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Rheumatologic complications of checkpoint inhibitor immunotherapy

Rheumatologic complications of checkpoint inhibitor immunotherapy
Literature review current through: Jan 2024.
This topic last updated: Jun 05, 2023.

INTRODUCTION — Immune checkpoint inhibitors (ICIs) are the most commonly used type of cancer immunotherapy but can cause a number of immune-related adverse events (irAEs), including a variety of rheumatologic manifestations. The irAEs result from damage that occurs due to immune activation and inflammation induced by these drugs and can affect nearly every organ system.

This class of drugs works by blocking inhibitory molecules on T cells, antigen-presenting cells, and tumors, thus allowing an enhanced endogenous T-cell-mediated immune response to cancer. The efficacy of ICIs was first demonstrated in metastatic melanoma, but many indications have since been approved, including non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, and other advanced malignancies (see specific disease-related topic reviews). (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy' and "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation" and "Systemic therapy of advanced clear cell renal carcinoma" and "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Targeted chemotherapy and immunotherapy'.)

The rheumatologic complications of ICIs and their management will be reviewed here. The range of irAEs with non-rheumatologic manifestations (eg, colitis, endocrine disease, and others) and rheumatic disorders occurring due to other types of cancer treatment are described in detail separately. (See "Toxicities associated with immune checkpoint inhibitors" and "Malignancy and rheumatic disorders", section on 'Rheumatic disorders associated with treatments for malignant disease'.)

IMMUNE CHECKPOINT INHIBITOR MECHANISM OF ACTION — The several approved immune checkpoint inhibitors (ICIs) target different sets of regulatory interactions. Normally, when a T cell is activated, multiple mechanisms control the level of activation both centrally and peripherally [1]. Two main interactions that control T-cell activation are cytotoxic lymphocyte antigen protein 4 (CTLA-4, also called CD152) on T cells binding with CD80/86 (also called B7-1 and B7-2) on antigen-presenting cells, and programmed cell death receptor 1 (PD-1) binding to programmed cell death ligand 1 (PD-L1, also known as B7-H1) or programmed cell death ligand 2 (PD-L2 [B7-H2]) (see "Principles of cancer immunotherapy"). By blocking these inhibitory pathways, checkpoint inhibitors allow for increased activation of T cells and a greater immune response against tumors.

The first approved ICI, ipilimumab, blocks the binding of CTLA-4 to its ligands CD80/86. Subsequent ICIs have targeted PD-1 (pembrolizumab, nivolumab, cemiplimab) or PD-L1 (eg, atezolizumab, avelumab, durvalumab) (figure 1). (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy'.)

PATHOGENESIS OF RHEUMATOLOGIC COMPLICATIONS — Immune checkpoint inhibitors (ICIs) can lead to off-target tissue damage known as immune-related adverse events (irAEs) due to nonspecific activation of T cells. Clinical manifestations of irAEs are diverse with respect to the organ systems involved, severity, and temporal relationship to ICI therapy [2].

The specific immune pathways that are relevant for the pathogenesis of particular irAEs are still under investigation. There are no published correlative data for the pathogenesis of rheumatologic irAEs, but there are some data from other types of irAEs. In colitis, levels of interleukin (IL) 17 were correlated with more severe disease, suggesting a role for this cytokine and the T-helper 17 (Th17) cell response in pathogenesis. Histology from multiple affected organs has shown diverse inflammatory infiltrates [3].

The immune checkpoints targeted by ICIs are relevant for classic rheumatologic diseases, suggesting a possible overlap in mechanism. As an example, abatacept, a fusion protein of the extracellular domain of cytotoxic lymphocyte antigen protein 4 (CTLA-4) and the Fc portion of immunoglobulin (Ig)G, has been an effective treatment for inflammatory arthritis, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and psoriatic arthritis. Its mechanism can be thought of as the converse of ipilimumab in that it blocks the activating interaction between CD28 and CD80/86, rather than blocking the inhibitory interaction.

CTLA-4 and other immune checkpoint molecules have also been implicated in the pathogenesis of systemic lupus erythematosus and Sjögren's disease [4]. Programmed cell death receptor 1 (PD-1) may be important to RA pathogenesis, as indicated by some mouse and human studies [5,6].

EPIDEMIOLOGY — Rheumatologic immune-related adverse events (irAEs) have been less consistently reported in the published literature than other types of irAEs. The most common symptom is arthralgia, which has generally been described in approximately 10 to 15 percent of patients, followed by myalgia and sicca complex, both occurring with a similar frequency as arthralgia [7]. However, estimates vary substantially; a 2017 systematic review found reported frequencies from 1 to 43 percent for arthralgia and 2 to 20 percent for myalgia [8]. The development of symptoms of an inflammatory systemic autoimmune disease, such as inflammatory arthritis, myositis, Sjögren's disease, or vasculitis, that may require referral to a rheumatologist is much less common, occurring in approximately 3.5 to 6.6 percent of patients treated with checkpoint inhibitors [9,10]. The known or suspected rheumatologic irAEs include inflammatory arthritis, sicca syndrome, inflammatory myopathy, vasculitis (including giant cell [temporal] arteritis [GCA], antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and single-organ vasculitis), polymyalgia rheumatica (PMR), eosinophilic fasciitis, sarcoidosis, digital ischemia, and systemic sclerosis (scleroderma) [8,10-25]. Though subacute cutaneous lupus and lupus nephritis have been described in the setting of immune checkpoint inhibitor (ICI) therapy, there have not been reports of systemic lupus erythematosus-like disease [22,26].

