Panniculitis in Rheumatology Practice

Panniculitis in Rheumatology Practice: Decoding the Puzzle

Dr Neeraj Manikath ,claude.ai

Abstract

Panniculitis represents a heterogeneous group of inflammatory disorders affecting the subcutaneous adipose tissue. These conditions present significant diagnostic and therapeutic challenges in rheumatology practice due to their diverse etiologies, overlapping clinical presentations, and histopathological features. This review provides a comprehensive analysis of panniculitis relevant to rheumatologists, focusing on classification, clinical evaluation, histopathology, and management strategies. Special attention is given to panniculitis associated with systemic rheumatic diseases and emerging concepts in pathophysiology. Understanding these complex disorders is essential for rheumatologists to establish accurate diagnoses and implement appropriate treatment protocols, ultimately improving patient outcomes.

Keywords: Panniculitis, Subcutaneous Fat, Erythema Nodosum, Lupus Panniculitis, Connective Tissue Disease, Rheumatology

Introduction

Panniculitis encompasses a diverse group of inflammatory conditions primarily affecting the subcutaneous adipose tissue (panniculus adiposus).[1] These disorders represent a diagnostic puzzle for rheumatologists, as they can manifest as isolated entities or occur in association with various systemic rheumatic diseases.[2] The complexity is heightened by overlapping clinical presentations, variable histopathologic findings, and multifactorial etiologies that often require a multidisciplinary approach.

For the practicing rheumatologist, panniculitis presents several challenges: first, recognition of its various clinical presentations; second, determination of whether the panniculitis is a primary condition or secondary to an underlying systemic disease; and third, selection of appropriate treatment strategies.[3] Recent advances in our understanding of the immunopathogenic mechanisms involved in panniculitis have led to improved classification systems and targeted therapeutic approaches.

This review aims to provide a comprehensive analysis of panniculitis from a rheumatologist's perspective, with emphasis on clinical evaluation, histopathologic classification, association with rheumatic diseases, and evidence-based management strategies. By "decoding the puzzle" of panniculitis, rheumatologists can enhance their diagnostic acumen and therapeutic decision-making for these challenging conditions.

Classification of Panniculitis

The traditional classification of panniculitis is based on histopathologic features, primarily distinguishing between predominantly septal and predominantly lobular patterns of inflammation, and the presence or absence of vasculitis.[4] This histopathologic approach, while useful, has limitations as many forms of panniculitis demonstrate overlapping or evolving patterns depending on the stage of the lesion.

Predominantly Septal Panniculitis

1. Without Vasculitis

• Erythema nodosum (most common form)

• Morphea/Eosinophilic fasciitis

• Necrobiosis lipoidica

2. With Vasculitis

• Polyarteritis nodosa

• Superficial migratory thrombophlebitis

Predominantly Lobular Panniculitis

1. Without Vasculitis

• Lupus panniculitis (lupus profundus)

• Panniculitis associated with dermatomyositis

• α1-antitrypsin deficiency panniculitis

• Pancreatic panniculitis

• Cold panniculitis

• Subcutaneous sarcoidosis

2. With Vasculitis

• Erythema induratum/nodular vasculitis

• Cutaneous polyarteritis nodosa

• ANCA-associated vasculitis with panniculitis

This classification system guides both the histopathologic evaluation and the clinical approach to diagnosis. However, recent understanding suggests that the pattern of inflammation may represent a spectrum rather than distinct entities, with some conditions showing mixed patterns or evolving from one pattern to another over time.[5]

Clinical Presentation and Evaluation

The clinical presentation of panniculitis typically includes subcutaneous nodules or plaques that may be tender, erythematous, and firm. While the lower extremities are most commonly affected, any area with substantial subcutaneous fat can be involved.[6] The distribution, morphology, and evolution of these lesions provide important diagnostic clues.

