# Immune Checkpoint Inhibitor-Related Rheumatic Complications

## Introduction

Immune checkpoint inhibitors have revolutionized the treatment of numerous malignancies but are accompanied by immune-related adverse events affecting virtually every organ system. Rheumatic immune-related adverse events affect approximately 5 to 10 percent of ICI-treated patients and remain underrecognized and underreported in the oncology literature. The three classes of approved ICIs include anti-CTLA-4 agents (ipilimumab), anti-PD-1 agents (nivolumab, pembrolizumab, cemiplimab), and anti-PD-L1 agents (atezolizumab, avelumab, durvalumab). Rheumatic irAEs can be the initial presentation that prompts rheumatology referral, and they present a unique therapeutic challenge: the need to suppress the aberrant autoimmune response while preserving the desired anti-tumor immune activity of the checkpoint inhibitor.

## Immune Checkpoint Biology

### CTLA-4 Pathway

CTLA-4 is expressed on T cells and competes with the co-stimulatory receptor CD28 for binding to B7 ligands (CD80 and CD86) on antigen-presenting cells. When CTLA-4 engages B7, it delivers an inhibitory signal that promotes T cell anergy and tolerance. Anti-CTLA-4 therapy with ipilimumab blocks this inhibitory checkpoint, resulting in enhanced T cell priming and activation. This mechanism acts primarily in lymph nodes during the T cell priming phase, leading to broad activation of T cell responses.

### PD-1/PD-L1 Pathway

PD-1 is expressed on activated T cells and binds to PD-L1, which is expressed on tumor cells, antigen-presenting cells, and various normal tissues, as well as to PD-L2. Engagement of PD-1 induces T cell exhaustion and tolerance, a mechanism exploited by tumors to evade immune surveillance. Anti-PD-1 and anti-PD-L1 therapies reactivate exhausted T cells in peripheral tissues and within the tumor microenvironment. This pathway acts primarily at the effector phase in tissues, distinguishing it from the priming-phase activity of CTLA-4 blockade.

### Mechanism of irAEs

Immune-related adverse events arise through several mechanisms related to the loss of peripheral tolerance. The removal of checkpoint-mediated immune restraint allows autoimmune attack on self-tissues. Pre-existing subclinical autoimmunity may be "unmasked" by ICI therapy, explaining why patients with pre-existing autoimmune conditions are at higher flare risk. Cross-reactivity between T cells targeting tumor neoantigens and structurally similar self-antigens contributes to organ-specific irAEs. Excessive pro-inflammatory cytokine release amplifies tissue damage. Combination ICI therapy with both anti-CTLA-4 and anti-PD-1 produces substantially higher irAE rates, approximately 55 to 60 percent compared with 15 to 30 percent with monotherapy.

## Rheumatic irAEs

### Inflammatory Arthritis (Most Common Rheumatic irAE)

#### Epidemiology

Inflammatory arthritis is the most common rheumatic irAE, with a prevalence of approximately 5 to 7 percent of ICI-treated patients. The onset is variable, with a median of 3 to 6 months after ICI initiation, though it can develop as early as weeks or as late as more than one year into treatment. A distinguishing feature of ICI-induced arthritis compared to many other irAEs is that it can persist after ICI discontinuation, potentially requiring long-term rheumatologic management.

#### Clinical Patterns

ICI-induced inflammatory arthritis presents in several distinct clinical patterns. A reactive arthritis-like pattern manifests as asymmetric oligoarthritis affecting large joints such as the knees and ankles, often accompanied by enthesitis and sometimes preceded by ICI-induced colitis. An RA-like pattern presents as symmetric polyarthritis involving small joints including the MCPs, PIPs, and wrists, though rheumatoid factor and anti-CCP antibodies are only rarely positive. A polymyalgia rheumatica-like pattern features proximal girdle pain and stiffness with elevated ESR and CRP, with bilateral shoulder bursitis demonstrable on ultrasound. Large joint monoarthritis affecting the knee or shoulder requires exclusion of septic arthritis and crystal disease. A psoriatic arthritis-like pattern can develop in conjunction with ICI-induced psoriasis, featuring dactylitis, enthesitis, and nail changes. Axial involvement with sacroiliitis has been reported but is rare.

