly from the reference population (Guaguère 2004; Miller 2013). However, FPP can occur in cats seronegative for both FIV and FeLV, indicating that retroviral infection is neither necessary nor sufficient to trigger the disease. It probably acts as an amplifying cofactor of preexisting immune dysregulation, lowering the tolerance threshold and promoting breakdown of B compartment homeostasis.
3.3. Suspected Environmental and Infectious Cofactors
Beyond retroviruses, other infectious agents have been suspected as potential triggers without formal proof being provided. Some authors have suggested the role of chronic antigenic stimulations linked to bacterial or fungal agents in contact with footpads, but no systematic microbiological culture has demonstrated a specific pathogen associated with the disease (Miller 2013). The hypothesis of contact hypersensitivity or foreign body reaction has been proposed, without experimental support. Cases of FPP occurring after vaccination or dietary change have been anecdotally reported, but no causal link has been established (Scarampella 2004). The role of epigenetic factors modulating expression of genes involved in B compartment regulation—such as post-translational modifications of histones or DNA methylation at PRDM1 and IRF4 promoters—remains an unexplored research field in feline medicine.
Molecular Immunopathology
4.1. Plasma Cell Ontogeny and Implicated Signaling Pathways
Understanding FPP requires detailed knowledge of plasma cell biology. Terminal differentiation of B lymphocytes into mature immunoglobulin-secreting plasma cells is orchestrated by a hierarchical network of transcription factors. The BLIMP-1 factor, encoded by the PRDM1 gene, acts as a transcriptional repressor of the B cell program, inhibiting expression of PAX5 and BCL6, two factors essential for maintaining germinal center B lymphocyte identity (Nutt 2015). Simultaneously, the IRF4 factor (MUM1) binds synergistically with BLIMP-1 to activate the secretory program, inducing expression of XBP1, a key mediator of the unfolded protein response (UPR) that allows expansion of the endoplasmic reticulum necessary for massive immunoglobulin production. In the context of FPP, this cascade appears constitutively activated in plasma cells resident in the footpad dermis, as suggested by intense immunostaining for MUM1/IRF4 and CD138 (syndecan-1) observed on biopsies (Mauldin 2016; Gross 2005).
The IL-6/JAK1/STAT3 signaling pathway plays a central role in plasma cell expansion. Interleukin 6, produced locally by macrophages and dermal fibroblasts in response to inflammatory signals, binds to its membrane receptor (IL-6Rα/gp130), activating JAK1 tyrosine kinase which phosphorylates STAT3 factor. Phosphorylated STAT3 dimerizes and translocates to the nucleus, where it directly induces transcription of PRDM1 and IRF4 (Nutt 2015). This autocrine and paracrine circuit could be perpetuated in footpads by a microenvironment rich in pro-inflammatory cytokines, particularly TNF-α and IL-1β, which in turn stimulate IL-6 production by stromal cells via activation of the canonical NF-κB pathway (p65/RelA). The cytokine BAFF (B-cell Activating Factor, also called BLyS), a member of the TNF superfamily, constitutes a crucial survival factor for long-lived plasma cells. BAFF binds to BCMA and TACI receptors expressed on the plasma cell surface, activating the non-canonical NF-κB pathway (RelB/p52) and inhibiting mitochondrial apoptosis through overexpression of BCL-2 and MCL-1 (Mackay 2009). Excess serum BAFF, documented in several human autoimmune diseases, could constitute an analogous pathophysiological mechanism in FPP, although measurement of this cytokine has not yet been performed specifically in affected cats.
4.2. Hypergammaglobulinemia and Immune Complex Deposits
Polyclonal hypergammaglobulinemia, found in 50 to 63% of cats with FPP, reflects diffuse and non-specific activation of the plasma cell compartment (Guaguère 2004). Serum protein electrophoresis reveals elevation of the gamma fraction without restricted peak, with IgG levels that can reach two to three times the upper normal limit. Excessive immunoglobulin production, in the absence of an identified target antigen, leads to formation of circulating immune complexes that deposit in highly vascularized tissues, particularly renal glomeruli and footpad dermis. These deposits have been demonstrated by direct immunofluorescence as granular deposits of IgG, IgM, and complement C3 fraction along the epidermal basement membrane and around dermal vascular walls (Gross 2005). The deposition mechanism resembles that of type III hypersensitivity reaction (Gell and Coombs classification), where intermediate-sized immune complexes escape clearance by the reticuloendothelial system and precipitate in vascular walls, triggering a local inflammatory cascade.
