Systemic immunopathological vasculitides are a large group of diseases associated with pathological autoimmunity. Their pathogenesis combines various links. Most often, they involve immune complex reactions due to hereditary and acquired defects in the physiological clearance of immune complexes. However, cytotoxic reactions and/or delayed-type hypersensitivity to vascular autoantigens are also common. Immune complexes tend to be deposited primarily in areas with relatively high blood pressure and convoluted vascular networks. Therefore, the most often affected are: vascular beds of the renal glomeruli, retina and vascular tracts of the eye, the periarticular vascular mesh, and choroid plexus. However, systemic immunopathological reactions can also cause other locations of inflammatory foci [1, 2]. That facets of pathogenesis, as well as the necessity to minimize organ damage, generally determine the tactics used to select biopsy sites for the pathomorphological diagnosis of these diseases.

The diagnosis of systemic vasculitis is probabilistic: clinicians integrate phenotype, laboratory biomarkers (including anti-neutrophil cytoplasmic autoantibodies (ANCA) when relevant), imaging, and — if feasible — also histopathologic data. Tissue confirmation retains enduring value because it can secure diagnosis when serology or imaging is equivocal; separate vasculitis from its mimics (infection, thrombosis/embolism, drug reactions, or malignancy); define vessel size and lesion pattern; and guide treatment intensity in organ-­damaging or life-threatening disease. Contemporary frameworks, including the 2012 Chapel Hill Consensus Conference (CHCC) nomenclature and the 2022 ACR/EULAR classification criteria for ANCA-associated vasculitides (AAV), refine clinicopathologic boundaries while acknowledging overlap phenotypes and secondary vasculitic syndromes complicating systemic autoimmune disease [3–6].

In routine practice, “traditional” biopsy sites dominate for pragmatic reasons: they are frequently involved, historically well studied, and supported by standardized pathology workflows. Kidney biopsy is central in suspected AAV with glomerulonephritis, providing histopathologic classification and risk stratification that influence prognosis and therapeutic choices [7, 8]. Skin biopsy offers rapid access to small-­vessel pathology and, when timed and sampled correctly, direct immunofluorescence (DIF) can add mechanistic information (immune-­complex patterns) that changes differential diagnosis and downstream testing [9, 10]. Nerve/muscle biopsy helps to confirm vasculitic neuropathy; combined sampling can modestly increase diagnostic yield in selected contexts at the cost of additional morbidity [11, 12]. Pulmonary tissue can demonstrate necrotizing granulomatous inflammation or capillaritis in granulomatosis-­polyangiitis (GPA) or ANCA-associated vasculitis (AAV), but is often a matter of high-risk in frail patients or in those with severe respiratory compromise; even when safely obtained, sensitivity is constrained by locality and disease phase [13].

Yet, conventional targets frequently fail clinicians at the bedside. Skin lesions may be absent, too old, or sampled too superficially. Renal biopsy may be contraindicated or delayed (due to anticoagulation, solitary kidney, or uncontrolled arterial hypertension). Nerve biopsy is invasive with potential permanent neurological deficit. Lung sampling may be unsafe or impractical. These constraints are particularly salient in secondary vasculitis (e. g., in rheumatoid vasculitis) where aggressive immunosuppression carries substantial toxicity and clinical mimics are common; here, “histologic certainty” can meaningfully alter risk–benefit calculus [14]. Against this backdrop, a practical question re-emerges: can less commonly sampled, relatively accessible tissues provide clinically decisive evidence when traditional sites are negative, unsafe, or unavailable?

Historically, rectal biopsy was proposed as a repeatable “blind” site capturing systemic vascular injury in submucosal vessels. Similarly, ocular surface tissue (conjunctiva) and oral mucosa (gingiva) can yield supportive or even strongly suggestive pathology in GPA when a corresponding phenotype exists, sometimes with lower morbidity than deep otorhinolaryngological, orbital, or pulmonary approaches [15–18]. Beyond these three, scattered case-based literature describes additional “underused” targets (e. g., major salivary glands in GPA), reinforcing a broader principle: biopsy site selection should match expected vessel size and tissue layer, not habit [19].