#### Diagnosis

Diagnostic evaluation of ICI-induced arthritis requires assessment of the pattern of joint involvement and its temporal relationship to ICI initiation. ESR and CRP are often elevated. Rheumatoid factor is positive in approximately 15 percent of cases, far lower than the 70 percent positivity rate in true rheumatoid arthritis, and anti-CCP is positive in only 5 to 10 percent. Imaging with ultrasound or MRI demonstrates synovitis, tenosynovitis, and enthesitis, though findings are typically non-erosive early in the disease course. Synovial fluid analysis shows an inflammatory pattern with more than 2000 white blood cells per microliter; infection and crystal disease must be excluded. An autoantibody panel including ANA, RF, and anti-CCP is usually negative and helps distinguish ICI-arthritis from pre-existing rheumatoid arthritis.

#### Management (per ASCO/NCCN/ACR guidelines)

Management follows a graded approach based on severity. Grade 1 (mild, without functional limitation) is treated with NSAIDs while continuing ICI therapy. Grade 2 (moderate, with limited function) is treated with low-dose prednisone at 10 to 20 mg daily, with consideration of a DMARD such as hydroxychloroquine, sulfasalazine, or methotrexate; ICI may be continued if the patient responds to treatment. Grade 3 (severe, disabling) requires prednisone at 0.5 to 1 mg/kg/day tapered appropriately, ICI should be held, and a DMARD such as methotrexate, sulfasalazine, or a TNF inhibitor should be added. Grade 4 (life-threatening) necessitates high-dose glucocorticoids, ICI should be held or permanently discontinued, and urgent rheumatology consultation is required. For chronic ICI-arthritis requiring steroid-sparing therapy, methotrexate, sulfasalazine, and hydroxychloroquine are first-line options. TNF inhibitors, particularly infliximab, are reserved for refractory cases and offer the added advantage of treating concurrent ICI-colitis. IL-6 inhibitors such as tocilizumab are under investigation, though concerns exist about masking cytokine release syndrome.

<image>A clinical presentation and management algorithm for immune checkpoint inhibitor-related inflammatory arthritis. Top panel: Show the three main clinical patterns on separate hand/body illustrations: (1) RA-like symmetric polyarthritis (MCPs, PIPs, wrists highlighted bilaterally), (2) Reactive arthritis-like asymmetric oligoarthritis (knee, ankle highlighted unilaterally with enthesitis at Achilles), (3) PMR-like proximal girdle pain (bilateral shoulders and hips highlighted). Bottom panel: Management algorithm starting with "ICI-induced inflammatory arthritis confirmed" → Grade 1 (mild): NSAIDs, continue ICI → Grade 2 (moderate): prednisone 10-20 mg + consider DMARD, continue ICI → Grade 3 (severe): prednisone 0.5-1 mg/kg, hold ICI, add DMARD → Grade 4 (disabling/refractory): high-dose GC, consider TNFi or tocilizumab, permanently discontinue ICI. Include a timeline showing median onset (3-6 months after ICI start) and note that arthritis can persist after ICI cessation.</image>

### Myositis (ICI-Related)

#### Epidemiology

ICI-related myositis affects approximately 1 percent of ICI-treated patients, with a higher incidence observed with anti-PD-1 agents. Its onset is typically early, often within the first 1 to 3 cycles of ICI therapy. The mortality rate is alarmingly high, approximately 30 percent when myocarditis coexists, making early recognition a clinical imperative.

#### Clinical Features

Proximal muscle weakness develops rapidly and can be severe. A distinctive feature of ICI-myositis, distinguishing it from classic inflammatory myopathies, is frequent involvement of extraocular muscles, producing ptosis, diplopia, and ophthalmoplegia, which reflects an overlap with myasthenia gravis. Bulbar muscle involvement causes dysphagia and dysarthria. Respiratory muscle weakness can progress to respiratory failure requiring ICU admission. The overlap with myasthenia gravis is substantial, with anti-acetylcholine receptor antibodies detected in approximately 20 to 40 percent of ICI-myositis patients. The most feared complication is the combined myositis-myasthenia-myocarditis syndrome, with myocarditis coexisting in 20 to 30 percent of cases and carrying an extremely high mortality of 50 to 60 percent.

#### Diagnosis

Creatine kinase is markedly elevated, often exceeding 10,000 IU/L. Troponin must be checked in every case; elevation mandates immediate cardiology consultation and cardiac MRI. Electromyography reveals an irritable myopathy pattern. MRI demonstrates muscle edema with STIR hyperintensity. Muscle biopsy shows necrotizing myopathy or inflammatory myopathy with macrophage and T cell infiltration. Anti-acetylcholine receptor antibodies and anti-striational antibodies should be screened to evaluate for myasthenia overlap. ECG, echocardiography, and cardiac MRI are mandatory to assess for myocarditis.