4.3. Complement Activation and Inflammatory Cascade
Immune complex deposits activate the classical complement pathway by fixation of C1q fragment to the Fc portion of aggregated immunoglobulins. This sequential activation (C1q → C1r/C1s → C4 → C2 → C3 convertase) leads to cleavage of C3 into C3a (anaphylatoxin) and C3b (opsonin), then to formation of the C5b-9 membrane attack complex causing direct cell lysis (Gross 2005). Anaphylatoxins C3a and C5a act as potent chemoattractants for neutrophils and macrophages, amplifying local inflammation. Release of lysosomal proteases (elastase, cathepsin G) by recruited neutrophils contributes to degradation of the footpad dermal extracellular matrix, explaining the characteristic soft and spongy texture of affected tissue (Miller 2013). Serum C3 measurement, when performed, sometimes shows a decrease compatible with consumption by in vivo activation, a classic phenomenon in immune complex diseases.
4.4. Matrix Metalloproteinases and Tissue Destruction
Destructive remodeling of footpad connective tissue involves matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases capable of degrading extracellular matrix components. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are particularly involved in degradation of type IV collagen and laminin at the basement membrane level, while MMP-1 (interstitial collagenase) cleaves fibrillar collagen types I and III that constitute most of the footpad dermal framework (Sapadin 2006). Expression of these MMPs is induced by TNF-α and IL-1β via activation of transcription factor AP-1 (c-Fos/c-Jun) and the NF-κB pathway. Progressive collagen destruction, combined with inflammatory edema and massive cellular infiltration, results in the characteristic volume increase of the footpad, whose consistency changes from firm to doughy. The central role of MMPs in pathogenesis provides direct pharmacological rationale for use of doxycycline, whose inhibitory activity on MMPs constitutes one of the best-documented mechanisms of action independent of its antibacterial activity (Griffin 2010).
Clinical Presentation
5.1. Footpad Semiology
The clinical presentation of FPP is usually characteristic and allows diagnostic orientation from macroscopic examination. The elementary lesion consists of diffuse and symmetric swelling of one or more footpads, giving the affected pad a swollen, rounded appearance, noticeably larger than normal. Metacarpal and metatarsal central pads are preferentially affected in more than 80% of cases, although digital pads may also be involved (Miller 2013). Involvement is most often bilateral and affects all four limbs simultaneously in approximately 50% of reported cases (Guaguère 2004). The pad surface has a violet-bluish to lilac coloration, sometimes described as local cyanosis, reflecting vascular engorgement and deep dermal inflammation. This hue is observed especially on lightly pigmented pads and may be masked on naturally dark pads. A highly evocative semiological sign lies in the striated appearance of the surface, with fine whitish crossed striations forming a network (cross-hatching), resulting from tension exerted by edematous tissue on the thinned pad epidermis (Gross 2005). Palpation reveals a soft and doughy consistency, clearly distinct from the normal firmness of a healthy pad, reflecting destruction of dermal collagen architecture and massive cellular infiltration. Pain is generally absent in early stages, and lameness, when present, most often indicates secondary ulceration.
Advanced form with opening of the central pad
5.2. Natural Evolution and Complications
FPP evolution is variable and unpredictable. A significant proportion of cases, estimated between 10 and 30%, may present spontaneous resolution without therapeutic intervention, within a period of several weeks to several months (Miller 2013). This spontaneous regression reinforces the hypothesis of a reactive process to a transient antigenic stimulus. However, evolution toward ulceration constitutes the most feared complication, occurring in 30 to 50% of untreated cases (Guaguère 2004). Ulceration manifests as loss of pad epidermis, exposing the infiltrated and fragile dermis, often accompanied by secondary hemorrhage sometimes profuse due to inflammatory neovascularization and fragility of vessel walls weakened by immune complex deposits and MMP action (Taylor 1990). Bacterial superinfection of the ulcer constitutes an additional risk, though not systematic. Pain accompanying ulceration then causes marked lameness, reluctance to move, and sometimes compulsive licking that perpetuates the erosive phenomenon. A few exceptional cases of recurrent bleeding having led to iron-deficiency anemia have been documented, emphasizing the need for hematological monitoring in cats with chronic ulcerations (Taylor 1990).
5.3. Associated Extra-paw Manifestations
FPP is not always limited to isolated paw involvement. Associations with other plasma cell manifestations have been documented, suggesting an underlying systemic process. Plasma cell stomatitis, characterized by plasma cell infiltration of oral mucosa (particularly the palate and glossopalatine arches), has been described concomitantly with FPP in 10 to 20% of cases according to series (Miller 2013; Guaguère 2004). Simultaneous association of these two entities in the same animal constitutes a strong argument in favor of a systemic B compartment disorder. Renal involvement, in the form of immune complex glomerulonephritis or, more rarely, reactive AA-type renal amyloidosis, has been reported in cats with chronic FPP (Dias Pereira 2003). Deposition of amyloid substance, consisting of fibrils derived from serum amyloid A protein (SAA) produced in excess by the liver under stimulation by IL-6 and TNF-α during chronic inflammation, can lead to progressive renal failure. These morbid associations confer on FPP a systemic dimension that extends beyond the strictly dermatological framework and justifies a complete biological workup in any diagnosed cat.