In a pharmacovigilance study of irAEs, arthritis, myositis, and sicca syndrome were over-reported in patients treated with ICI combination therapy as compared with monotherapy and were more frequently reported in anti-programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy as compared with anti-cytotoxic lymphocyte antigen protein 4 (CTLA-4) monotherapy [27].

Among those with preexisting autoimmune diseases, flares of disease or development of symptoms of another autoimmune disease may occur in up to 71 percent of such patients and require rheumatologic management [28]. (See 'Preexisting rheumatologic disease' below.)

Reasons for the variation and sometimes very low frequency of reports are not entirely clear but may be related to a lack of recognition of musculoskeletal symptoms by treating providers or the fact that rheumatologic irAEs are rarely life-threatening and are thus not often graded as severe.

How commonly arthralgia actually represents a true inflammatory arthritis is also unclear. In oncology clinical trials, including those using ICIs, there are multiple ways in which a given clinical finding or symptom can be coded for data collection (eg, joint effusion, arthralgia, arthritis), making it difficult to identify a true association. For other rheumatologic irAEs, epidemiologic data are even more limited. Dry mouth or dry eyes were reported in 3 to 24 percent of patients in those trials, while myalgia was present in 2 to 21 percent [8]. Myositis and vasculitis were not consistently reported in the published clinical trials, and most information concerning these entities is from case reports.

GENERAL PRINCIPLES OF EVALUATION AND MANAGEMENT — The clinical spectrum of rheumatologic immune-related adverse events (irAEs) with exposure to immune checkpoint inhibitors (ICIs) ranges widely, with presentations mirroring many classic rheumatologic diseases, although some characteristic features may be lacking, depending upon the syndrome and individual patient. It is common for patients with rheumatologic irAEs to have other non-rheumatologic irAEs; thus, obtaining a detailed history and performing a thorough physical examination are important, regardless of the presentation. (See "Toxicities associated with immune checkpoint inhibitors".)

In patients with one of these syndromes, the severity of the irAE, future plans for cancer therapy, status of the tumor response to ICIs, and patient and oncologist preference must all be considered in deciding on treatment for rheumatologic irAEs. We discuss treatment options with both the patient and referring oncologist before determining the specific plan of action.

The clinical need and the relative risks and benefits of rheumatologic and oncologic treatment options influence the management approach. As examples, certain medications like hydroxychloroquine or low-dose glucocorticoids may be used concurrently with ICI therapy and may be beneficial in patients with mild arthritis, while use of others, particularly those that interfere with T-cell function or the biologic disease-modifying antirheumatic drugs (DMARDs) that may be needed in patients with severe inflammatory arthritis, have not often been used concurrently with ICIs, although there are reports of tocilizumab and tumor necrosis factor (TNF) inhibitor use in patients actively receiving ICIs [29,30]. Close consultation with the patient's oncologist is important in deciding whether to continue or discontinue ICI therapy and the most appropriate interventions in a given patient.

Treatment approaches are based upon case reports and case series, but clinical trials have not been performed to compare treatment options. Our approaches are similar to those proposed by professional societies (table 1) [31,32].

INFLAMMATORY ARTHRITIS

Clinical manifestations and diagnosis — Inflammatory arthritis, with joint pain, tenderness, swelling, and warmth, has been the most commonly reported rheumatologic immune-related adverse event (irAE) [10,12,21,22,33]. The arthritis can develop at almost any time during immune checkpoint inhibitor (ICI) therapy, from two weeks to over a year from ICI initiation [10,12,21]. Symptoms and findings can be protracted in some patients. Several different clinical presentations of inflammatory arthritis with different patterns of joint involvement and ranging from mild to severe have been reported [12,21,34]; joint damage with erosions can occur within months of developing symptoms in a subset of patients [12]. These presentations have included:

Small-joint polyarthritis, sometimes in a pattern similar to rheumatoid arthritis (RA) [10,12,21,33]

Larger joint oligoarthritis with or without inflammatory back pain, including a pattern similar to reactive arthritis (ie, a large-joint, lower-extremity predominant arthritis with sterile urethritis and conjunctivitis) [12]

New-onset psoriatic arthritis, which has been reported in a patient on nivolumab with a family history of psoriasis, though no personal history [10,23]

Data from initial studies suggested that the pattern of arthritis may vary by the type of ICI exposure. Patients treated with anti-programmed cell death receptor 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) monotherapy are more likely to have initial small joint involvement and inflammatory arthritis as their only irAE. By contrast, patients who have received combination ICI therapy with cytotoxic lymphocyte antigen protein 4 (CTLA-4) and PD-1 inhibition are more likely to present with knee arthritis, to have had another irAE, and to have reactive arthritis-like disease [34].

