Rheumatological Adverse Events Associated with Cancer Immunotherapy

 Rheumatological Adverse Events Associated with Cancer Immunotherapy: A Comprehensive Review

Dr Neeraj Manikath ,claude.ai

 Abstract

The advent of immune checkpoint inhibitors (ICIs) and other immunotherapeutic agents has revolutionized cancer treatment, offering improved outcomes for many malignancies that were previously associated with poor prognosis. However, by enhancing immune system activity, these therapies can trigger a wide spectrum of immune-related adverse events (irAEs), including rheumatological manifestations. This review summarizes the current understanding of rheumatological adverse events associated with immunotherapy, focusing on their prevalence, clinical presentation, pathophysiology, diagnostic approach, and management strategies. Rheumatologists play a crucial role in the multidisciplinary care of patients receiving immunotherapy, as early recognition and appropriate management of rheumatological irAEs can prevent treatment discontinuation and improve patient outcomes. This article aims to provide postgraduate rheumatology students with a comprehensive understanding of immunotherapy-related rheumatological complications to enhance clinical practice and patient care.

Keywords: immune checkpoint inhibitors; immune-related adverse events; inflammatory arthritis; myositis; sicca syndrome; polymyalgia rheumatica; vasculitis

Introduction

Cancer immunotherapy represents a paradigm shift in oncological treatment, harnessing the body's immune system to target malignant cells. Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as the cornerstone of immunotherapy, demonstrating remarkable efficacy across multiple cancer types.[1] These agents target inhibitory immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1), effectively "releasing the brakes" on the immune system.

The principal classes of ICIs currently approved for clinical use include:
- Anti-CTLA-4 antibodies (e.g., ipilimumab)
- Anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab)
- Anti-PD-L1 antibodies (e.g., atezolizumab, durvalumab, avelumab)

Additionally, other immunotherapeutic approaches include:
- Chimeric antigen receptor (CAR) T-cell therapy
- Bispecific T-cell engagers (BiTEs)
- Cancer vaccines
- Oncolytic viruses
- Cytokine therapies

While these agents have transformed the treatment landscape for advanced malignancies, the augmentation of immune system activity can lead to a diverse array of immune-related adverse events (irAEs) affecting virtually any organ system.[2] Rheumatological irAEs constitute a significant subset of these complications, with manifestations ranging from inflammatory arthritis to systemic vasculitis.

This review aims to provide a comprehensive overview of rheumatological adverse events associated with immunotherapy, focusing on:
1. Epidemiology and risk factors
2. Pathophysiological mechanisms
3. Clinical spectrum and classification
4. Diagnostic approach
5. Management strategies
6. Long-term outcomes and impact on cancer therapy

Epidemiology and Risk Factors

The reported prevalence of rheumatological irAEs varies considerably across studies, reflecting differences in study design, patient populations, and diagnostic criteria. Overall, rheumatological manifestations are estimated to occur in 5-20% of patients receiving ICIs, with higher rates observed in those receiving combination therapy.[3,4]

 General Incidence
Recent meta-analyses suggest the following approximate incidence rates:
- Inflammatory arthritis: 5-7%
- Myositis: 1-2%
- Sicca syndrome: 3-5%
- Polymyalgia rheumatica (PMR)-like syndrome: 2-3%
- Vasculitis: <1%

 Risk Factors
Several factors may predispose individuals to developing rheumatological irAEs:[5,6]

1. Treatment-related factors:
   - Combination immunotherapy (e.g., anti-CTLA-4 plus anti-PD-1) carries a higher risk than monotherapy
   - Anti-CTLA-4 agents appear to have higher irAE rates than PD-1/PD-L1 inhibitors
   - Cumulative dose and duration of treatment

2. Patient-related factors:
   - Personal or family history of autoimmune disease
   - Female sex
   - Genetic predisposition (HLA-DR4 and certain polymorphisms)
   - Pre-existing autoantibodies
   - Prior radiation therapy