Diagnostic Approach
6.1. Clinical Examination and Orientation Criteria
Diagnosis of FPP is based on a cluster of clinical, cytological, and histopathological arguments. Careful clinical examination of all four limbs, including inspection and palpation of all pads, constitutes the first step. The conjunction of painless swelling of one or more central pads, purple coloration, and doughy consistency in an adult cat strongly suggests the diagnosis. Complete dermatological examination should search for possible associated skin lesions at other sites, as well as oral cavity examination for concomitant plasma cell stomatitis. Evaluation of general condition, renal palpation, and lymph node status are part of the initial clinical workup (Miller 2013).
6.2. Contribution of Cytology
Fine-needle aspiration of the swollen pad, performed with a 22 to 25 gauge needle, constitutes a rapid and minimally invasive complementary examination, feasible during consultation. Smearing on a slide and May-Grünwald-Giemsa (MGG) or Diff-Quick staining reveals a cellular infiltrate composed of more than 80% mature plasma cells, recognizable by their eccentric nucleus, “spoke-wheel” chromatin, and abundant basophilic cytoplasm with a clear perinuclear halo corresponding to the hypertrophied Golgi apparatus (Gross 2005). Presence of Mott cells, plasma cells whose cytoplasm is distended by multiple spherical eosinophilic inclusions corresponding to Russell bodies (immunoglobulins aggregated in dilated endoplasmic reticulum), is a highly suggestive sign of FPP. These inclusions result from dysfunction of the UPR (XBP1-dependent) pathway no longer able to manage the secretory protein overload (Nutt 2015). Cytology, while strongly suggestive of the diagnosis, does not alone allow exclusion of extramedullary plasmacytoma, and histopathological confirmation remains recommended in atypical or unilateral cases.
6.3. Histopathology: The Diagnostic Standard
Skin biopsy, obtained by wedge biopsy or punch biopsy (6 mm punch), provides definitive diagnosis. Histopathological examination reveals a diffuse or nodular dermal infiltrate composed almost exclusively of mature plasma cells, occupying superficial and deep dermis, often extending to subcutaneous tissue (Gross 2005; Mauldin 2016). Plasma cells are well differentiated, without significant cytonuclear atypia, and the mitotic index is low, generally less than 1 mitosis per high-power field (×400), which formally distinguishes FPP from plasmacytoma. Lobular architecture of pad adipose tissue is preserved but invaded by the infiltrate. The epidermal basement membrane often appears thinned, and the overlying epidermis is atrophic, which predisposes to ulceration. Leukocytoclastic vasculitis, with fibrinoid necrosis of dermal arteriole walls and parietal infiltration by neutrophils with fragmented nuclei, frequently accompanies the plasma cell infiltrate and indicates immune complex participation in pathogenesis (Gross 2005). Immunohistochemistry confirms expression of CD79a (pan-B marker), CD138, and MUM1/IRF4 by plasma cells, with polyclonal expression of kappa and lambda light chains excluding monoclonal proliferation (Mauldin 2016). Russell bodies are demonstrated by PAS (Periodic Acid-Schiff) staining, appearing as PAS-positive, diastase-resistant intracytoplasmic inclusions.
6.4. Biological and Serological Workup
Biological workup completes the diagnostic picture and provides prognostic information. Complete blood count may reveal moderate lymphocytosis in some cats, as well as regenerative anemia in cases of chronic hemorrhage from ulcerated pads. Serum protein electrophoresis constitutes a key examination, demonstrating polyclonal hypergammaglobulinemia in 50 to 63% of cases, with total protein levels sometimes exceeding 90 g/L (Guaguère 2004). Specific immunoglobulin measurement, when available, shows predominant elevation of IgG, but IgA and IgM may also be increased. FIV and FeLV serology is systematically recommended, performed by rapid immunochromatography (detection of anti-FIV antibodies and FeLV p27 antigen) or ELISA, with PCR confirmation in case of clinical discordance (Hartmann 2012). Renal biochemistry (creatinine, SDMA, urine protein/creatinine ratio) should be evaluated to detect possible immune complex glomerulonephritis or associated renal amyloidosis. ANA detection by indirect immunofluorescence on HEp-2 cells completes the immunological workup, although its positive predictive value remains modest in cats (Dias Pereira 2003).
6.5. Differential Diagnosis
Differential diagnosis of FPP includes several entities affecting cat footpads. Extramedullary plasmacytoma, rare in paw location, is distinguished by its generally solitary, unilateral character, and higher mitotic index (> 5 mitoses/10 fields ×400) associated with monoclonality on immunohistochemistry (Mauldin 2016). Eosinophilic granuloma affecting pads is characterized by eosinophil-predominant infiltrate with flame-shaped collagenolysis images. Bacterial pododermatitis presents signs of infection (purulent exudate, warm swelling, marked pain). Pemphigus foliaceus, a frequent cause of crusty pododermatitis in cats, is distinguished by presence of pustules, crusts, and acantholysis on cytology and histology. Squamous cell carcinomas of pads, observed especially in white cats, typically present as asymmetric ulcero-proliferative lesions. Diffuse cutaneous mastocytosis, though very rare, can mimic pad swelling (Miller 2013; Hnilica 2017).
