This stuff is still weird - Side effects to immunotherapy - Part 11! Heart problems, diabetes, arthritis - Oh MY!!! BUT!!! Colitis may be associated with a favorable response!!!!

I have published all sorts of posts that relate to side effects caused by immunotherapy.  B, my dedicated researcher and caregiver, goes through ALL newly published data on a regular basis, passing on things he thinks may interest me.  Some I post right away.  Others I collect until publishing seems important.  Side effect to immunotherapy was once a huge unknown.  These days, we pretty much know the things it causes routinely - fatigue, rash, joint pain.  Folks are now well versed in the most common side effects and have become familiar with the more unfortunate and rare ones as well.  This was the last in my ongoing series:  Do melanoma peeps with side effects to immunotherapy have a better response? - Side effects of immunotherapy - Part 10!!!

Now there are these:

Rare side effect of adjuvant ipilimumab after surgical resection of melanoma: Guillain-Barré syndrome. Patel, Liu, Amaraneni, Sindhu. BMJ Case Rep. 2017 Dec 13.

Guillain-Barré syndrome is a life-threatening neurological disorder that presents with rapid ascending paralysis and areflexia. Guillain-Barré syndrome is traditionally associated with infections from a gastrointestinal or respiratory tract source. We report the case of a 71-year-old man with melanoma who was treated with ipilimumab as adjuvant immunotherapy and subsequently developed Guillain-Barré syndrome. The diagnosis was made clinically through physical exam findings. He was successfully treated with a combination of intravenous immunoglobulin therapy and corticosteroids.

Late-Onset Fulminant Myocarditis With Immune Checkpoint Inhibitor Nivolumab. Yamaguchi, Morimoto, Okumura, et al.  Can J Cardiol. 2018 June.

A 60-year-old man was diagnosed with melanoma. After receiving 13 infusions of nivolumab, he had fulminant myocarditis. The myocardial biopsy specimen revealed extensive lymphocytic infiltration, interstitial edema, and myocardial necrosis, with predominant CD4+, CD8+, CD20-, and programmed death-1- markers. Programmed death-1 ligand 1 (PD-L1) was predominantly expressed on the surface of the damaged myocardium. Although it is reported that myocarditis induced by the human anti-programmed death-1 inhibitor nivolumab therapy rarely occurred at > 2 months use in clinical trials, this case showed that even if at a late phase, long-term use of immune checkpoint inhibitors might to lead immune-related adverse events including myocarditis.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study. Gauci, Boudou, Baroudjian, et al.  Cancer Immunol Immunother. 2018 May 28.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment. However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy. From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Salem, Manouchehri, Moey, et al. Lancet Oncol. 2018 Nov 9.

Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs.

In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. 

We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs), pericardial diseases (12 800 vs 95), and vasculitis (33 289 vs 82), including temporal arteritis (696 vs 18) and polymyalgia rheumatica (1709 vs 16). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma, with death occurring in 61 (50%) of 122 myocarditis case, 20 (21%) of 95 pericardial disease cases, and 5 (6%) of 82 vasculitis cases.

Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).

Checkpoint Inhibitor-Associated Arthritis: A Systematic Review of Case Reports and Case Series.  Ghosh, Tiongson, Stewart, et al.  J Clin Rheumatol.  2020 Apr 25.

OBJECTIVE: We performed a systematic literature review to identify all reports of immune checkpoint inhibitor-associated inflammatory arthritis to describe it phenotypically and serologically. METHODS: PubMed, Embase, and Cochrane databases were searched for reports of musculoskeletal immune-related adverse events secondary to ICI treatment. Publications were included if they provided individual patient level data regarding the pattern of joint involvement. Descriptive statistics were used to summarize results. RESULTS: A total of 4339 articles were screened, of which 67 were included, encompassing 372 patients. The majority of patients had metastatic melanoma (57%), and they were treated with anti-PD1 or anti-PDL1 therapy (78%). Median time to onset of arthritis was 4 months (range, 1 day to 53 months). Forty-nine percent had polyarthritis, 17% oligoarthritis, 3% monoarthritis, 10% arthralgia, and 21% polymyalgia rheumatica. More than half of patients were described as having a "rheumatoid arthritis-like" presentation. Nine percent tested positive for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. Seventy-four percent required corticosteroids, and 45% required additional medications. Sixty-three percent achieved arthritis control, and 32% were ultimately able to discontinue antirheumatic treatments. Immune checkpoint inhibitors were continued in 49%, transiently withheld in 11%, and permanently discontinued due to musculoskeletal immune-related adverse events in 13%. CONCLUSIONS: Half of reported immune checkpoint inhibitor-associated arthritis cases present with polyarthritis (often RA-like), but only 9% are seropositive. Polymyalgia rheumatica is also common. Most patients respond to steroids alone, but about half require additional medications. Further studies are needed to determine long-term musculoskeletal outcomes in these patients, and the impact of arthritis treatment on cancer survival.

Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response.  Zou, Abu-Sbeih, Ma, et al.  J Natl Compr Canc Netw. Dec 2020.

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes.

Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (less than or equal to 3 months) and chronic (greater than 3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis.

Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use, long duration of IMDC symptoms and hospitalization, a histologic feature of chronic active colitis or microscopic colitis, and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%) and was accompanied by improved overall survival. Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival.

Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.

You would think that the direct suffering that cancer of all stripes causes is more than enough.  Side effects from treatment seem to be a most unjust additional insult.  Sigh.....  Still, every day - unknown to most - cancer survivors shoulder that burden and carry on.  Pretty damn impressive, if you ask me!  It is good to know that if you have borne the burden of colitis, you may have gained at least some benefit in exchange for your misery!!!

Hang tough peeps!  You ROCK!!! - c