The diagnosis is primarily made clinically, based upon the history and physical examination of a new-onset arthritis following the initiation of an ICI. A detailed history should be obtained to help determine if any features of arthritis or potentially associated features like skin psoriasis were present before the ICI was started. An inflammatory arthritis should be present on physical examination, and the pattern of involvement should be characterized. In patients without preceding symptoms and the absence of features to suggest a classic form of inflammatory arthritis, a diagnosis of ICI-induced arthritis can be made.

Laboratory studies can be helpful but are not critical for diagnosis. Most patients have been seronegative for rheumatoid factor (RF) and cyclic citrullinated peptide (CCP), but a group of seropositive patients has also been reported [33]. An elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be present, although the utility of these markers to identify inflammatory arthritis is compromised by the comorbid malignancy, which may also affect the ESR and CRP.

Plain radiographs of affected joints should be obtained at the time of the initial evaluation for arthritis but are less sensitive for early changes, as in other forms of inflammatory arthritis; however, these also serve as a baseline for comparison with later studies. Imaging with magnetic resonance imaging (MRI) and ultrasound has shown synovitis, tenosynovitis, enthesitis, enthesophytes, and bony erosive disease [11,12,35]. These findings may be helpful in distinguishing inflammation and synovitis from noninflammatory pain in patients in whom that determination remains uncertain.

Other conditions that may mimic ICI-related inflammatory arthritis should be included in the differential diagnosis. These conditions and a fuller review of their respective diagnoses and differential diagnoses are discussed in detail separately and include:

Unrelated or coincidental presentations of a rheumatic disease with inflammatory arthritis (see "Evaluation of the adult with polyarticular pain" and "Diagnosis and differential diagnosis of rheumatoid arthritis")

Paraneoplastic syndromes (see "Malignancy and rheumatic disorders", section on 'Paraneoplastic rheumatic manifestations')

Polyarthralgia due to medications or to fibromyalgia/central pain sensitization (see "Clinical manifestations and diagnosis of fibromyalgia in adults" and "Differential diagnosis of fibromyalgia")

Bony metastasis causing erosive joint change, which should be suspected if there is a joint with disproportionate erosive disease or a joint that does not improve with therapy when the rest of the arthritis is improving

Treatment — The approach to treatment of inflammatory arthritis occurring as an irAE is based upon case reports, case series, and personal experience, with modifications of the usual treatment approaches that would be taken, in the absence of ICI therapy, for these and similar conditions. Treatment should be individualized based upon the clinical findings and severity of the symptoms and findings related to the arthritis, as well as the need to optimize antineoplastic therapy; treatment recommendations and decisions should be made in close collaboration with the patient's oncologist. (See 'General principles of evaluation and management' above.)

Initial treatment of mild arthritis — In patients with mild forms of arthritis (without significant functional compromise), we suggest a nonsteroidal antiinflammatory drug (NSAID) or low-dose glucocorticoids. ICI therapy is usually continued in such patients.

Oral NSAIDs (eg, orally administered naproxen 375 to 500 mg twice daily, ibuprofen 600 to 800 mg three times daily) are typically used, but some patients with very mild disease may benefit adequately from a topical NSAID (eg, diclofenac gel). There is no evidence to indicate a preference for any specific NSAID. The drug should be used in the lowest dose necessary once a response is achieved and for the shortest duration needed. Comorbidities and relative contraindications to NSAID use, such as renal, cardiovascular, and gastrointestinal (GI) disease, as well as advanced age, should be considered in the treatment decision, and patients should be monitored appropriately and with particular attention to GI symptoms, given the frequency of GI adverse effects with ICI therapy, including diarrhea and colitis. (See "Nonselective NSAIDs: Overview of adverse effects" and "Immune checkpoint inhibitor colitis".)

In patients in whom NSAIDs should be avoided, or in whom a more rapid response is desired than expected with an NSAID, we use prednisone (initially 10 to 20 mg daily), then assess the response after one to two weeks, adjusting the dose to minimize glucocorticoid exposure while controlling disease symptoms and findings. Many oncologists are comfortable using 10 mg prednisone daily and sometimes higher doses for a finite amount of time while continuing ICIs. Limited data support the safety of concurrent glucocorticoid therapy with ipilimumab, one of the ICIs [36].

In patients with only a few (one to three) joints involved, we administer intraarticular glucocorticoid injections in affected joints, if feasible, which may reduce the need for other interventions [37]. The approach to using intraarticular glucocorticoids is the same as for RA. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Intraarticular therapy'.)

Initial treatment of moderate or severe arthritis — In patients with moderate or severe arthritis, with involvement of multiple joints and impairment of function, we suggest moderate- to high-dose oral glucocorticoids (eg, prednisone 40 mg daily up to 1 mg/kg daily); higher doses are sometimes required [12].

In patients who require these higher doses of glucocorticoids (eg, over 20 mg daily of prednisone or equivalent), the ICI is sometimes held temporarily. In patients in whom the prednisone can be tapered to a lower dose and if the patient is doing well, the ICI is usually restarted while continuing the glucocorticoid.