Therapeutic Management
7.1. Therapeutic Abstention and Spontaneous Resolution
The possibility of spontaneous resolution, documented in 10 to 30% of cases, constitutes a fundamental decision-making element (Miller 2013). In cats with limited, non-ulcerated, and non-painful involvement, an observation period of four to six weeks may be considered before any pharmacological intervention, with close clinical monitoring. This “watchful waiting” approach is justified especially since available treatments are not without side effects and the disease is not life-threatening in the absence of complications. The decision to treat is based on presence of ulceration, pain, lameness, recurrent hemorrhages, or lesion progression despite surveillance (Bettenay 2003).
7.2. Doxycycline: Pharmacological Rationale and Efficacy Data
Doxycycline constitutes, since the pioneering work of Bettenay and colleagues, the most widely documented first-line treatment in management of feline plasma cell pododermatitis. Its use is not based on antibacterial action—the condition having no demonstrated bacterial infectious etiology—but on its pleiotropic immunomodulatory properties, shared with the entire tetracycline family (Bettenay 2003). Molecularly, doxycycline inhibits the activity of several matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, by chelation of zinc ions necessary for their catalytic site. This inhibition limits degradation of type IV collagen and basement membrane, processes directly involved in destructive tissue remodeling observed within affected pads (Guaguère 2004). Furthermore, doxycycline exerts anti-inflammatory action by reducing prostaglandin E2 (PGE2) production via suppression of cyclooxygenase 2 (COX-2) expression in activated macrophages, and by decreasing nitric oxide (NO) synthesis through inhibition of inducible NO synthase (iNOS) (Sapadin 2006).
An additional mechanism, often underestimated in veterinary literature, concerns doxycycline’s ability to modulate T lymphocyte activation. In vitro work demonstrates that tetracyclines reduce T lymphocyte proliferation stimulated by mitogens and decrease expression of major histocompatibility complex class II (MHC-II) on antigen-presenting cell surfaces, thereby attenuating the adaptive immune amplification loop (Niimi 1998). In the context of plasma cell pododermatitis, where polyclonal hypergammaglobulinemia reflects dysregulated B activation, this action on antigen presentation has direct pathophysiological relevance.
The standard therapeutic protocol is based on oral administration of doxycycline at a dosage of 10 mg/kg once daily, for a minimum duration of six to eight weeks (Bettenay 2003). Compliance may be compromised by the risk of esophageal stricture, a cat-specific complication induced by tablet retention in the esophagus and local release of acidic pH causing focal mucosal necrosis. Prevalence of this complication has been estimated at approximately 3 to 5% of cats receiving solid forms of doxycycline without water follow-up (German 2005). Systematic administration of a 3 to 6 mL water bolus after each dose, or use of liquid formulation, significantly reduces this risk. Retrospective data compiled by Guaguère and Bensignor report a complete or partial clinical response rate of 50 to 65% after a first course of doxycycline, with observable improvement from the third week of treatment in responders (Guaguère 2004). Resolution manifests as progressive reduction of paw swelling, pad repigmentation, and regression of characteristic whitish striations.
Relapses after treatment discontinuation constitute a frequent clinical reality, documented in approximately 30 to 50% of initially responding cases within three to six months (Scarampella 2018). This observation suggests that doxycycline does not correct the underlying pathogenic mechanism but attenuates its effector manifestations. The question of maintenance treatment at reduced dose (5 mg/kg/day or every other day) remains debated for lack of controlled trial, although some clinicians empirically resort to it with results considered satisfactory in chronic relapsing forms.
7.3. Systemic Glucocorticoids
Systemic glucocorticoids represent the second most frequently employed therapeutic line, particularly when doxycycline proves insufficient or when clinical severity requires rapid immunosuppression. Their mechanism of action is based on binding to the cytoplasmic glucocorticoid receptor (GR), which, after nuclear translocation, acts as a transcription factor modulating expression of more than 200 genes involved in immune and inflammatory response (Cain 2017). The main anti-inflammatory effect passes through inhibition of transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), thus blocking transcription of interleukin-1β (IL-1β), IL-6, TNF-α, and multiple chemokines responsible for plasma cell recruitment within paw dermis.