This review aims to: (i) map uncommon biopsy sites used for vasculitis diagnosis, with emphasis on rectum, conjunctiva, and gingiva; (ii) summarize diagnostic yield and safety where data exist; (iii) compare these sites with conventional strategies; and (iv) translate evidence into a practical, phenotype-­first approach suited to clinical review readership.

2.1. Review design

A narrative review was performed with a structured, multi-­source literature search complemented by reference chaining and targeted retrieval of older clinico-­pathologic series. It was focused on biopsy sites uncommon in routine vasculitis work-up, especially when used as a primary diagnostic tissue or as a surrogate (“blind”) site.

2.2. Eligibility criteria

We included publications describing histopathologic evaluation of uncommon biopsy sites in: (i) primary systemic vasculitides, especially GPA, microscopic poliangiitis (MPA) and eosinophilic granulomatosis with poliangiitis (EGPA) or in polyarteritis nodosa (PAN) and (ii) secondary vasculitis associated with systemic diseases (emphasis on rheumatoid vasculitis and lupus-­related gastrointestinal vasculitis/enteritis). Eligible designs: case reports/series, retrospective cohorts, clinico-­pathologic studies, books and systematic reviews if the biopsy site and histologic findings were explicit. We excluded reports lacking tissue confirmation from the uncommon site or not specifying the sampled site/technique sufficiently to interpret results. PubMed and elibrary.ru databases were used, without language restrictions.

2.3. Information sources and search strategy

Because uncommon biopsy sites are often represented in case-based literature, we combined database searching (MEDLINE/PubMed/elibrary.ru as the anchor) with extensive backward/forward citation chasing from seed papers, books and systematic reviews that explicitly searched multiple platforms. In particular, we used systematic reviews of oral GPA that searched Embase, Web of Science, elibrary.ru and additional indices as “retrieval amplifiers” to reduce the risk of missing non-traditionally indexed cases [20, 21]. Grey literature signals (conference abstracts, theses repositories, institutional archives) were screened when discovered via open-web indexing; however, for verifiability and stable identifiers, the final reference list prioritizes peer-reviewed, traceable items with PMID and/or DOI, or with elibrary.ru EDN code.

Seed sources included: the rectal biopsy clinico-­pathologic series [15], conjunctival biopsy reports and series of ocular involvement in GPA [16–18, 22,23], and the “strawberry gingivitis” clinicopathologic paper and oral GPA systematic reviews [19–21].

2.4. Outcomes

Primary outcome: diagnostic yield (positivity rate) of the uncommon biopsy site for histologic vasculitis compatible with systemic vasculitis, as reported by authors or extractable from numerators/denominators. Secondary outcomes: complications, technical requirements (serial levels, special stains), and circumstances where biopsy altered management or avoided higher-risk sampling.

2.5. Data extraction and synthesis

We extracted disease context, biopsy site and lesional/non-lesional status, technique when reported, histologic pattern, yield, and complications. Given heterogeneity and predominance of case-based evidence, meta-analysis was not planned. We performed structured qualitative synthesis emphasizing clinically actionable interpretation: when a site should be selected, what processing is required, and what a negative result can and cannot exclude.

The results obtained are presented in the text and in tables (Table 1 and Table 2).

Notes: RA, rheumatoid arthritis; RV, rheumatoid vasculitis; GPA, granulomatosis with polyangiitis; AAV, ANCA-associated vasculitis; PAN, polyarteritis nodosa; SLE, systemic lupus erythematosus; NR, not reported.