3. Cancer-related factors:
   - Type of malignancy (melanoma and lung cancer appear to have higher rates)
   - Tumor burden and stage

The time to onset of rheumatological irAEs is variable, with some manifestations appearing within weeks of treatment initiation, while others develop after months or even following treatment discontinuation.[7]

Pathophysiological Mechanisms

The pathogenesis of rheumatological irAEs is complex and not fully elucidated. Several mechanisms have been proposed:[8,9]

 1. Enhanced T-cell activity
ICIs remove inhibitory signals that normally limit T-cell responses, leading to:
- Expansion of autoreactive T-cell clones
- Increased production of pro-inflammatory cytokines
- Altered T-cell receptor (TCR) repertoire diversity

 2. Molecular mimicry
Structural similarities between tumor antigens and self-antigens may result in cross-reactive immune responses, especially when immune tolerance mechanisms are disrupted.

 3. Pre-existing autoimmunity
Latent autoimmune conditions may be unmasked or exacerbated by immune checkpoint blockade.

 4. Altered cytokine milieu
Dysregulated production of cytokines, including TNF-α, IL-6, IL-17, and interferon-γ, contributes to tissue inflammation.

 5. Complement activation
Complement-mediated tissue damage has been implicated in some irAEs.

 6. Epitope spreading
Initial immune responses against tumor antigens may spread to include related self-antigens.

Recent studies suggest that the composition of the gut microbiome may influence susceptibility to irAEs, highlighting the complex interplay between host factors and treatment response.[10]

 Clinical Spectrum of Rheumatological irAEs

 1. Inflammatory Arthritis

ICI-induced inflammatory arthritis represents the most common rheumatological irAE and can manifest in several distinct patterns:[11,12]

 a. Rheumatoid arthritis (RA)-like
- Symmetric polyarthritis affecting small joints of hands and feet
- Morning stiffness lasting >30 minutes
- Occasionally associated with rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA)
- Radiographic changes typically absent in early stages

 b. Reactive arthritis-like
- Asymmetric oligoarthritis predominantly affecting lower extremities
- May be accompanied by enthesitis, dactylitis, or extra-articular manifestations
- Potential association with conjunctivitis and urethritis

 c. Psoriatic arthritis-like
- Dactylitis, enthesitis, and nail changes
- Asymmetric joint involvement
- May be accompanied by psoriasiform skin lesions

 d. Undifferentiated arthritis
- Features that do not fit established classification criteria

Unlike traditional inflammatory arthritis, ICI-induced arthritis often has an acute onset and rapid progression, sometimes affecting large joints such as knees, ankles, and wrists in early stages.

 2. Myositis

ICI-induced myositis presents with characteristic features:[13,14]

- Proximal muscle weakness
- Elevated creatine kinase (CK) levels, often markedly high (>1000 U/L)
- Myalgia and muscle tenderness
- Bulbar symptoms (dysphagia, dysarthria) in severe cases
- Potential cardiac involvement (myocarditis), which carries high mortality

ICI-myositis differs from idiopathic inflammatory myopathies in several aspects:
- More rapid onset and progression
- Higher frequency of myocarditis and myasthenia gravis overlap
- Lower prevalence of classic autoantibodies (anti-Jo-1, anti-Mi-2)
- Distinct histopathological features with predominant CD8+ T-cell infiltration

 3. Polymyalgia Rheumatica (PMR)-like Syndrome

Characterized by:[15]
- Bilateral shoulder and hip girdle pain and stiffness
- Prominent morning stiffness (>45 minutes)
- Elevated inflammatory markers (ESR, CRP)
- Rapid response to glucocorticoids
- Often associated with older age (>50 years)

Giant cell arteritis (GCA) may occasionally accompany PMR-like syndrome, presenting with headache, jaw claudication, visual disturbances, and temporal artery tenderness.