Prednisolone, administered orally at a dose of 1 to 2 mg/kg/day for two to four weeks then in progressive tapering over four to six weeks, produces clinical response in 60 to 70% of cases according to published retrospective series (Taylor 2004). Methylprednisolone acetate by subcutaneous injection (4 mg/kg) has been used in refractory cases, with reported efficacy but less favorable long-term tolerance profile due to prolonged duration of action and impossibility of dose adjustment (Guaguère 2004). Dose-dependent adverse effects—polyuria-polydipsia, polyphagia, increased susceptibility to diabetes mellitus, urinary tract infections—limit long-term use in cats, a species notoriously sensitive to corticoid-induced insulin resistance. Development of iatrogenic diabetes mellitus has been estimated at 5 to 10% in cats receiving glucocorticoids for more than three months, this prevalence varying according to cumulative dose and individual risk factors such as obesity and advanced age (Lowe 2008).
Glucocorticoid weaning constitutes a delicate therapeutic time. Too rapid tapering exposes to relapse, while prolonged maintenance increases iatrogenic risks. Initial doxycycline-prednisolone combination, with relay by doxycycline alone after obtaining clinical remission, offers a pragmatic compromise often adopted in specialized practice (Scarampella 2018).
7.4. Cyclosporine and Calcineurin Inhibitors
Cyclosporine (cyclosporine A, CsA) has emerged as the therapeutic alternative of choice in refractory forms of feline plasma cell pododermatitis. Its mechanism of action, distinct from that of glucocorticoids, is based on formation of a complex with intracellular cyclophilin; this complex inhibits calcineurin, a calcium-dependent phosphatase essential for dephosphorylation of transcription factor NFAT (Nuclear Factor of Activated T-cells). Blocking NFAT prevents transcription of IL-2, a major cytokine of T helper lymphocyte clonal proliferation, and consequently reduces T help provided to B lymphocytes for isotype switching and plasma cell differentiation (Robson 2003). In a disease characterized by dense plasma cell infiltration and hypergammaglobulinemia, this targeting of T-B dialogue has direct pathophysiological relevance.
The recommended dosage in cats is 5 to 7 mg/kg/day orally, administered on an empty stomach to optimize bioavailability, which varies from 25 to 35% according to individuals (Latimer 2014). Several case series report response rates of 60 to 85% with cyclosporine, including in animals that had not responded to doxycycline or glucocorticoids (Bettenay 2003; Scarampella 2018). The onset of action is generally four to six weeks, a delay consistent with the mode of action on adaptive immune response. Digestive adverse effects—vomiting, diarrhea—affect approximately 15 to 25% of cats at treatment initiation, but frequently resolve with gradual dose introduction over one week or concomitant administration with a small amount of food (Roberts 2016).
Opportunistic infectious risk deserves careful monitoring. Toxoplasmosis reactivation, though rarely documented under cyclosporine in cats, has been reported during prolonged immunosuppression and constitutes a relative contraindication in seronegative individuals exposed to a high-risk environment (Last 2004). A pre-therapeutic Toxoplasma gondii serological workup is recommended by several experts, although the level of evidence remains limited for this specific indication. Topical tacrolimus (FK-506), another calcineurin inhibitor, has not been the subject of targeted studies in plasma cell pododermatitis, probably due to difficulty of application on the irregular pad surface and poor percutaneous penetration through thickened paw epidermis.
7.5. Other Immunomodulators
Several immunomodulatory agents have been used occasionally, without any benefiting from a level of evidence equivalent to that of doxycycline or cyclosporine. Chlorambucil, an alkylating agent of the nitrogen mustard family, has been used in severe and recalcitrant forms at a dosage of 0.1 to 0.2 mg/kg every other day, in combination with prednisolone (Taylor 2004). Its mechanism is based on DNA alkylation of proliferating lymphocytes, inducing interstrand cross-links that prevent replication and transcription, with preferential action on B lymphocyte lineages, which theoretically justifies its use in a plasma cell-mediated disease. The hematological toxicity profile requires monitoring by complete blood count every two to three weeks during the first two months of treatment. Significant myelosuppression, defined by neutropenia below 2,500/μL, occurs in approximately 10 to 15% of treated cats and requires temporary suspension (Lowe 2008).
Mycophenolate mofetil, a selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in de novo purine synthesis in lymphocytes, has been anecdotally reported in a few cases of plasma cell pododermatitis with variable results, at a dosage of 10 mg/kg twice daily orally (Backel 2013). Absence of controlled trial and scarcity of pharmacokinetic data in cats limit its recommendation.
Recombinant interferons represent a distinct immunomodulatory approach. Recombinant feline omega interferon (rFeIFN-ω), whose action passes through activation of the JAK-STAT pathway (particularly STAT1 and STAT2) via the type I interferon receptor, induces expression of interferon-stimulated genes (ISGs) and modulates the Th1/Th2 balance, which could theoretically correct the immune bias underlying plasma cell infiltration (de Mari 2004). A few clinical cases have reported improvement after subcutaneous or per-mucosal injection of omega interferon, but data remain too sporadic to draw solid conclusions.