Conventional site	Typical vasculitis context	What it adds uniquely	Notes for comparison with uncommon targets
Kidney	AAV with glomerulonephritis	Diagnostic confirmation + prognostic classification and renal risk stratification	Often highest-stakes biopsy; uncommon sites rarely replace it when renal involvement is present
Lung	GPA/AAV pulmonary disease	Can show necrotizing granulomatous inflammation or capillaritis	Procedural risk varies widely; sensitivity constrained by focality; uncommon superficial sites may be preferable in high-risk situations
Skin	Small-vessel vasculitis; systemic vasculitis with rash	Rapid access; DIF can subtype immune-complex patterns	Yield depends on lesion age, depth, and timing; if absent or nondiagnostic, uncommon phenotype-driven sites may help
Peripheral nerve ± muscle	Vasculitic neuropathy	Documents epineurial vasculitis; combined biopsy can increase yield	Invasive with potential permanent deficit; rectal/muscle surrogate approaches may be considered when risk is unacceptable

Table 2. Conventional biopsy sites in systemic vasculitis: what they add, and how they compare conceptually to uncommon targets

Notes: AAV, ANCA-associated vasculitis; GN, glomerulonephritis; DIF, direct immunofluorescence; ENT, ear-nose-throat.

3.1. Rectal biopsy (submucosal vessels): the best-documented “blind” uncommon site, especially in rheumatoid vasculitis

Rectal biopsy is the most robustly documented uncommon site for systemic vasculitis, particularly in rheumatoid vasculitis. In the classic clinicopathologic experience [15] vasculitis was identified in rectal biopsies from 22 patients; 16 had vasculitis complicating rheumatoid arthritis, three had polyarteritis nodosa, and three had overlap syndromes. The most common pattern was necrotizing vasculitis of small arteries, described as histologically indistinguishable from PAN; subacute/chronic and leukocytoclastic features were also described. The key conceptual contribution of this work is not merely that vasculitis can be found in the rectum, but that submucosal vessels can serve as a surrogate compartment for systemic vascular injury when clinically threatened organs are not safely accessible.

The authors stated that an “adequate biopsy” was positive in 40% of patients with clinical vasculitis and rheumatoid arthritis. In 46 rheumatoid arthritis controls without clinical vasculitis, only one rectal biopsy was positive [15]. Although not designed as a formal diagnostic accuracy study, this control signal implies that rectal biopsy positivity is uncommon in unselected RA without vasculitis, supporting a clinically meaningful specificity in the appropriate pre-test context (suspected rheumatoid vasculitis).

Technique and processing are important as the determinants of yield. Rectal vasculitis can be focal; a single involved artery may be detected only after serial step sections through the specimen, and interpretation benefits from appropriate stains to define arterial wall injury and exclude mimics [15]. Practically, rectal biopsy “yield” is not purely anatomical; it is a function of sampling depth (submucosa), processing intensity (levels), and the pathologist’s directed search for small/medium-­artery lesions rather than superficial mucosal inflammation.

Safety and avoidable harm. Rectal biopsy was described as safe and repeatable in experienced hands, but serious complications occurred when technique deviated: two perforations were reported in patients biopsied via sigmoidoscope [15]. The practical lesson for modern practice is that rectal biopsy should be framed as low morbidity only when performed with technique that prioritizes controlled depth and minimizes perforation risk, with operator experience and institutional protocolization.

Clinical correlates and severity signal. Within the same series, rheumatoid arthritis patients with rectal vasculitis had higher mortality and more neuropathy than those with negative biopsies [15]. While confounding by severity is likely (sicker patients are more likely to have positive systemic vasculitis), this supports that a positive “blind” rectal biopsy is rarely incidental and often marks a high-risk systemic phenotype where timely aggressive therapy may be justified.

There is a question, how rectal biopsy fits contemporary rheumatoid vasculitis? Contemporary rheumatoid vasculitis is less common than in earlier decades, consistent with epidemiologic declines reported in large cohorts [24]. Nonetheless, it remains serious and diagnostically challenging; modern reviews emphasize the importance of clinicopathologic confirmation and careful exclusion of mimics before initiating high-risk immunosuppression [14]. Diagnostic strategy work in suspected rheumatoid vasculitis supports structured integration of clinical features, biomarkers, and tissue confirmation [25, 26]. In this framework, rectal biopsy can be positioned as a surrogate tissue option when conventional targets are absent or unsafe, particularly when neuropathy, systemic features, and high pre-test probability coexist.