Key Clinical Features to Assess:

1. Morphology and Distribution

• Size, shape, color, and consistency of lesions

• Predilection for particular anatomic sites

• Bilateral versus unilateral involvement

• Symmetric versus asymmetric distribution

2. Associated Symptoms

• Pain, tenderness, warmth

• Ulceration or scarring

• Systemic symptoms (fever, malaise, arthralgia)

3. Temporal Pattern

• Acute versus chronic

• Migratory versus fixed

• Recurrent versus persistent

4. Associated Conditions

• Underlying rheumatic diseases

• Infections

• Malignancies

• Medications

Diagnostic Approach

The evaluation of panniculitis should follow a systematic approach:[7]

1. Detailed History

• Onset and evolution of lesions

• Associated symptoms

• Recent infections or medication changes

• Family history of autoimmune diseases

• Occupational exposures

2. Physical Examination

• Complete skin examination

• Assessment for extracutaneous manifestations

• Evaluation for signs of systemic rheumatic diseases

3. Laboratory Studies

• Complete blood count with differential

• Inflammatory markers (ESR, CRP)

• Autoimmune serologies (ANA, ENA panel, ANCA)

• Complement levels

• α1-antitrypsin level and phenotype

• Pancreatic enzymes

• Infection screen when appropriate

4. Imaging Studies

• Ultrasonography can assess extent and depth of involvement

• MRI may help characterize deep lesions and guide biopsy

• PET-CT may be useful in cases with suspected malignancy

5. Skin Biopsy

• Essential for definitive diagnosis

• Deep incisional biopsy including subcutis and fascia

• Both H&E and special stains may be required

• Tissue culture for infectious causes when indicated

It is important to recognize that the clinical presentation alone is often insufficient for a specific diagnosis, and histopathologic evaluation is usually necessary.[8]

Histopathology: The Key to Diagnosis

Histopathologic examination remains the gold standard for the diagnosis of panniculitis. A deep incisional biopsy that includes epidermis, dermis, and subcutaneous fat down to the fascia is essential for proper evaluation.[9]

Histopathologic Patterns

1. Septal Panniculitis

• Inflammation predominantly involving the fibrous septa

• Relative sparing of fat lobules

• Typical of erythema nodosum

• May demonstrate granulomatous inflammation

• Fibrosis in chronic lesions

2. Lobular Panniculitis

• Primary involvement of fat lobules

• May show adipocyte necrosis

• Can feature lymphocytic infiltrates (as in lupus panniculitis)

• May include histiocytes, foam cells, or multinucleated giant cells

• Can demonstrate "rimming" of adipocytes by lymphocytes

3. Mixed Panniculitis

• Features of both septal and lobular inflammation

• May represent evolution of the disease process

• Common in later stages of many forms of panniculitis

4. With or Without Vasculitis

• Presence of vessel wall damage and neutrophilic infiltration

• Fibrinoid necrosis in medium-sized vessel vasculitis

• May observe thrombosis, hemorrhage, or endothelial swelling

Special Stains and Immunohistochemistry

Various stains and immunohistochemical techniques can provide additional diagnostic information:[10]

1. Special Stains

• PAS and GMS for fungal organisms

• Acid-fast stains for mycobacteria

• Elastin stains for assessment of vessel integrity

• Oil red O for fat changes (requires frozen sections)

2. Immunohistochemistry

• CD3, CD4, CD8 for T-cell characterization

• CD20 for B-cells

• CD68 for histiocytes/macrophages

• IgG, IgM, C3 for immune complex deposits (particularly in lupus panniculitis)

3. Additional Studies

• PCR for specific infectious agents

• Polarizing microscopy for crystalline deposits

• Tissue culture when infection is suspected

The interpretation of panniculitis histopathology requires expertise and close correlation with clinical findings. Collaboration between rheumatologists, dermatologists, and dermatopathologists is often necessary for accurate diagnosis.[11]

Panniculitis Associated with Rheumatic Diseases

Panniculitis can occur in association with various systemic rheumatic diseases, either as a specific manifestation or as a coincidental finding. Understanding these associations is crucial for comprehensive management.

Lupus Erythematosus Panniculitis (LEP)

LEP, also known as lupus profundus, represents a distinct variant of cutaneous lupus erythematosus characterized by inflammation of the deep dermis and subcutaneous fat.[12] It may occur as an isolated phenomenon or in association with discoid or systemic lupus erythematosus.