Unable to adequately taper glucocorticoids — In patients with mild to moderate, but persistent, inflammatory arthritis who cannot be weaned to a low dose (eg, prednisone less than 7.5 to 10 mg daily) or entirely off glucocorticoids we suggest a conventional synthetic disease-modifying antirheumatic drug (DMARD), such as sulfasalazine (SSZ), hydroxychloroquine (HCQ), or methotrexate (MTX) in the same fashion as these might be used in RA or spondyloarthritis. (See "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of peripheral spondyloarthritis".)

The decisions of whether the ICI can or should be held needs to be made on an individual basis together with the treating oncologist, especially in cases where glucocorticoids cannot be tapered.

SSZ, HCQ, and MTX have each been reported in case reports and case series as being effective in some patients with ICI-related inflammatory arthritis [11,12,21]. These agents, as well as leflunomide, have been used concurrently with ICIs, although no systematic study of efficacy and other outcomes has been performed.

Severe arthritis — In selected patients with severe arthritis who are refractory to glucocorticoid therapy or unable to wean to low-dose (prednisone less than 7.5 to 10 mg daily) glucocorticoids, we use a tumor necrosis factor (TNF) inhibitor. There are no data to indicate a preference for one TNF inhibitor over another; infliximab (5 mg/kg with standard loading-dose regimens then every six to eight weeks), adalimumab (40 mg every other week to as frequently as every week), and etanercept (50 mg every week) have effectively controlled arthritis symptoms in our experience, and benefit has also been reported, but only small numbers of patients have been treated with any of these agents [12,21].

TNF inhibitors may be preferred over conventional DMARDs in patients in whom it is undesirable to wait for several weeks for a response to MTX or other conventional synthetic DMARDs or in whom comorbidities (eg, liver disease, cytopenias) may preclude use of such agents.

Precautions, dosing, and strategies for use of these agents are generally the same as in patients with RA and other related conditions. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab' and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)

The authors have rarely treated patients concurrently with biologic therapy while they have been receiving ICIs; this has been reported with tocilizumab for arthritis [29] and infliximab for colitis [29,30] (see 'Other agents' below). Patients have received TNF inhibitors during a break in therapy and have been rechallenged with ICIs subsequently.

Other agents — Data regarding the efficacy and safety of other agents are extremely limited. The following has been noted:

Tocilizumab – There are limited reports of interleukin (IL) 6 inhibition with tocilizumab to treat inflammatory arthritis [29]. This can be considered in patients who have contraindications to TNF inhibitors or do not respond to TNF inhibitors after two months. Tocilizumab has been used concurrently with ICIs in a small number of patients [29]. There have been concerns about using tocilizumab in patients treated with ICIs given the risk of colitis and intestinal perforation, which has been reported with both. However, in limited data available to date, there is no evidence that concurrent use of these agents increases the risk of GI complications [38,39]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab' and "Immune checkpoint inhibitor colitis".)

Other medications – There have been cases reported of psoriatic arthritis triggered by immunotherapy [23]. Apremilast, IL-17, and IL-12/23 inhibitors have been used in treating these patients and those with psoriasis due to ICIs, although there are case reports of tumor progression with IL-17 inhibition [40-42]. (See "Treatment of psoriatic arthritis".)

Prognostic implications — In most studies, tumor prognosis does not appear to be adversely affected by the presence or treatment of new-onset inflammatory arthritis associated with ICI therapy [36,43-46], but the arthritis may persist following discontinuation of the ICI and require ongoing intervention [12,21,34,46,47].

With all immunomodulatory agents, there is a theoretical concern of impairing tumor response to ICIs. As an example, there are limited data in patients treated with ipilimumab for melanoma regarding the effects on the malignancy of treatment of the arthritis or other rheumatic irAE with glucocorticoids or short-term infliximab [36]; in this study, the response of the tumor was not impaired, as indicated by no evidence of either a decrease in overall survival or in time to treatment failure.

Another study followed 60 patients referred to an academic arthritis center for inflammatory arthritis associated with ICI therapy, with 75 percent requiring immunosuppressive therapy (glucocorticoids in 80 percent and conventional and/or biologic DMARDs in 40 percent); progression of the tumors was no more common among patients treated with conventional and/or biologic DMARDs than those who were not (17 versus 22 percent) [46]. Further, a statistically nonsignificant trend suggested the possibility that patients with persistent inflammatory arthritis might have a better tumor response. Another finding in this study was the demonstration that inflammatory arthritis often persisted following ICI discontinuation. Patients were followed after the ICI therapy was stopped for a median of nine months; active inflammatory arthritis persisted at three and six months in 71 and 49 percent of patients, respectively, confirming observations from smaller studies of continued arthritis activity for sustained periods after cessation of ICI use [12,21,34,47]. Improvement in the arthritis was less likely in those with longer duration ICI use, combination ICI therapy, and in those with other irAE.