3.2. Conjunctival biopsy: phenotype-­driven, minimally invasive tissue in GPA when ocular surface disease is present

The evidence base for conjunctival biopsy in GPA is smaller and largely case-based, but the clinical logic is strong: ocular involvement may precede systemic features, and conjunctival tissue can be sampled with relatively low morbidity compared with orbital or pulmonary biopsies. In an open-access report, a patient was diagnosed with GPA based on conjunctival biopsy pursued specifically to avoid more invasive lung biopsy after bronchoalveolar lavage was non-diagnostic [16]. Earlier and additional reports similarly describe conjunctival biopsy contributing decisively to diagnosis, including presentation with conjunctival ulceration where biopsy confirmed the clinical suspicion [17, 18].

When conjunctival biopsy is most plausible. Across published cases, conjunctival biopsy is most informative when it targets active, lesional tissue (e. g., conjunctival inflammation, ulceration) rather than normal-­appearing conjunctiva [16–18]. Limited samples may show vasculitis and mixed inflammatory infiltrates compatible with GPA even when classic necrotizing granulomatous features are absent, mirroring broader sensitivity constraints of GPA histology across sites.

Ocular case series emphasize that “classic triad” sensitivity is imperfect even in deeper tissues. In a series of orbital biopsies in Wegener’s granulomatosis, the triad of vasculitis, necrosis, and granulomatous inflammation was present in only about half of specimens, illustrating why a spectrum-­based interpretation is necessary and why clinical correlation remains essential [22]. Large experience cohorts also document the diversity of ocular manifestations and reinforce the value of establishing pathologic diagnosis when feasible [23].

Clinical advantage can be assessed as follows. Conjunctival biopsy’s value is time-to-supportive histology in a high-risk phenotype: when ocular disease is evolving and systemic suspicion is high, a low-morbidity biopsy may accelerate initiation of induction therapy and avoid higher-risk procedures. Since the literature is largely case-based, conjunctival biopsy should be presented as an opportunistic, phenotype-­driven target rather than a screening biopsy; negative results should not meaningfully lower probability of a disease if the sampled tissue was non-lesional or superficial.

3.3. Gingival biopsy: “strawberry gingivitis” as a high-yield phenotype in GPA

Oral cavity is a valuable source of diagnostic information in almost all somatic diseases, even those standing far from dental medicine area. Oral involvement in GPA is uncommon overall, but gingival lesions can be striking and may represent an early diagnostic clue. The classic paper on “strawberry gums” compared gingival histology in a case of GPA with 14 similar reported cases and emphasized that the accepted histopathologic triad was often sparse [19]. Instead, a distinctive constellation — pseudoepitheliomatous hyperplasia, microabscesses, and multinucleate giant cells — was present in almost all cases, and the authors concluded that this pattern in the right clinical context is virtually diagnostic [19]. This paper is particularly important for practice because it shifts the diagnostic mindset from “did we see the full triad?” to “did we see the disease-­associated pattern expected in this phenotype?”

Systematic evidence synthesis supporting phenotype targeting. Subsequent systematic reviews reinforce gingiva as a common oral site in reported cases and highlight strawberry gingivitis as a recurring presentation; they also document that biopsy is most commonly taken from the gums in oral GPA reports [20, 21]. One systematic review of oral GPA reported strawberry gingivitis as the most common clinical presentation among collected cases and described the gingiva as the most frequently affected site [20]. Another systematic review and case report synthesis of orofacial manifestations similarly underscores the value of dentists and clinicians recognizing oral phenotypes that can precede systemic confirmation [21].

Clinical implications for interpretation. Gingival biopsy is best framed as “high-yield when phenotype-­present.” It is not a general surrogate site for GPA in the absence of oral disease. When strawberry gingivitis is present, however, gingival biopsy can be disproportionately valuable because the clinical phenotype predicts a characteristic histologic signature even in case of a limited disease.