Clinical features include:

• Deep, firm, subcutaneous nodules or plaques

• Predilection for face, upper arms, upper trunk, and buttocks

• Lesions may resolve with atrophic depression or lipoatrophy

• May be associated with overlying discoid lesions

Histopathology typically shows:

• Lobular lymphocytic panniculitis

• Lymphocytic vasculitis

• Hyaline fat necrosis

• Mucin deposition

• Lymphoid follicle formation

• Hyalinization of subcutaneous fat

LEP is associated with anti-Ro/SSA antibodies in approximately 70% of cases, even in patients without systemic lupus erythematosus.[13] Management typically involves antimalarials, systemic corticosteroids, and immunosuppressive agents in refractory cases.

Dermatomyositis-Associated Panniculitis

Panniculitis is a rare but well-documented cutaneous manifestation of dermatomyositis, occurring in approximately 2-5% of cases.[14] It may precede, coincide with, or follow the development of myositis.

Key features include:

• Painful subcutaneous nodules, often on extremities

• May show calcification (calcinosis cutis)

• Sometimes associated with lipodystrophy

• Can be a marker of severe disease

Histopathology demonstrates:

• Lobular panniculitis with lymphocytic infiltration

• Interface dermatitis often present

• Membrane attack complex (C5b-9) deposition along the dermoepidermal junction

• Mucin deposition in dermis

• Vasculopathy with endothelial tubuloreticular inclusions

The presence of panniculitis in dermatomyositis may be associated with a more severe disease course and increased risk of interstitial lung disease.[15] Treatment typically requires aggressive immunosuppression, often with high-dose corticosteroids and steroid-sparing agents.

Systemic Sclerosis and Mixed Connective Tissue Disease

Panniculitis is uncommon in systemic sclerosis but can occur, particularly in the early edematous phase of the disease. It may also manifest in mixed connective tissue disease (MCTD), where it shares features with both lupus panniculitis and dermatomyositis-associated panniculitis.[16]

Features in systemic sclerosis and MCTD:

• Predominantly affects extremities

• May precede skin fibrosis

• Often associated with Raynaud's phenomenon

• Can show calcification in chronic lesions

Histopathologic findings typically include:

• Mixed septal and lobular panniculitis

• Vascular changes with endothelial cell swelling

• Progressive fibrosis of septa

• Atrophy of fat lobules

Treatment is directed at the underlying connective tissue disease, with consideration of vasodilators for associated vascular manifestations.

Sarcoidosis

Subcutaneous sarcoidosis (Darier-Roussy sarcoid) presents as panniculitis and is estimated to occur in 1.4-6% of patients with systemic sarcoidosis.[17] It typically manifests as firm, non-tender nodules on the extremities.

Histopathology shows:

• Naked granulomas in fat lobules

• Absence of caseous necrosis

• Multinucleated giant cells containing asteroid or Schaumann bodies

• Minimal fat necrosis

Subcutaneous sarcoidosis often responds to systemic corticosteroids, methotrexate, or antimalarials. The presence of panniculitis in sarcoidosis does not necessarily indicate a worse prognosis but warrants evaluation for systemic involvement.[18]

Rheumatoid Arthritis

Rheumatoid nodulosis can manifest as a form of panniculitis in patients with rheumatoid arthritis, particularly those with high titers of rheumatoid factor.[19] These nodules typically occur over pressure points and extensor surfaces.

Histopathologic features include:

• Central fibrinoid necrosis

• Palisading granulomatous inflammation

• Surrounding chronic inflammation with lymphocytes and plasma cells

• Vasculopathy with endothelial activation

Treatment may include methotrexate, although paradoxically, methotrexate can sometimes induce or exacerbate rheumatoid nodules.[20]

Specific Forms of Panniculitis Relevant to Rheumatologists

Erythema Nodosum (EN)

Erythema nodosum is the most common form of panniculitis encountered in rheumatology practice. It typically presents as tender, erythematous nodules on the anterior tibial surfaces. EN is often idiopathic but can be associated with various conditions relevant to rheumatologists:[21]

• Sarcoidosis

• Inflammatory bowel disease

• Behçet's disease

• Streptococcal infections

• Tuberculosis

• Medications (sulfonamides, oral contraceptives)

Histopathology shows septal panniculitis without vasculitis, characterized by neutrophilic infiltration in early lesions, evolving to granulomatous inflammation in later stages. Treatment addresses the underlying cause when identified, with NSAIDs or potassium iodide for symptomatic relief.[22] Short courses of systemic corticosteroids may be necessary for severe or recalcitrant cases.