In several other studies of patients treated with PD-1 inhibitors who developed irAEs, having the irAE was associated with better cancer outcomes [43-45,48]. Timing of immunosuppression, including glucocorticoid use, may be important. In this respect, another study, of patients with non-small-cell lung cancer who were treated with either PD-1 or PD-L1 blockade, found that patients also being treated with ≥ 10 mg daily of prednisone for lung cancer-related symptoms at the onset of ICI therapy had poorer tumor responses to PD-1 or PD-L1 blockade [49]. Understanding how glucocorticoid and other immunosuppression used to treat irAEs might affect outcomes with respect to tumor response will benefit from further study.

SICCA SYNDROME/OTHER OCULAR DISORDERS

Clinical features — Severe salivary hypofunction and keratoconjunctivitis sicca resembling Sjögren's disease have been reported in patients treated with immune checkpoint inhibitors (ICIs) [12]. This can be abrupt in onset, often developing within the first three months of ICI therapy [50]. In many patients, the dry mouth symptoms have been predominant without concomitant dry eyes. Parotid swelling has rarely been observed.

Most patients lack the autoantibodies to Ro/SSA and La/SSB frequently seen in patients with non-ICI related Sjögren's disease, similar to the usual lack of rheumatoid arthritis (RA)-related antibodies in patients with inflammatory arthritis as an immune-related adverse event (irAE) [12]. (See 'Clinical manifestations and diagnosis' above.)

Other ocular manifestations including uveitis, peripheral ulcerative keratitis, and other forms of ocular inflammation due to ICIs have also been reported [51].

Labial salivary gland biopsies have demonstrated multiple types of histopathologic findings; some patients exhibit changes very similar to Sjögren's disease, while some others exhibit a histologic pattern that is distinct from typical Sjögren's disease, including mild to severe sialadenitis with diffuse T-cell lymphocytic infiltration and acinar injury [50].

Management — We use a very similar approach to the treatment of checkpoint inhibitor-induced sicca syndrome to that used for treating sicca symptoms in primary Sjögren's disease:

In patients with dry mouth symptoms, dental care remains important, and saliva substitutes and sialagogues can be used to relieve symptoms. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry mouth' and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease".)

In patients with parotid gland swelling, prednisone at doses of 10 to 40 mg daily tapered off over weeks has been helpful in resolving this issue in a limited number of cases [12].

Treatment of more severe oral manifestations was described in one series of 20 patients with ICI-induced sicca symptoms, in which ICI therapy was discontinued either temporarily or permanently in the majority of patients [50]. Prednisone was used in 10 of these patients, with starting doses ranging from 10 to 80 mg daily. The authors advised that for patients with grade 2 or 3 symptoms (ie, those who need to drink copious fluids to chew, swallow, and clear their mouth of residue; to restrict their diet to purees or soft, moist foods; or to use oral lubricants), ICI therapy should be held and prednisone 20 to 40 mg daily should be prescribed for two to four weeks, followed by a taper. Referral to an oral medicine specialist should also be considered. If sicca symptoms improve, ICI can be resumed after approximately three months [50].

In patients with dry eyes, we advise use of artificial tears, and patients should avoid other medications causing dryness. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy".)

In patients with severe or refractory symptoms with initial therapy for dry eye, referral to ophthalmology is indicated to confirm the diagnosis and evaluate for any other ocular pathology that may be related to checkpoint inhibition. (See "Treatment of moderate to severe dry eye in Sjögren’s disease" and "Toxicities associated with immune checkpoint inhibitors", section on 'Eye'.)

POLYMYALGIA RHEUMATICA/GIANT CELL (TEMPORAL) ARTERITIS

Clinical features and diagnosis — Polymyalgia rheumatica (PMR) may occur in isolation or with giant cell arteritis (GCA) during treatment with immune-checkpoint inhibitors (ICIs) [20,21,52,53]. In one series of 20 patients with PMR, the median time to PMR onset was 12 weeks after initiation of ICI therapy [53]. As with traditional PMR/GCA, patients with ICI-induced disease have been older adults, with all patients from several case reports and series through 2019 being over age 57 [20,21,52,53].

In patients in whom GCA is suspected (eg, based upon loss of vision or diplopia, a severe or unusual headache, scalp [especially temporal] tenderness, temporal vascular prominence, jaw or tongue claudication), prompt temporal artery biopsy is key to confirming this diagnosis. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated due to malignancy and are not useful unless there are baseline or prior data. If inflammatory markers are normal, however, GCA is very unlikely. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis".)

Symptoms of PMR have been very similar to those seen in patients who have not received ICIs, including proximal, especially shoulder, stiffness and pain without true weakness [20,21]. In one report of two cases, both patients had combined features of PMR and GCA, while reports of three patients with PMR [21] and one of GCA [52] described patients with one but not the other. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)

Temporal artery biopsy findings have been the same as for non-checkpoint inhibitor-related GCA [21]. (See "Diagnosis of giant cell arteritis", section on 'Temporal artery biopsy'.)