#### Management

ICI-related myositis, particularly when complicated by myocarditis or respiratory failure, constitutes a medical emergency. High-dose glucocorticoids are administered, typically methylprednisolone at 1 to 2 mg/kg/day intravenously for severe cases, with consideration of pulse dosing at 1000 mg daily for 3 days. Intravenous immunoglobulin at 2 g/kg over 5 days is indicated, especially when myasthenia overlap is present. Plasma exchange is employed for myasthenia crisis or refractory disease. The ICI must be permanently discontinued. Pyridostigmine alone should be avoided because it may worsen cardiac conduction in the setting of myocarditis. Abatacept and ruxolitinib (a JAK inhibitor) have been reported as rescue therapies for refractory ICI-myocarditis.

| Rheumatic irAE | Prevalence | Onset | Clinical Pattern | Key Diagnostic Feature | Persistence After ICI Stop | First-line Treatment |
|----------------|-----------|-------|-----------------|----------------------|---------------------------|---------------------|
| Inflammatory arthritis | 5-7% | 3-6 months | RA-like, ReA-like, PMR-like, PsA-like | RF/anti-CCP usually negative | **Often chronic** (~50% need DMARD at 1 yr) | NSAIDs → GC → MTX/SSZ → TNFi |
| Myositis | ~1% | 1-3 cycles | Proximal weakness, ocular involvement | CK >10,000; **check troponin** (myocarditis in 20-30%) | Usually resolves | High-dose GC ± IVIG; **permanently stop ICI** |
| PMR-like | 2-3% | Variable | Bilateral shoulder/hip girdle pain | Elevated ESR/CRP; bilateral bursitis on US | Variable | GC (standard PMR doses) |
| Sicca syndrome | 3-5% | Variable | Dry eyes/mouth | Anti-Ro/SSA usually **negative**; T cell-predominant biopsy | Often persistent | Symptomatic (tears, pilocarpine) |
| Vasculitis (GCA/LVV-like) | <1% | Variable | Temporal headache, girdle pain | PET-CT: large vessel FDG uptake | Variable | GC |
| Sarcoid-like | <1% | Variable | Hilar LAD, pulmonary nodules, skin | Non-caseating granulomas; **mimics cancer progression** | Usually resolves | GC |
| Myocarditis (overlap) | 0.5-1% | Early (1-3 cycles) | Heart failure, arrhythmia | Troponin elevation; cardiac MRI | — | **Emergency**: IV GC, IVIG, PLEX; stop ICI permanently |

### Other Rheumatic irAEs

#### Sicca Syndrome (ICI-Sjogren)

ICI-induced sicca syndrome presents with new-onset dry eyes and dry mouth after ICI therapy. It differs from primary Sjogren syndrome in that anti-Ro/SSA and anti-La/SSB antibodies are usually negative and salivary gland biopsy shows T cell-predominant rather than B cell-predominant inflammation. Parotid swelling may occur. Treatment is primarily symptomatic with artificial tears and pilocarpine; glucocorticoids are used for severe cases. Sicca syndrome does not usually require ICI discontinuation.

#### Vasculitis

ICI-induced vasculitis can present in patterns resembling giant cell arteritis or polymyalgia rheumatica, with temporal headache, proximal girdle pain, and elevated ESR and CRP. PET-CT may demonstrate large vessel FDG uptake. Small-vessel vasculitis typically manifests as cutaneous leukocytoclastic vasculitis and is rarely systemic. ANCA-positive vasculitis with GPA-like and MPA-like presentations has been reported in rare cases. Treatment follows standard vasculitis management with glucocorticoids.

#### Sarcoidosis-like Reactions

Non-caseating granulomas can develop during ICI therapy, producing hilar lymphadenopathy, pulmonary nodules, and skin lesions. These findings can mimic cancer progression on imaging, potentially leading to incorrect staging. Biopsy may be required to distinguish granulomatous inflammation from tumor. Treatment with glucocorticoids is effective, and the reaction often resolves after ICI discontinuation.

#### Lupus-like Syndrome

SLE-like features including rash, arthritis, serositis, and cytopenias may develop. ANA may become positive, though anti-dsDNA is less commonly detected. The presentation is usually mild and glucocorticoid-responsive. Cutaneous lupus is more common than systemic involvement.