α1-Antitrypsin Deficiency Panniculitis

This rare form of panniculitis occurs in individuals with α1-antitrypsin deficiency, particularly those with PiZZ phenotype.[23] It presents as painful, suppurative nodules that may ulcerate and drain an oily material. Trauma often triggers lesions.

Histopathology shows:

• Lobular panniculitis with neutrophilic infiltration

• Massive necrosis of adipocytes

• Absent or minimal vasculitis

• Liquefactive necrosis of fat lobules

Diagnosis requires measurement of serum α1-antitrypsin levels and phenotyping. Treatment options include augmentation therapy with intravenous α1-antitrypsin, dapsone, or tetracyclines.[24]

Pancreatic Panniculitis

Occurring in approximately 2-3% of patients with pancreatic disease (particularly acute or chronic pancreatitis and pancreatic carcinoma), pancreatic panniculitis presents as painful, erythematous nodules that may ulcerate and exude a brownish, oily material.[25]

Histopathology demonstrates:

• Lobular panniculitis with adipocyte necrosis

• Characteristic "ghost cells" (anucleate adipocytes)

• Basophilic calcium deposits

• Neutrophilic infiltration

Diagnosis is supported by elevated serum amylase and lipase levels. Treatment focuses on the underlying pancreatic disease, with supportive care for skin lesions.[26]

Cold Panniculitis

Cold panniculitis occurs after cold exposure and is more common in infants and young children due to their higher proportion of saturated fatty acids in subcutaneous fat.[27] It presents as firm, erythematous plaques at sites of cold exposure.

Histopathology shows:

• Lobular panniculitis with mixed inflammatory infiltrate

• Adipocyte necrosis

• Microvesicular fat changes

• Minimal vasculitis

Treatment is generally supportive, with avoidance of cold exposure.

Lipodermatosclerosis

Lipodermatosclerosis is a form of panniculitis occurring in the context of chronic venous insufficiency, particularly in individuals with obesity.[28] It presents as painful induration of the lower legs, often with an "inverted champagne bottle" appearance.

Histopathology demonstrates:

• Mixed septal and lobular panniculitis

• Membranocystic changes in adipocytes

• Microvascular changes

• Progressive fibrosis

Management involves compression therapy, elevation, weight reduction, and treatment of venous insufficiency. Pentoxifylline, stanozolol, and systemic corticosteroids have shown variable efficacy.[29]

Pathophysiology: Recent Advances

The pathogenesis of panniculitis involves complex interactions between adipocytes, immune cells, and vascular structures. Recent advances have enhanced our understanding of these mechanisms:

Immunologic Mechanisms

Adipose tissue is increasingly recognized as an active immunologic organ capable of producing adipokines that modulate inflammation.[30] Research has identified several key mechanisms in panniculitis:

1. Adipocyte-Immune Cell Interactions

• Adipocytes express toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns

• Activation of these receptors leads to production of proinflammatory cytokines (IL-6, TNF-α)

• Recruitment of innate immune cells, particularly neutrophils and macrophages

2. Cytokine Networks

• TNF-α and IL-1β are key mediators in many forms of panniculitis

• IL-17 pathway activation has been implicated in erythema nodosum

• Type I interferons play a crucial role in lupus panniculitis

3. Adaptive Immunity

• T-cell subsets (particularly Th1 and Th17) contribute to granuloma formation

• B-cells and autoantibodies are important in connective tissue disease-associated panniculitis

• Regulatory T-cells may be defective, leading to uncontrolled inflammation

Vascular Factors

Microvascular changes play a significant role in the development of panniculitis:[31]

1. Endothelial Activation

• Upregulation of adhesion molecules (ICAM-1, VCAM-1)