Imaging in checkpoint inhibitor-induced PMR or GCA has not been well characterized, but ultrasound or MRI may be helpful to support a PMR diagnosis if bursitis or tendonitis in classic areas is seen [21]. Imaging studies may be particularly useful in those who do not have elevated inflammatory markers but do have PMR-type symptoms.

Approach to treatment — Treatment for both GCA and PMR is very similar to that in patients without ICI therapy. As in the classic forms of PMR and GCA, we use glucocorticoids as the mainstay of therapy. (See "Treatment of giant cell arteritis" and "Treatment of polymyalgia rheumatica".)

Giant cell arteritis – In patients with GCA, we use standard or slightly higher doses of prednisone (50 to 60 mg daily) based upon the published reports [20,21]. In patients with GCA, the ICI has been held during initial treatment or discontinued because of the high dose of glucocorticoids required for the initial treatment of GCA. Published evidence is lacking regarding the glucocorticoid dose during a taper at which patients can be safely rechallenged with ICIs, and this assessment should be made collaboratively with the patient's oncologist.

The role of biologic agents such as tocilizumab to manage GCA in these patients is unclear. (See 'Other agents' above.)

Polymyalgia rheumatica – In patients with PMR (without concurrent GCA), we advise starting doses of prednisone for PMR of 15 to 25 mg daily initially, followed by a gradual taper. Because of the lower doses used compared with patients with GCA, these patients generally would not necessitate discontinuation of the ICI. In one series of 20 patients with ICI-induced PMR, tocilizumab was used as a glucocorticoid-sparing agent in two patients [53].

Evidence to guide dosing in these patients is lacking other than the evidence of benefit in the small number of patients who have been treated.

INFLAMMATORY MYOPATHIES — Dermatomyositis and polymyositis have been described as immune-related adverse events (irAEs) of checkpoint inhibitor therapy [14-16]. Muscle involvement is similar to classic forms of the diseases (ie, proximal muscle predominant), but respiratory distress was described in two patients with polymyositis [16,54], and distal and facial muscle involvement have been described [15]. Additionally, patients with concomitant myasthenia gravis and/or myocarditis and myositis due to immune checkpoint inhibitors (ICIs) have been reported [55-58]. When myositis is suspected, evaluating for concomitant myasthenia gravis and myocarditis with the physical examination and laboratory testing is needed. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Diagnosis is based upon physical examination and elevated muscle enzyme levels and can be aided by electromyography (EMG) or muscle MRI. An irritable myopathy on EMG, as seen in classic dermatomyositis or polymyositis, has also been described [15]. The role of muscle biopsy is unclear, as there are limited published reports of muscle biopsy findings with ICI-induced inflammatory myopathy. One report of a muscle biopsy did note an endomysial inflammatory infiltrate similar to polymyositis [15], and another report also noted a CD4 and CD8 lymphocytic endomysial infiltrate [54]. A subsequent report suggests marked necrosis and a large component of macrophagic cells in a perivascular pattern [59]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Clinical manifestations'.)

For cases of checkpoint inhibitor-induced myositis in the published literature, glucocorticoids have been the mainstay of treatment. Initial doses of prednisone from 30 mg daily up to 1 gram of intravenous methylprednisolone have been used, followed by gradual glucocorticoid tapers [14-16,21]. Intravenous immune globulin (IVIG) has been used when weakness is severe, diaphragmatic involvement or dysphagia is present, and in the case of concomitant myasthenia gravis [60]. ICIs have been discontinued in all published cases. It is unclear if patients can be safely rechallenged with checkpoint inhibitors in the setting of clinical improvement.

OTHERS — There are case reports/series of other rheumatologic immune-related adverse events (irAEs):

ANCA-associated vasculitis – Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis leading to glomerulonephritis and pulmonary disease have been reported in patients receiving anti-programmed cell death receptor 1 (PD-1) therapy [61-63]. There are also several cases of pauci-immune glomerulonephritis where patients have tested negative for ANCA [64].

Eosinophilic fasciitis – Eosinophilic fasciitis was seen in a patient treated with pembrolizumab (anti-PD-1) [17]. This patient presented with myalgias, then developed tethering of the skin and peripheral eosinophilia. Fascial biopsy was ultimately consistent with eosinophilic fasciitis. (See "Eosinophilic fasciitis".)

Systemic sclerosis (scleroderma) – Systemic sclerosis has been described in two patients on pembrolizumab; one patient had diffuse skin disease while the other had the limited form [25]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Digital ischemia – Rapidly progressive digital ischemia was seen in a patient treated with ipilimumab and nivolumab, though the authors were unsure whether it was a treatment effect or a paraneoplastic syndrome [24].

Single-organ vasculitis – Single-organ vasculitis involving the uterus and retina have also been reported [18,19]. (See "Overview of and approach to the vasculitides in adults", section on 'Single-organ vasculitis' and "Retinal vasculitis associated with systemic disorders and infections".)

The best treatment approaches for the rarely reported rheumatologic irAEs, such as critical digital ischemia, eosinophilic fasciitis, systemic sclerosis, sarcoidosis, and lupus nephritis, have not been determined. Rheumatologists should follow treatment recommendations for the classic forms of the diseases, where that is possible, but continue to discuss treatment options in an ongoing collaboration with the referring oncologist and the patient.