7.6. Surgical Treatment
Surgical excision of affected pads constitutes an option reserved for focal forms severely ulcerated with secondary septic complications or for cases totally refractory to all medical options. Podoplasty has been described in isolated case reports, with resection of severely remodeled tissue followed by closure by advancement flap or second-intention healing under semi-occlusive dressing (Guaguère 2004). Functional outcomes depend on the extent of resection and number of pads involved. Multipaw involvement, which concerns 40 to 50% of cases, makes this approach technically difficult and ethically questionable when it would involve bilateral resection of weight-bearing pads.
Digital amputation has been reported in rare situations where a single digital pad presented irreducible swelling with deep ulceration and secondary osteomyelitis, but this eventuality remains exceptional in plasma cell pododermatitis, which rarely reaches underlying bone (Taylor 2004). Use of CO₂ laser for controlled vaporization of excess tissue has been empirically mentioned, but no study formally evaluates its efficacy or healing profile in this specific indication. Postoperative management systematically involves concomitant immunomodulatory treatment to prevent local recurrence, confirming that surgery treats only the tissue consequence without correcting causal immune dysregulation.
Prognosis and Long-term Follow-up
8.1. Response Rates and Remission Duration
Prognostic evaluation of feline plasma cell pododermatitis is based on essentially retrospective data, the absence of randomized controlled trials constituting a major limitation in comparative assessment of therapeutic response rates. Published series, collectively grouping between 100 and 150 documented cases over the past three decades, converge toward a generally favorable prognosis profile for non-ulcerated forms managed early (Guaguère 2004; Scarampella 2018). The complete remission rate, defined as total clinical resolution of paw lesions and normalization of pad texture, varies from 30 to 50% according to publications and treatment employed. Partial remission, characterized by clinical improvement exceeding 50% but with persistence of residual thickening or depigmentation, concerns an additional 20 to 30% of treated cases.
The natural history of the disease is remarkable for the possibility of spontaneous remissions, reported in 10 to 20% of cases according to the most complete retrospective series published to date (Bettenay 2003). This phenomenon, exceptional in feline immune-mediated diseases, raises the question of endogenous immunological regulation capable of restoring tolerance or suppressing the pathogenic plasma cell clone. The hypothesis of modulation by regulatory T lymphocytes (Treg), via production of IL-10 and TGF-β, which exert negative feedback on B differentiation and plasma cell survival, could explain this self-resolution phenomenon (Groux 1997). Direct demonstration of this hypothesis in plasma cell pododermatitis remains to be established by dynamic immunophenotyping studies.
Remission duration after medical treatment varies considerably. In doxycycline responders, median remission duration has been estimated between three and twelve months, with bimodal distribution: a group of durable responders (remission exceeding one year) and a group of early relapsers (remission less than three months) (Scarampella 2018). This heterogeneity suggests existence of pathogenically distinct subpopulations, potentially identifiable by immunological or histopathological biomarkers that remain to be defined. Under cyclosporine, prolonged remissions appear more frequent, with reported median durations of six to eighteen months, although therapeutic dependence—need to maintain low-dose maintenance treatment—concerns a significant proportion of cases (Bettenay 2003).
8.2. Identified Prognostic Factors
Identification of reliable prognostic factors remains a challenge in the absence of sufficiently large prospective cohorts. Several clinical and biological parameters have been associated, retrospectively and with variable levels of significance, with probability of therapeutic response. Degree of ulceration at diagnosis constitutes the most regularly identified negative prognostic factor: pads presenting deep ulceration with exposed underlying dermis respond less favorably to doxycycline alone and more frequently require second-line immunosuppression (Taylor 2004). Pathophysiological explanation lies in irreversible fibrous remodeling and secondary bacterial colonization that maintain the local inflammatory circle independently of the primary immunological mechanism.
Serum gammaglobulin level at diagnosis appears inversely correlated with prognosis: cats presenting marked hypergammaglobulinemia (exceeding 20 g/L) show lower complete remission rates than those whose gammaglobulins remain moderately elevated (Gruffydd-Jones 1980; Guaguère 2004). This observation reinforces the idea of a severity continuum reflected by the amplitude of systemic immune activation. Number of pads affected at initial presentation has also been correlated with prognosis: involvement of four or more pads is associated with significantly higher relapse probability than that observed in monopaw or bipaw forms (Scarampella 2018). FIV serology, when positive, does not appear to deterministically influence therapeutic response in available series, although the number of co-infected cases remains too small to draw statistically robust conclusions (Bettenay 2003).
Age at diagnosis has not been identified as an independent prognostic factor reproducibly, although some authors report a tendency toward more severe and relapsing forms in individuals under three years, potentially related to immaturity of immunological tolerance mechanisms (Taylor 2004). Development of standardized clinical scores, integrating lesional extent, degree of ulceration, biological parameters, and infiltrating immunophenotype, constitutes an unmet need that would allow homogenization of prognostic evaluation and comparison between studies.