• Enhanced leukocyte recruitment

• Microthrombi formation

2. Hypoxia

• Tissue hypoxia triggers inflammatory responses

• Hypoxia-inducible factor (HIF) activation

• Production of reactive oxygen species

3. Vascular Damage

• Neutrophil extracellular traps (NETs) contribute to vessel damage

• Complement activation enhances vascular injury

• Fibrinoid necrosis in vasculitis-associated panniculitis

Metabolic Factors

The metabolic functions of adipose tissue contribute to panniculitis pathogenesis:[32]

1. Lipid Metabolism Dysregulation

• Free fatty acid release from damaged adipocytes acts as a proinflammatory stimulus

• Saturated fatty acids activate TLR4 signaling

• Oxidized lipids promote inflammation

2. Adipokine Imbalance

• Decreased adiponectin (anti-inflammatory)

• Increased leptin (proinflammatory)

• Dysregulated production of other adipokines (resistin, visfatin)

These advances in understanding the pathophysiology of panniculitis have translational implications, suggesting potential targets for novel therapeutic approaches.[33]

Diagnostic Algorithm

Based on clinical features and histopathology, we propose the following diagnostic algorithm for evaluating panniculitis in rheumatology practice:

1. Initial Assessment

• Detailed history and physical examination

• Basic laboratory studies

• Consider non-invasive imaging

2. Skin Biopsy

• Deep incisional biopsy including subcutaneous fat

• Histopathologic classification (septal vs. lobular, with or without vasculitis)

• Special stains and immunohistochemistry as indicated

3. Targeted Investigations Based on Histopathology

a. For Predominantly Septal Panniculitis

• If classic erythema nodosum: search for associated conditions

• If granulomatous: consider sarcoidosis evaluation

• If with vasculitis: evaluate for polyarteritis nodosa

b. For Predominantly Lobular Panniculitis

• If lymphocytic with mucin: evaluate for lupus erythematosus

• If neutrophilic with fat necrosis: check pancreatic enzymes, α1-antitrypsin level

• If granulomatous: consider infectious causes, sarcoidosis

• If with vasculitis: evaluate for cutaneous polyarteritis nodosa, ANCA-associated vasculitis

4. Integration of Findings

• Correlation of clinical, laboratory, and histopathologic findings

• Multidisciplinary discussion when appropriate

• Consideration of overlap syndromes

This algorithmic approach facilitates systematic evaluation and enhances diagnostic accuracy for panniculitis in rheumatology practice.

Management Strategies

Treatment of panniculitis should be tailored to the specific diagnosis and underlying cause. General principles and specific approaches include:

General Principles

1. Identify and Address Underlying Causes

• Discontinue offending medications

• Treat underlying infections

• Manage associated systemic diseases

2. Supportive Measures

• Rest and elevation of affected areas

• Compression therapy when appropriate

• Analgesia for painful lesions

3. Graduated Therapeutic Approach

• Begin with less aggressive therapies when possible

• Escalate treatment for refractory cases

• Consider combination therapy for complex cases

Specific Therapeutic Approaches

1. Erythema Nodosum

• NSAIDs for symptomatic relief

• Potassium iodide (300-900 mg daily)

• Colchicine (0.5-1.2 mg daily)

• Short course of systemic corticosteroids for severe cases

• Rarely, immunosuppressants for recalcitrant disease[34]

2. Lupus Panniculitis

• Antimalarials (hydroxychloroquine 200-400 mg daily)

• Systemic corticosteroids (0.5-1 mg/kg/day)

• Methotrexate (15-25 mg weekly)

• Thalidomide (50-100 mg daily) for refractory cases

• Mycophenolate mofetil or tacrolimus for resistant cases[35]

3. Panniculitis Associated with Dermatomyositis

• High-dose corticosteroids (1-2 mg/kg/day)

• Steroid-sparing agents (methotrexate, azathioprine, mycophenolate mofetil)

• IVIG (2 g/kg over 5 days) for severe or refractory cases

• JAK inhibitors showing promise in recent studies[36]

4. α1-Antitrypsin Deficiency Panniculitis

• α1-antitrypsin augmentation therapy (60 mg/kg weekly)