 4. Sicca Syndrome

ICI-induced sicca syndrome manifests as:[16]
- Xerostomia (dry mouth)
- Xerophthalmia (dry eyes)
- Salivary gland enlargement in some cases
- Potential rapid progression to severe salivary hypofunction
- Generally lacks classic Sjögren's syndrome autoantibodies (anti-Ro/SSA, anti-La/SSB)

 5. Vasculitis

Various vasculitic patterns have been reported, including:[17]
- Large vessel vasculitis (resembling GCA or Takayasu arteritis)
- Medium vessel vasculitis (polyarteritis nodosa-like)
- Small vessel vasculitis (leukocytoclastic vasculitis, IgA vasculitis)
- Single-organ vasculitis (e.g., central nervous system vasculitis)

 6. Less Common Manifestations

- Systemic lupus erythematosus (SLE)-like syndrome
- Sarcoidosis-like granulomatous disease
- Eosinophilic fasciitis
- Digital ischemia
- Raynaud's phenomenon
- Systemic sclerosis-like manifestations

 Diagnostic Approach

Early recognition of rheumatological irAEs is crucial for appropriate management and favorable outcomes. The diagnostic approach includes:

 1. Clinical Assessment

- Comprehensive history, focusing on:
  - Timing of symptom onset in relation to immunotherapy
  - Pattern of joint/muscle involvement
  - Associated symptoms

- Detailed physical examination:
  - Joint assessment (swelling, tenderness, range of motion)
  - Muscle strength testing
  - Skin examination for rashes or other cutaneous manifestations
  - Assessment for systemic symptoms

 2. Laboratory Investigations

- Inflammatory markers:
  - Erythrocyte sedimentation rate (ESR)
  - C-reactive protein (CRP)

- Muscle enzymes:
  - Creatine kinase (CK)
  - Aldolase
  - Lactate dehydrogenase (LDH)
  - Transaminases (AST, ALT)

- Autoantibody testing:
  - Antinuclear antibodies (ANA)
  - Rheumatoid factor (RF)
  - Anti-citrullinated protein antibodies (ACPA)
  - Myositis-specific antibodies
  - Anti-neutrophil cytoplasmic antibodies (ANCA)

- Complement levels
- Complete blood count (CBC)
- Renal and liver function tests

 3. Imaging Studies

- Ultrasonography:
  - Sensitive for detecting early synovitis and tenosynovitis
  - Useful for monitoring treatment response

- Magnetic resonance imaging (MRI):
  - Gold standard for myositis assessment
  - Sensitive for detecting arthritis, enthesitis, and synovitis
  - Useful for evaluating large vessel vasculitis

- Conventional radiography:
  - Limited value in early inflammatory arthritis
  - May show erosive changes in established disease

- CT angiography or MR angiography:
  - For suspected large vessel vasculitis

 4. Tissue Sampling

- Synovial fluid analysis:
  - Cell count and differential
  - Crystal examination
  - Microbiology studies to exclude infection

- Muscle biopsy:
  - For suspected myositis, particularly with atypical presentations
  - May show necrotizing myopathy with CD8+ T-cell infiltration

- Skin or nerve biopsy:
  - For suspected vasculitis or other inflammatory dermatoses

- Minor salivary gland biopsy:
  - For suspected sicca syndrome to assess for lymphocytic sialadenitis

 5. Functional Assessment

- Schirmer's test and ocular staining score for sicca symptoms
- Salivary flow measurement
- Pulmonary function tests when interstitial lung disease is suspected
- Electromyography (EMG) for neuromuscular evaluation

 Management Strategies

The management of rheumatological irAEs requires a balanced approach that adequately controls autoimmune manifestations while preserving the anticancer benefits of immunotherapy. Treatment decisions should be made in collaboration with the patient's oncologist, considering the severity of the irAE, the cancer status, and available therapeutic alternatives.[18,19]

 1. General Principles

- Grading of irAE severity (based on CTCAE criteria):
  - Grade 1: Mild, asymptomatic or mild symptoms
  - Grade 2: Moderate, limiting instrumental ADL
  - Grade 3: Severe, limiting self-care ADL
  - Grade 4: Life-threatening
  - Grade 5: Death related to irAE