Comorbidities and Concept of Feline Plasma Cell Syndrome
9.1. Plasma Cell Stomatitis
Association between feline plasma cell pododermatitis and plasma cell stomatitis (also designated chronic feline gingivostomatitis with plasma cell predominance) has been recognized since princeps descriptions of the disease and constitutes the strongest clinical argument in favor of a systemic plasma cell syndrome in cats (Gruffydd-Jones 1980). Co-occurrence prevalence varies from 10 to 35% according to series, the upper range being reported in studies that systematically explored the oral cavity in cats with pododermatitis (Guaguère 2004; Scarampella 2018). Plasma cell stomatitis is histologically characterized by dense plasma cell infiltrate of gingival and oral lamina propria, with Mott cells and Russell bodies identical to those observed in pads. Immunohistochemical analysis reveals predominance of polyclonal IgG, similar to the serum profile, and local overexpression of IL-1β, IL-6, and TNF-α in affected mucosae (Harley 2003).
Molecularly, chronic feline stomatitis has been associated with activation of the NF-κB pathway and overexpression of RANKL (Receptor Activator of Nuclear Factor Kappa-B Ligand) in gingival tissues, contributing to alveolar bone resorption observed in advanced forms (Arzi 2010). This latter pathway distinguishes stomatitis from pododermatitis, where the osteolytic component is absent or minimal. Stomatitis-pododermatitis comorbidity does not appear linked to FIV or FeLV status exclusively, since it is documented in cats seronegative for both retroviruses (Bettenay 2003). This finding reinforces the hypothesis of a common immunological background predisposing to aberrant plasma cell activation in distinct anatomical sites sharing characteristics of antigenic exposure (oral mucosae and paw epithelium, both subjected to chronic mechanical and microbial stimulations).
9.2. Glomerulonephritis and Renal Amyloidosis
Renal involvement constitutes a potentially serious complication of feline plasma cell pododermatitis, reported in a limited but significant number of cases. Immune complex glomerulonephritis has been histologically documented in cats presenting plasma cell pododermatitis associated with proteinuria and progressive azotemia (Gruffydd-Jones 1980). The pathogenic mechanism involves deposition of circulating immune complexes—formed by excess polyclonal immunoglobulins and their corresponding antigens—in the glomerular mesangium and along the glomerular basement membrane, with local complement activation by the classical pathway (C1q → C4 → C2 → C3) and recruitment of neutrophils and macrophages contributing to endothelial and podocyte lesions (Center 1990).
AA-type renal amyloidosis has been reported in rare cases of chronic plasma cell pododermatitis, serum amyloid A protein (SAA) being an acute phase protein synthesized by hepatocytes under the effect of IL-6 and IL-1β—cytokines whose production is chronically elevated in systemic plasma cell inflammation (DiBartola 1997). Exact prevalence of renal involvement remains difficult to estimate in the absence of systematic evaluation of proteinuria and renal function in published cohorts. However, recommendation of urine protein/creatinine ratio (UPCR) at diagnosis and in longitudinal follow-up appears justified in cats presenting marked hypergammaglobulinemia or chronic disease evolving for more than six months (Scarampella 2018).
9.3. Toward a Unified Nosological Spectrum
Accumulation of clinical and histopathological observations leads to considering plasma cell pododermatitis not as an isolated dermatological entity, but as the paw manifestation of a systemic feline plasma cell syndrome. This concept, implicit in Gruffydd-Jones’s work since 1980, has been formalized by Guaguère and Bensignor, who propose a nosological framework integrating pododermatitis, plasma cell stomatitis, immune complex glomerulonephritis and, more rarely, extra-paw plasma cell dermatitis affecting the pinna or nasal planum (Guaguère 2004). Pathophysiological unity of this spectrum is based on the common denominator of dysregulation of terminal B-plasma cell differentiation, with excessive polyclonal immunoglobulin production and tissue plasma cell deposition in anatomical sites predisposed by their local immune microenvironment.
This model recalls, by analogy, monoclonal gammopathies of undetermined significance (MGUS) and low-grade lymphoproliferative syndromes in human medicine, without establishing a strict parallel due to the polyclonal—not monoclonal—character of B activation observed in feline plasma cell syndrome (Mellor 2006). The boundary between polyclonal reactional activation and pre-neoplastic clonal proliferation would deserve exploration by B clonality techniques (PCR-PARR, for PCR for Antigen Receptor Rearrangement), which would allow detection of a possible dominant subclone within the apparently polyclonal infiltrate. Werner and colleagues’ study, having applied the PARR technique to plasma cell pododermatitis biopsies, confirmed polyclonal character in the majority of tested cases, but oligoclonal rearrangement was identified in approximately 15% of samples, raising the question of possible progression toward MALT (Mucosa-Associated Lymphoid Tissue) lymphoma in certain chronic cases (Werner 2011).