It is important to note that other rheumatologic irAEs may be possible with checkpoint inhibition that have not been reported. A careful history of cancer therapies will be useful in evaluating any patient with rheumatologic symptoms and history of malignancy, particularly in advanced-stage cancers where ICIs are typically used.

PREEXISTING RHEUMATOLOGIC DISEASE

Course and outcomes — Approximately one-third or more of patients with preexisting rheumatic or other systemic or autoimmune disease have experienced flares of their prior disorder in association with treatment using immune checkpoint inhibitors (ICIs) for malignancy [28,65-67]. Many have been successfully managed with glucocorticoids or other treatments, but some have required discontinuation, usually temporarily, of their ICI. The response to immunotherapy and the risk of autoimmune disease exacerbation and immune-related adverse events (irAEs) in patients with a range of non-rheumatologic autoimmune disorders are described in more detail separately. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Pre-existing autoimmune disease'.)

A 2018 systematic review of multiple case reports, case series, and observational studies identified 123 patients (from 49 publications) with autoimmune diseases who were treated with ICIs, of whom 92 (75 percent) experienced exacerbation of preexisting autoimmune disease, irAEs, or both [67]. Patients with rheumatic disease represented about 60 to 65 percent of all patients as well as those with irAEs. Fewer adverse events were seen in patients being treated with immunosuppressive therapy at the time ICIs were started, and only 16 percent required further immunosuppressive therapies other than glucocorticoids for management of these occurrences. Half of the patients did not require ICI discontinuation, but three patients died. Of 20 patients with rheumatoid arthritis (RA) described, 10 experienced disease exacerbation and eight a de novo irAE. Among 28 patients with psoriatic arthritis or psoriasis, 22 had an exacerbation of the disease, while seven had a de novo irAE. More accurate estimates of risks and outcomes will require data from additional large cohorts, especially given the inclusion of many patients in this series from case reports and small series selected for reporting.

Common themes emerge from several retrospective studies that have evaluated the use of ICIs in those with preexisting autoimmune disease:

Frequency of flares – In studies including a variety of autoimmune diseases, 30 to 50 percent of patients experienced disease flare following exposure to an ICI [28,65,66,68]. In one study, disease flares were most common among patients with psoriasis or psoriatic arthritis versus other autoimmune diseases (including RA, inflammatory bowel disease, and systemic lupus erythematosus) [28].

Severity of flares – In these studies, most disease flares were managed with glucocorticoids alone, with a temporary interruption in ICI therapy [65,66]. A minority of patients required discontinuation of ICI therapy.

Impact on prognosis – In a study of 101 patients with RA who received ICI therapy, the cumulative incidence of all-cause mortality and severe adverse events (excluding RA flares) was equivalent among RA versus control patients [68]. In another study of 112 patients with autoimmune disease treated with ICI therapy, the median tumor progression-free survival was shorter in patients already receiving immunosuppressive agents when ICIs were also initiated (4 versus 12 months); these findings were unlike those in most studies of new-onset irAE in patients without preexisting autoimmune disease and associated concurrent immunosuppressive therapy but similar to observations for patients with non-small-cell lung cancer being treated with ≥10 mg daily of prednisone for lung cancer-associated symptoms at the start of ICI therapy [49]. (See 'Prognostic implications' above.)

Maintenance treatment while on immune checkpoint inhibitors — Patients with established rheumatic diseases should continue to be monitored closely by their treating rheumatologist, as well as their oncologist, when starting and continuing therapy with an ICI. The effects of antirheumatic medications on tumor immunotherapy are uncertain. For some medications, including hydroxychloroquine (HCQ), sulfasalazine (SSZ), and low-dose glucocorticoids, which have been used concurrently with checkpoint inhibition to treat underlying autoimmune disease, there is a low suspicion that they will interfere with immunotherapy.

The effect of concurrent methotrexate (MTX) use is unclear, but trials with the antineoplastic agent pemetrexed, an antimetabolite and antifolate agent, along with ICIs and some limited clinical experience, suggest that the use of such combinations are a possible therapeutic strategy [69,70]. However, the efficacy of pemetrexed in systemic inflammatory arthritis and other autoimmune disorders is unknown.

Although TNF inhibitors and interleukin (IL) 6 inhibitors have been reported to treat ICI-induced arthritis, their concomitant administration with ICIs has not been systematically studied [29]. There are no data evaluating the use of other biologic or targeted immunomodulatory therapies such as abatacept or Janus kinase (JAK) inhibitors. Based upon the mechanism of action of abatacept, the authors would avoid its use in the treatment of irAEs, particularly in patients treated with anti-CTLA-4 ICIs [37].

Treatment of flare while on immune checkpoint inhibitors — For mild flares of RA, nonsteroidal antiinflammatory drugs (NSAIDs) have been used successfully, while more severe flares have required prednisone 1 mg/kg daily followed by a taper [71]. With certain preexisting autoimmune diseases like inflammatory bowel disease, severe flares may require treatment with TNF inhibitors and temporarily holding the ICI. (See 'Course and outcomes' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of toxicities due to checkpoint inhibitor immunotherapy".)