• Dapsone (50-200 mg daily)

• Tetracyclines (doxycycline 100 mg twice daily)

• Liver transplantation for severe cases with hepatic involvement[37]

5. Pancreatic Panniculitis

• Treatment of underlying pancreatic disease

• Pancreatic enzyme replacement

• Octreotide in selected cases

• Surgical intervention for pancreatic neoplasms when appropriate[38]

6. Lipodermatosclerosis

• Compression therapy

• Pentoxifylline (400 mg three times daily)

• Stanozolol (2 mg daily) or danazol

• Systemic corticosteroids for acute flares

• Intralesional triamcinolone for localized areas[39]

Emerging Therapies

Recent advances in targeted therapies show promise for refractory panniculitis:

1. Biologic Agents

• TNF-α inhibitors for granulomatous panniculitis

• IL-1 receptor antagonists for neutrophilic panniculitis

• IL-6 inhibitors for panniculitis associated with systemic inflammation

• B-cell depletion therapy for lupus panniculitis[40]

2. JAK Inhibitors

• Emerging evidence for efficacy in lupus panniculitis and dermatomyositis-associated panniculitis

• May address the interferon signature in connective tissue disease-associated panniculitis[41]

3. Small Molecule Inhibitors

• Phosphodiesterase-4 inhibitors (apremilast)

• Sphingosine-1-phosphate receptor modulators

• Bruton's tyrosine kinase inhibitors[42]

The choice of therapy should be guided by the specific diagnosis, severity of disease, comorbidities, and patient preferences. A multidisciplinary approach involving rheumatologists, dermatologists, and other specialists is often beneficial for optimal management.

Conclusion

Panniculitis represents a challenging group of disorders that require a systematic approach to diagnosis and management. For rheumatologists, recognition of panniculitis as a manifestation of systemic rheumatic diseases is particularly important, as early diagnosis and appropriate treatment can prevent progression and complications.

Recent advances in our understanding of the immunopathogenesis of panniculitis have led to improved classification systems and targeted therapeutic approaches. The traditional histopathologic classification remains useful but should be integrated with clinical, laboratory, and imaging findings for comprehensive evaluation.

The diagnostic algorithm proposed in this review aims to guide rheumatologists through the complex process of evaluating panniculitis. Treatment strategies should be tailored to the specific diagnosis and underlying cause, with consideration of newer targeted therapies for refractory cases.

Future directions in panniculitis research include better characterization of pathogenic mechanisms, identification of biomarkers for specific subtypes, and development of more targeted therapies. Collaborative research between rheumatologists, dermatologists, pathologists, and basic scientists will be essential to further "decode the puzzle" of panniculitis and improve outcomes for affected patients.

Clinical Pearls for Rheumatology Practice

1. Approach to Panniculitis

• Always biopsy unexplained subcutaneous nodules

• Obtain deep incisional biopsy including epidermis through fascia

• Consider repeat biopsy if initial findings are inconclusive

• Remember that histopathology may evolve over time

2. Red Flags for Systemic Disease

• Persistent or recurrent lesions despite treatment

• Associated constitutional symptoms

• Unusual distribution (face, upper trunk)

• Atypical age of onset

• Lipoatrophy after resolution of lesions

3. Diagnostic Pitfalls

• Misdiagnosis as cellulitis or abscess

• Sampling error in biopsy (too superficial)

• Mixed or evolving histopathologic patterns

• Coexistence of multiple panniculitis subtypes

• Poststeroid panniculitis mimicking relapse

4. Therapeutic Considerations

• Treat underlying cause when identified

• Consider empiric therapy for presumed diagnosis when appropriate

• Monitor for treatment-related complications

• Recognize potential paradoxical reactions (e.g., methotrexate-induced nodulosis)

• Consider multidisciplinary approach for complex cases

5. Prognosis and Follow-up

• Most isolated panniculitis has favorable prognosis

• Panniculitis associated with malignancy may have poor prognosis

• Risk of recurrence varies by subtype

• Long-term sequelae may include lipoatrophy, fibrosis

• Follow-up interval should be tailored to specific diagnosis and disease activity

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