Perspectives and Research Directions
10.1. Diagnostic and Prognostic Biomarkers
Development of objective, non-invasive or minimally invasive biomarkers represents a priority for improving early diagnosis, therapeutic monitoring, and prognostic stratification of feline plasma cell pododermatitis. Serum protein electrophoresis, though useful for documenting hypergammaglobulinemia, lacks specificity and sensitivity for longitudinal monitoring. Measurement of serum free light chains (sFLC), widely used in human hematology for monitoring monoclonal gammopathies and myelomas, constitutes a relevant biomarker candidate. Free kappa and lambda light chains are produced in excess during plasma cell activation and their κ/λ ratio reflects the balance or clonal imbalance of the B population (Bradwell 2001). An ELISA test adapted to feline immunoglobulins has been developed, but its analytical and clinical validation in the specific context of plasma cell pododermatitis remains to be performed (Tasca 2018).
Serum cytokines offer another biomarker exploration axis. Measurement of IL-6, whose role in plasma cell survival via STAT3 activation is well established in human oncology (Kishimoto 2005), could allow identification of patients at risk for systemic forms (glomerulonephritis, amyloidosis). Similarly, serum BAFF (B-cell Activating Factor of the TNF Family), a major cytokine for mature B lymphocyte and plasma cell survival via activation of the non-canonical NF-κB pathway (RelB/p52), constitutes a potential biomarker and therapeutic target. Elevated BAFF levels have been correlated with severity of systemic autoimmune diseases in humans (systemic lupus erythematosus, Sjögren’s syndrome), and extrapolation to feline plasma cell syndrome appears biologically founded, though not yet experimentally explored (Mackay 2009).
The advent of tissue transcriptomics by RNA sequencing (RNA-seq) applied to pad biopsies would allow mapping gene expression of the plasma cell infiltrate, identifying molecular signatures associated with therapeutic response and potentially discovering therapeutic targets hitherto unsuspected. Decreasing cost of next-generation sequencing makes this approach feasible within multicenter studies, provided a tissue biobank is established in coordinated fashion.
10.2. Emerging Targeted Therapies
Beyond JAK inhibitors already mentioned, several emerging therapeutic classes in human medicine could find application in feline plasma cell syndrome. Anti-BAFF antibodies (belimumab) and anti-APRIL (A PRoliferation-Inducing Ligand, a BAFF-related ligand), which block plasma cell survival signals, have demonstrated efficacy in human lupus with significant reduction in autoantibody titers and decreased disease activity (Furie 2011). Development of feline-specific anti-BAFF monoclonal antibodies would represent a considerable advance, but faces the usual obstacles of development cost, GMP (Good Manufacturing Practice) production, and regulated veterinary clinical trials.
Proteasome inhibitors, such as bortezomib, which induce plasma cell apoptosis through accumulation of misfolded proteins and activation of the endoplasmic reticulum stress pathway (UPR, Unfolded Protein Response), constitute an attractive approach for selectively targeting disease effector cells (Neubert 2008). Their use in veterinary medicine remains confined to experimental oncology, with limited toxicological data in cats (thrombocytopenia, potential peripheral neurotoxicity).
Therapies based on autologous regulatory T cells expanded ex vivo, which aim to restore immunological tolerance by adoptive transfer of CD4+CD25+FoxP3+ Treg, represent the most ambitious horizon of research in immunotherapy for autoimmune diseases. Protocols for cell sorting, expansion, and reinjection developed in humans (Bluestone 2015) could theoretically be adapted to cats, but technical and financial challenges remain considerable, and no preclinical trial has been initiated in the specific context of plasma cell pododermatitis.
Conclusion
Feline plasma cell pododermatitis, long considered an anecdotal dermatological curiosity, now asserts itself as a fascinating clinical model at the interface of veterinary dermatology, immunology, and hematology. Understanding of this disease has progressed substantially since the princeps descriptions of Gruffydd-Jones in 1980, moving from a purely descriptive entity to an immunopathological syndrome whose molecular mechanisms—polyclonal plasma cell activation, dysregulation of IL-6/STAT3 and BAFF/NF-κB axes, immune complex deposition—are now partially elucidated. The therapeutic arsenal, dominated by doxycycline and cyclosporine, offers satisfactory response rates in the majority of cases, but the relapsing profile of the disease and heterogeneity of individual responses underscore the limitations of current approaches. The concept of systemic feline plasma cell syndrome, integrating pododermatitis, plasma cell stomatitis, and renal involvement, provides a coherent nosological framework that should guide future research toward systematic evaluation of extra-paw manifestations and prognostic stratification based on objective biomarkers. The rise of targeted therapies and regenerative medicine approaches offers encouraging prospects, provided the veterinary community equips itself with prospective multicenter studies and case registries allowing achievement of statistical power necessary for validation of these innovations.
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