SUMMARY AND RECOMMENDATIONS

A spectrum of immune-related adverse events (irAEs) with rheumatologic phenotypes have been seen as a result of immune checkpoint inhibitor (ICI) therapy for cancer, including inflammatory arthritis, myositis, sicca syndrome, and vasculitis. Precise epidemiology is unknown, but inflammatory arthritis appears to be the most common clinical presentation seen by rheumatologists. It is also common for patients with rheumatologic irAEs to have other non-rheumatologic irAEs. (See 'Immune checkpoint inhibitor mechanism of action' above and 'Pathogenesis of rheumatologic complications' above and 'Epidemiology' above.)

For patients with a rheumatologic irAE, the severity of the irAE, future plans for cancer therapy, status of the tumor response to ICIs, the relative risks and benefits of rheumatologic and oncologic treatment options, and patient and oncologist preference must all be considered in determining the management approach. (See 'General principles of evaluation and management' above.)

Inflammatory arthritis can develop at almost any time during ICI therapy, and several different patterns of joint involvement and disease ranging from mild to severe have been reported; rheumatoid factor and anti-citrullinated peptide antibodies are often absent. (See 'Clinical manifestations and diagnosis' above.)

For patients with inflammatory arthritis secondary to ICI therapy, our initial approach to treatment is based upon the severity of symptoms (see 'Treatment' above):

For most patients with mild arthritis (without significant functional compromise), we suggest a nonsteroidal antiinflammatory drug (NSAID) rather than glucocorticoids (Grade 2C). ICI therapy is usually continued in such patients. Oral NSAIDs (eg, naproxen 375 to 500 mg twice daily, ibuprofen 600 to 800 mg three times daily) are typically used. As an alternative, particularly in patients in whom NSAIDs should be avoided or a more rapid response is desired than expected with an NSAID, we prefer prednisone (initially 10 to 20 mg daily). In patients with only a few joints involved, we administer intraarticular glucocorticoid injections in affected joints, if feasible, which may reduce the need for other interventions. (See 'Initial treatment of mild arthritis' above.)

For patients with moderate or severe arthritis involving of multiple joints, we suggest moderate- to high-dose oral glucocorticoids (Grade 2C). The usual dose range is prednisone 40 mg daily up to 1 mg/kg daily, but higher doses are sometimes required. The ICI is sometimes held temporarily until the prednisone can be tapered to lower doses (eg, below 20 mg daily of prednisone or equivalent) and the patient is doing well. (See 'Initial treatment of moderate or severe arthritis' above.)

For patients with inflammatory arthritis secondary to ICI therapy that does not respond to initial therapy, our approach is as follows:

For patients with persistent mild to moderate inflammatory arthritis who cannot be weaned to a low dose (eg, prednisone less than 7.5 to 10 mg daily) or entirely off glucocorticoids, we suggest a conventional synthetic disease-modifying antirheumatic drug (DMARD), such as sulfasalazine (SSZ), hydroxychloroquine (HCQ), or methotrexate (MTX) as used in RA (Grade 2C). The decisions of whether the ICI can or should be held needs to be made on an individual basis together with the treating oncologist, especially in cases where glucocorticoids cannot be tapered. (See 'Unable to adequately taper glucocorticoids' above.)

Our preference for selected patients with severe arthritis who are refractory to glucocorticoid therapy or unable to wean to low-dose glucocorticoids (prednisone less than 7.5 to 10 mg daily) is to use a tumor necrosis factor (TNF) inhibitor. Tocilizumab and other agents have also been used in such patients. Based upon the mechanism of action of abatacept, we avoid its use in the treatment of irAEs, particularly in patients treated with anti-cytotoxic lymphocyte antigen protein 4 (CTLA-4) ICIs. (See 'Severe arthritis' above and 'Other agents' above.)

Salivary hypofunction and keratoconjunctivitis sicca resembling Sjögren's disease have been reported in patients treated with ICIs. In many patients, the dry mouth symptoms have been predominant without concomitant dry eyes; parotid swelling has been rare. Most patients lack the autoantibodies to Ro/SSA and La/SSB. The treatment approach is similar to that for Sjögren's disease without ICI exposure. (See 'Sicca syndrome/other ocular disorders' above.)

Polymyalgia rheumatica (PMR) may occur in isolation or with giant cell (temporal) arteritis (GCA) during ICI treatment; as with usual PMR/GCA, patients with ICI-induced disease have been older adults. Other conditions seen include inflammatory myositis and several less common conditions. (See 'Polymyalgia rheumatica/giant cell (temporal) arteritis' above and 'Inflammatory myopathies' above and 'Others' above.)

Patients with preexisting rheumatologic and other autoimmune disease have been treated successfully with ICIs, but a significant proportion can have an exacerbation of their underlying autoimmune disease. For this reason, they should continue to be monitored by their treating rheumatologist. (See 'Preexisting rheumatologic disease' above.)

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Topic 114506 Version 17.0

References

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