3.4. Muscle biopsy: a surrogate compartment bridging conventional and “uncommon” strategies

Skeletal muscle is sometimes considered conventional, yet its role as a relatively safe surrogate tissue — especially when kidney biopsy is contraindicated and no high-yield skin/ENT lesion is available — makes it conceptually similar to uncommon surrogate sites. In a single-­centre cohort evaluating muscle biopsy in AAV, muscle specimens were positive for vasculitis in 45/78 included cases (58%) at diagnosis, and the authors concluded that muscle biopsy is safe and efficient, with yield influenced by ANCA type, sex, and neutrophil count [27]. The key practice message is not that muscle replaces renal biopsy when glomerulonephritis is present, but that it can provide histologic confirmation when renal biopsy is unsafe or delayed and clinical urgency remains high.

In suspected vasculitic neuropathy, combined nerve/muscle biopsy can increase the probability of histologic confirmation. A study focused on additional yield reported incremental diagnostic value of combined biopsy in vasculitic neuropathy [11], and a large retrospective series supports combined nerve and muscle biopsy as a long-standing diagnostic approach in selected cases [12]. These data support a broader strategy: when lesion distribution is patchy and sensitivity is moderate at any single site, pairing adjacent tissues can increase yield without necessarily doubling complication risk.

3.5. Secondary vasculitis beyond rheumatoid arthritis: SLE gastrointestinal vasculitis/enteritis as a depth-and-compartment problem

A comprehensive diagnostic review should extend beyond primary vasculitis because clinicians frequently face secondary vasculitis in systemic disease where biopsy feasibility is constrained. In SLE, lupus mesenteric vasculitis is recognized as a cause of acute abdominal pain and is reviewed in Nat. Rev. Rheumatol. [28]. Lupus enteritis has also been synthesized with a series plus systematic review, underscoring diagnostic complexity and therapeutic implications [29]. For the present topic — uncommon sites — the key conceptual message is that negative endoscopic mucosal biopsies may occur when clinically relevant injury is in deeper submucosal or mesenteric vessels. This reframes site selection as an anatomic-­layer problem: sampling must match expected vessel caliber and compartment. Rectal submucosal biopsy is conceptually aligned with this “compartment matching” principle, even if the direct evidence base is strongest in rheumatoid vasculitis.

3.6. Other underused biopsy targets: a brief map of additional sites with case-based support

Besides rectum, conjunctiva, and gingiva, additional underused biopsy targets sometimes appear in the literature, typically as case reports/series rather than accuracy studies. Major salivary gland enlargement has been reported as a presenting feature of GPA, highlighting that accessible glandular tissue can sometimes yield diagnostic pathology when ENT or pulmonary targets are nondiagnostic or unsafe [30]. While these reports do not provide robust sensitivity estimates, they reinforce the clinical heuristic: when an unusual organ is clinically involved and safely accessible (salivary gland, oral lesions, or ocular surface), lesional biopsy may outperform “traditional” sites that are absent or risky.

4.1. Why uncommon sites matter: histology as a Bayesian test, not a binary oracle

Histology in vasculitis should be treated as a diagnostic test which utility depends on pre-test probability, lesion age, sampling adequacy, and pathology processing [2]. Uncommon sites can outperform expectations when selected because the phenotype predicts disease there (strawberry gingivitis; active conjunctival inflammation), or because they sample a compartment that reflects systemic vascular injury (rectal submucosa in rheumatoid vasculitis). The practical aim is not novel; it is to maximize the post-test probability change per unit procedural risk.

Rectal biopsy illustrates this principle vividly. A 40% positivity rate in clinically suspected rheumatoid vasculitis with adequate biopsy [15] can convert a high-risk, treatment-­consequential suspicion into histologically proven disease — an especially important transition when aggressive therapy is contemplated and alternative diagnoses remain plausible [14, 25]. Conjunctival and gingival biopsies illustrate the complementary principle of phenotype targeting: superficial biopsies can be diagnostically leveraged when the clinical presentation itself enriches the sample for disease-­associated lesions [16–19].