#### Scleroderma-like Reactions

Skin tightening and fibrosis are rare ICI-related complications that may more closely resemble eosinophilic fasciitis or morphea than systemic sclerosis. Deep biopsy demonstrating fascial inflammation helps establish the diagnosis.

## Key Considerations for Rheumatologists

### Collaboration with Oncology

Immunosuppressive therapy for rheumatic irAEs must always be discussed with the treating oncologist before initiation. ICI therapy may need to be held for grade 3 or higher irAEs or permanently discontinued for grade 4 irAEs and myocarditis. Regarding anti-tumor efficacy, short-course glucocorticoids lasting less than 4 weeks and low-dose glucocorticoids less than 10 mg prednisone appear safe and do not compromise anti-tumor response. Data on the impact of TNF inhibitors and other immunosuppressants on anti-tumor efficacy are limited, warranting judicious use. An intriguing observation is that the development of irAEs may paradoxically indicate a more robust anti-tumor response, with some studies suggesting improved oncologic outcomes in patients who develop irAEs.

### Pre-existing Autoimmune Disease and ICI Use

Patients with pre-existing autoimmune disease, including rheumatoid arthritis, SLE, and psoriasis, experience flare rates of approximately 40 to 50 percent when treated with ICIs. However, pre-existing autoimmune disease is not an absolute contraindication to ICI therapy; the decision requires individualized risk-benefit assessment. Close rheumatology monitoring during ICI treatment is essential, and prophylactic increases in immunosuppression may be necessary.

### Chronicity of Rheumatic irAEs

Rheumatic irAEs are among the longest-lasting irAEs across all organ systems. Inflammatory arthritis can persist for months to years after ICI discontinuation, with approximately 50 percent of patients requiring ongoing DMARD therapy at one year. Myositis usually resolves with treatment but may recur. Sicca syndrome is often persistent. This chronicity underscores the need for ongoing rheumatology follow-up even after oncologic treatment has been completed.

### Screening Before ICI Initiation

Baseline laboratory assessment before ICI initiation should include RF and anti-CCP to identify pre-existing autoimmunity, TSH for thyroid irAE monitoring, CK as a baseline for myositis detection, and HbA1c for type 1 diabetes irAE assessment. A baseline joint assessment should be considered in patients with pre-existing rheumatic disease.

<image>A comprehensive overview diagram of all rheumatic immune-related adverse events from checkpoint inhibitors. Show a central human figure with the three ICI targets illustrated at top (CTLA-4 on T cell → ipilimumab, PD-1 on T cell → nivolumab/pembrolizumab, PD-L1 on tumor cell → atezolizumab/durvalumab). From the figure, draw arrows to each rheumatic irAE with approximate prevalence: Inflammatory arthritis (5-7%): hands, knees highlighted. Myositis (1%): proximal muscles highlighted with danger symbol for myocarditis overlap. PMR-like (2-3%): shoulders and hips. Sicca syndrome (3-5%): eyes and salivary glands. Vasculitis (<1%): temporal arteries, skin. Sarcoid-like (<1%): lungs, lymph nodes. Lupus-like (<1%): butterfly rash, joints. For each, include a small box with key diagnostic features and first-line treatment. Highlight myositis in red as highest acuity with note "Check troponin - myocarditis overlap in 20-30%."</image>

## Key Clinical Pearls

- ICI-related myositis with concurrent myocarditis has ~50-60% mortality; ALWAYS check troponin and ECG in ICI-myositis
- ICI-induced inflammatory arthritis often persists after ICI discontinuation, unlike many other irAEs that resolve
- Anti-CCP and RF are usually NEGATIVE in ICI-arthritis; their presence suggests pre-existing RA unmasked by ICI
- Short-course glucocorticoids (<4 weeks, <10 mg prednisone) appear safe and do not compromise anti-tumor efficacy
- Infliximab serves dual purpose in patients with ICI-colitis + ICI-arthritis
- Pre-existing autoimmune disease is NOT an absolute contraindication to ICI therapy; close rheumatology monitoring is essential

## References
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2. Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435.
3. Moreira A, et al. Myositis and neuromuscular side effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106:12-23.
4. Roberts J, et al. Rheumatic immune-related adverse events in cancer immunotherapy. Lancet Rheumatol. 2022;4(8):e604-e618.
5. Bass AR, et al. 2024 American College of Rheumatology Guideline for the Management of Immune Checkpoint Inhibitor-Related Rheumatic and Musculoskeletal Adverse Events. Arthritis Care Res. 2024.