- Immunotherapy considerations:
  - Grade 1: Continue immunotherapy with close monitoring
  - Grade 2: Consider temporary hold of immunotherapy
  - Grade 3-4: Permanent discontinuation often recommended

- Multidisciplinary approach involving:
  - Rheumatologist
  - Oncologist
  - Other specialists as needed (dermatologist, neurologist, etc.)
  - Clinical pharmacist

 2. Pharmacological Interventions

 a. Glucocorticoids
- First-line therapy for most moderate to severe rheumatological irAEs
- Dosing depends on severity:
  - Grade 1: Topical or low-dose oral prednisone (≤10 mg/day)
  - Grade 2: Prednisone 0.5-1 mg/kg/day
  - Grade 3-4: Methylprednisolone 1-2 mg/kg/day IV

- Prolonged steroid tapering (over 4-8 weeks) is often necessary to prevent relapse
- Steroid-sparing strategies should be considered for prolonged courses

 b. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)
- Methotrexate: Often used for persistent inflammatory arthritis
- Hydroxychloroquine: Suitable for mild arthritis and sicca symptoms
- Sulfasalazine: Alternative for arthritis, particularly in patients with contraindications to methotrexate
- Leflunomide: Option for refractory inflammatory arthritis

 c. Biologic disease-modifying antirheumatic drugs (bDMARDs)
- TNF inhibitors (infliximab, adalimumab):
  - Effective for steroid-refractory inflammatory arthritis
  - Caution regarding potential impact on tumor response

- IL-6 inhibitors (tocilizumab):
  - Emerging option for inflammatory arthritis and PMR-like syndrome
  - May have less impact on antitumor immunity

- CTLA-4 agonists (abatacept):
  - Theoretical concern for antagonizing anti-tumor effect
  - Limited evidence but may be considered in select cases

- Rituximab:
  - For refractory cases, particularly those with autoantibody positivity
  - Consideration for vasculitis

d. Targeted synthetic DMARDs (tsDMARDs)
- JAK inhibitors (tofacitinib, baricitinib):
  - Emerging data for refractory inflammatory arthritis
  - Monitoring for adverse events essential

 e. Other interventions
- Intravenous immunoglobulin (IVIG):
  - For severe myositis, particularly with myasthenia overlap
  - Option for refractory inflammatory arthritis

- Plasma exchange:
  - Reserved for severe, life-threatening conditions unresponsive to other therapies

- Mycophenolate mofetil:
  - Option for refractory cases, particularly with overlap features

 3. Non-pharmacological Management

- Physical therapy and rehabilitation:
  - Crucial for maintaining function in inflammatory arthritis and myositis
  - Tailored exercise programs to prevent deconditioning

- Artificial tears and saliva substitutes for sicca symptoms
- Supportive care for symptom management
- Patient education regarding disease management and medication side effects

 4. Monitoring and Follow-up

- Regular clinical assessment:
  - Joint counts and functional assessments
  - Muscle strength evaluation
  - Quality of life measures

- Laboratory monitoring:
  - Inflammatory markers (ESR, CRP)
  - Muscle enzymes when appropriate
  - Organ function tests based on therapy

- Imaging:
  - Ultrasound or MRI to assess treatment response in arthritis
  - Cardiac monitoring for patients with myositis

- Monitoring for long-term complications:
  - Glucocorticoid-related adverse effects
  - DMARD-specific toxicities
  - Cancer response and progression

 Impact on Cancer Therapy and Outcomes

The development of rheumatological irAEs has complex implications for cancer treatment and outcomes:

1. Association with Cancer Response

Several studies suggest that the development of irAEs may be associated with improved tumor response and survival outcomes.[20,21] This association appears to be particularly strong for:
- Vitiligo in melanoma patients
- Inflammatory arthritis in various malignancies
- Thyroiditis in multiple tumor types

However, this relationship is not universal across all irAE types, and causality remains difficult to establish.