4.2. Technique is not optional: processing determines “yield”

Across sites, yield is inseparable from technique, and many negative biopsies reflect the method rather than biology [2].

Rectum: vasculitis may be focal; submucosal depth and serial step sections matter, and complication risk depends strongly on procedural approach and operator experience [15]. The same “site” can be low yield if sampled too superficially, and high risk if sampled too aggressively or with suboptimal instrumentation.

Gingiva: a diagnostic signal often lies in a characteristic constellation; over-reliance on the full classic triad can reduce sensitivity in limited disease [19–21]. “Pattern-­based” pathology reporting is therefore an enabling step for clinical utility.

Conjunctiva: lesional targeting matters; small samples may show supportive vasculitis/inflammation rather than necrotizing granulomas [16–18, 22]. Negative non-lesional conjunctival biopsies should not meaningfully lower suspicion.

A clinician-­facing review should therefore treat biopsy as a protocol (site selection + technique + processing + clinicopathologic correlation) rather than a single event. Communicating with pathologists about serial levels, stains (as appropriate), and the suspected vessel caliber/layer can materially alter diagnostic yield.

4.3. Rheumatoid vasculitis as the archetype for a “blind” surrogate biopsy

Rheumatoid vasculitis remains a prototypical diagnostic dilemma: rare but severe, heterogeneous in presentation, and often requiring high-toxicity therapy [2]. Epidemiologic data show substantial declines in prevalence in modern cohorts [24], but contemporary reviews emphasize that it remains a high-mortality complication when present and deserves rigorous confirmation and exclusion of mimics [14]. In this niche, rectal biopsy provides unusually concrete yield data for a surrogate site [15]. Diagnostic strategy work supports structured integration of features and tissue confirmation to raise diagnostic certainty before escalation of immunosuppression [25, 26]. Rectal biopsy can be positioned within this structured approach as a surrogate option when no safer lesional site exists.

4.4. Ocular and oral targets in GPA: speed, morbidity, and diagnostic leverage

Time-to-diagnosis matters in GPA because ocular disease can threaten vision and airway disease can evolve quickly. Conjunctival biopsy may deliver supportive histology while avoiding deeper, higher-risk sampling in selected patients [16–18]. Gingival biopsy in strawberry gingivitis can be disproportionately valuable because the clinical phenotype predicts a highly characteristic histologic pattern that can be strongly supportive even in limited disease [19–21]. Both examples highlight an underappreciated clinical skill: “micro-­phenotyping” to choose the best low-morbidity tissue rather than defaulting to high-risk targets or repeating low-yield biopsies.

4.5. What uncommon sites can and what they cannot replace

Uncommon sites rarely replace kidney biopsy in suspected AAV glomerulonephritis, where renal histology provides classification and prognostic stratification that can guide therapy intensity [7, 8]. Nor do they replace biopsy of the most threatened organ when it is feasible and safe. Their roles are more precise:

1. Surrogate sites when threatened-­organ biopsy is contraindicated (rectum in suspected rheumatoid vasculitis without accessible lesions; muscle in AAV when kidney is unsafe) [15, 27].

2. Phenotype-­driven high-yield sites when a specific lesion exists (strawberry gingivitis; inflamed conjunctiva) [16–21].

3. Adjunct sites to increase overall diagnostic probability after a negative conventional biopsy when clinical suspicion remains high and the costs of delay are substantial [2].

5.1. A phenotype-­first algorithm for choosing biopsy site

Step 1: Define the vasculitis category and expected vessel layer. Use CHCC nomenclature and ACR/EULAR classification constructs to anchor expected vessel size and tissue compartment [2–6]. This informs whether the most informative tissue is likely glomerular, alveolar-­capillary, dermal postcapillary venular, submucosal arterial, or perineural/epineurial.

Step 2: Identify threatened-­organ urgency and whether that organ must be biopsied.

In suspected AAV with renal involvement, renal histology is often pivotal for prognostic stratification and management [7, 8].

In suspected GPA with pulmonary/orbital masses, tissue may be decisive but may be high-risk; even then, classic triad sensitivity is imperfect [22, 23].

Step 3: If threatened-­organ biopsy is unsafe or repeatedly non-diagnostic, select a low-morbidity surrogate aligned with biology and phenotype [2].

Suspected rheumatoid vasculitis with high clinical probability and no accessible lesion: consider rectal submucosal biopsy in experienced hands with protocolized processing [15].

Suspected AAV when renal biopsy is contraindicated: consider muscle biopsy as an adjunct for histologic confirmation [27].

Suspected GPA with ocular surface inflammation/ulceration: consider conjunctival biopsy of active disease [16–18].

Suspected GPA with strawberry gingivitis: prioritize gingival biopsy with pattern-­based pathologic interpretation [19–21].

If an unusual but accessible organ is clinically involved (e. g., salivary gland enlargement): consider lesional biopsy where safe [30].

5.2. Practical pathology checklist

Ask explicitly for multiple levels/serial step sections when vasculitis is suspected and focality is likely (rectal submucosa; small biopsy specimens) [15].

Clarify the suspected vessel caliber and compartment in the request (e. g., “submucosal small/medium arteries”, “mucosal pattern consistent with strawberry gingivitis”) [19].

When interpreting limited ocular/oral specimens, ask the pathologist to comment on supportive patterns even if the full classic triad is absent (to avoid false reassurance) [19–22].

5.3. Safety and avoidable harm

The rectal biopsy illustrates that “low morbidity” depends on technique: perforations were reported when biopsies were taken via sigmoidoscope in the classic series [15]. Conjunctival and gingival biopsies are generally minor procedures, but complication risk depends on lesion location, anticoagulation status, ocular comorbidity, and operator expertise.

5.4. Limitations and research agenda

The evidence base is uneven: rectal biopsy has cohort-like data in rheumatoid vasculitis [15], whereas conjunctival and gingival biopsies are predominantly case-based (though supported by systematic reviews for oral manifestations) [16–21]. Standardized reporting of biopsy technique, processing (levels), histologic criteria, and denominator definitions is frequently missing, limiting direct comparisons and preventing robust sensitivity/specificity estimation for many uncommon sites.

Priorities for future work include: prospective multicentre registries capturing biopsy site selection, technique, processing details, complications, and incremental diagnostic yield; studies quantifying the added value of surrogate sites after negative conventional biopsies; and analyses of time-to-treatment and avoidance of high-risk procedures when phenotype-­driven superficial biopsies are used earlier in the diagnostic pathway [2].

Uncommon biopsy sites are not curiosities; they are pragmatic tools that can increase diagnostic certainty when used in the right phenotype, with correct technique and appropriate pathology processing. Rectal biopsy remains the best-supported “blind” surrogate site for systemic vasculitis complicating rheumatoid arthritis, with classic data demonstrating meaningful positivity when an adequate submucosal biopsy is obtained and processed appropriately. Conjunctival and gingival biopsies provide low-morbidity tissue support in GPA when ocular surface inflammation or strawberry gingivitis is present, respectively. Muscle biopsy functions as a useful surrogate in AAV when renal biopsy is contraindicated.

A modern diagnostic strategy should therefore be anatomy- and phenotype-­driven: biopsy the threatened organ when feasible, but when risk is high or yield is low, deliberately select an alternative site that matches expected vessel size and compartment. This approach can reduce diagnostic delay, avoid unnecessary high-risk procedures, and strengthen confidence in initiating immunosuppression, particularly in secondary vasculitis contexts where the stakes of overtreatment and undertreatment are both high.

Funding: The authors declare no funding.

Conflict of interest: The authors declare no conflict of interest.

Authors’ contributions: J.F.C. conceived and designed the study. J.F.C., L.P.C., and V.J.U. collected the data. J.F.C. and L.P.C. analyzed and interpreted the data. J.F.C., L.P.C., and V.J.U. drafted the manuscript. L.P.C. and V.J.U. critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Use of AI: Artificial intelligence was not used in the preparation of the article.