 2. Implications for Immunotherapy Continuation

The decision to continue, temporarily hold, or permanently discontinue immunotherapy requires careful consideration of:
- Severity and type of rheumatological irAE
- Response to immunosuppressive therapy
- Cancer status and available treatment alternatives
- Patient preferences and quality of life

For mild to moderate rheumatological irAEs that respond well to treatment, immunotherapy may often be continued with close monitoring. Severe or life-threatening manifestations typically necessitate permanent discontinuation.

 3. Long-term Outcomes

The natural history of immunotherapy-induced rheumatological manifestations remains incompletely characterized. Available evidence suggests:[22,23]
- Some patients experience resolution of symptoms upon immunotherapy discontinuation
- Many patients require prolonged immunosuppressive therapy
- A subset develops chronic rheumatological disease despite immunotherapy cessation
- Reactivation can occur with immunotherapy rechallenge

 4. Quality of Life Considerations

Rheumatological irAEs can significantly impact quality of life through:
- Pain and functional limitations
- Treatment-related side effects
- Psychological burden of managing concurrent conditions
- Uncertainty regarding long-term prognosis

Comprehensive supportive care and patient-centered decision-making are essential components of management.

 Special Considerations

 1. Pre-existing Rheumatological Conditions

Historically, patients with pre-existing autoimmune diseases were excluded from immunotherapy clinical trials. However, growing evidence suggests that many patients with stable rheumatological conditions can safely receive ICIs with appropriate monitoring:[24,25]
- Approximately 30-50% experience flares of their underlying condition
- De novo irAEs occur at rates similar to the general population
- Most flares can be managed without permanent immunotherapy discontinuation
- Baseline immunosuppression may influence flare risk

Pre-treatment optimization of disease control and collaborative management between rheumatologists and oncologists are essential.

 2. Combination Immunotherapy and Novel Agents

As immunotherapeutic approaches evolve, novel challenges emerge:
- Combination regimens (e.g., anti-CTLA-4 plus anti-PD-1) are associated with higher irAE rates
- Dual immune checkpoint blockade may cause more severe and earlier-onset rheumatological manifestations
- Novel agents (e.g., anti-LAG3, anti-TIM3) may have distinct irAE profiles
- Combination with targeted therapies may modify irAE risk and presentation

 3. Biomarkers and Prediction

Identifying biomarkers to predict rheumatological irAEs represents an area of active research:
- Peripheral blood immune cell phenotyping
- Cytokine profiles
- Genetic polymorphisms (particularly HLA associations)
- Microbiome characteristics
- Pre-existing autoantibodies

Currently, no validated biomarkers are available for routine clinical use.

 Future Directions

The field of immunotherapy-related rheumatological complications continues to evolve rapidly. Key areas for future research include:

1. Prospective registries and long-term follow-up studies to better characterize the natural history of rheumatological irAEs

2. Biomarker development for risk stratification and early detection

3. Optimization of treatment algorithms based on irAE subtype and severity

4. Investigation of targeted therapies that can effectively manage irAEs while preserving anti-tumor immunity

5. Development of prevention strategies for high-risk patients

6. Refinement of rechallenge protocols for patients who require ongoing immunotherapy

7. Understanding the mechanistic relationship between irAEs and tumor response

8. Integration of patient-reported outcomes in clinical trials and real-world studies

 Conclusion

Rheumatological immune-related adverse events represent a significant clinical challenge in the expanding landscape of cancer immunotherapy. Their diverse manifestations, variable time course, and potential impact on cancer treatment necessitate a systematic approach to diagnosis and management. Collaboration between rheumatologists and oncologists is essential for optimizing outcomes in affected patients.

As immunotherapy indications continue to expand, rheumatologists will increasingly encounter these complications in clinical practice. A thorough understanding of their presentation, pathophysiology, and management principles is crucial for providing high-quality care to this unique patient population. Future research should focus on identifying predictive biomarkers, refining treatment strategies, and clarifying the relationship between irAEs and cancer outcomes.

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