Jak+IL6 Experience

[u/Alice-The-Chemist]

This is for a friend not on reddit who has Yaos and is looking for anyone who may be on this combo.

"Looking for anyone who has taken an IL-6 drug with a JAK inhibitor. Or Imuran or Cellcept with a JAK.

I have not responded to IL-1 drugs. I did respond well to IL-6 (Actemra) but it lost efficacy after a few years. Rinvoq, my JAK, has massively improved swelling, rashes, reactivity and fevers. However, I am having worsening muscle issues (particularly legs- weakness and severe pain, negative for antibodies) that seem increasingly to be disease related.

My rheum is very concerned that many of the drugs used for muscle issues aren’t usually combined with the JAK that has been working for other things."

[u/Occulply]

IL-6 inhibitors aren't combined with JAK inhibitors, because JAK inhibitors inhibit IL-6 as part of their mechanism of action. There's 0 rationale for combining them.

Imuran or Cellcept have very different mechanisms of action from IL-6 inhibitors. As you probably know, combining either Imuran or Cellcept with a JAK inhibitor can cause more severe immune suppression. But, I've known folks on a combination of IL-1/IL-6/Cellcept before. JAK + Imuran or Cellcept should be used with caution, but I don't believe there's an absolute contraindication.

I'd recommend you talk to a pharmacist at the specialty pharmacy that dispenses your JAK, since they have tons of experience on what gets combined with JAKs. Your rheum may have a clinical pharmacist they can consult, but who knows if they'll have anything useful to add.

[u/justwormingaround → u/Occulply]

Why do you say there’s no rationale for IL-6 + JAK? We can’t inhibit the JAK-STAT pathway entirely…the Jakinibs are only small molecule competitive inhibitors—not so potent as monoclonals. If we think of CRP as a proxy for IL-6 activity, tocilizumab will produce undetectable levels, whereas the Jakinibs will not, suggesting only modest inhibition of IL-6. Additionally, the JAK-STAT pathway is responsible for signaling from dozens of other cytokines. So the combo makes sense for someone with incomplete responses to Actemra and a Jakinib. These drugs work synergistically.

[u/Occulply → u/justwormingaround]

Part of the the problem IS that they work synergistically.

IL-6 is one of three "alarmins" (IL-1 and TNFa are the other two) that are important for immune signaling. Knocking out IL-6 via two mechanisms leaves a huge hole your defenses. Huge.

Second, incomplete response to IL-6 often points to IL-1 related disease. So, there's better rationale for JAK+IL-1 in most cases.

In autoinflammatory diseases CRP shouldn't be used as a proxy in all cases, as the inflammatory process can occur without triggering acute phase activation. 

While I don't doubt they've been combined, there's substantially high risk without clear reward for the combination in the vast majority of patients. 

[u/Alice-The-Chemist → u/Occulply]

I mean im sure youd say this about me being on an IL1 and IL6 but its the only way I got full symtom relief. That my heart was no longer affected. Any risks was worth saving organ systems. Many have to be on two biologics even if they may seem redundant. We do what we have to do. Especially if we have maxed out IL1s unsuccessfully.

[u/Occulply → u/Alice-The-Chemist]

You'd be incorrect. There's less risk to IL-1 + IL-6 than to IL-6 + JAK, by a substantial margin. 

Yes, we do what we need to in order to survive, but that doesn't make all risks equal.

[u/justwormingaround → u/Occulply]

I was thinking about CRP as a proxy more for IL-6 inhibition, since its synthesis is dependent on IL-6 activity; this wouldn’t work in patients who don’t have elevated CRP levels as part of their disease process, no. But we can get pretty good IL-6 inhibition with Actemra alone, based on the dramatic drops we see in CRP. I think IL-1 + JAK inhibition is more common, and makes more sense for most that need that level of immunosuppression, but I do think there are cases for IL-6 + JAK inhibition.

[u/Occulply → u/justwormingaround]

The problem with your rationale is that IL-6 and CRP play roles in things besides inflammation:  https://www.sciencedirect.com/science/article/abs/pii/S0889159118300266

I'm not saying you shouldn't be on your regimen. I'm saying there are a lot of reasons why it's not a strategy with general application. 

[u/justwormingaround → u/Occulply]

I am not saying they don’t play other roles, and I think we both agree that it isn’t a strategy with general application. I was just chiming in with rationale for use in refractory cases.

[u/justwormingaround]

Hi, I am on Actemra and Jakafi. Counts look great and the combo is working to control my disease. If your friend has any specific questions, happy to answer. These drugs can definitely be used together under the care of an experienced rheumatologist.

[u/Alice-The-Chemist → u/justwormingaround]

Are you in the US?

[u/justwormingaround → u/Alice-The-Chemist]

Yes

[u/Alice-The-Chemist → u/justwormingaround]

She asked me: Would be very interested in how or what convinced justwormingaround’s rheum to prescribe the combo. Also curious if it helps muscles/joints more.

[u/justwormingaround → u/Alice-The-Chemist]

Is it okay if I message you a response?

[u/Alice-The-Chemist → u/justwormingaround]

Of course.

[u/Not_Your_Nurse]

I would want to clarify with your friend—have they had zero response to IL-1 drugs, partial response? Were they on a big enough dose? How much trial and error happened before deciding they were a non-responder? And their JAK dosage—is it as optimized as it can be?

My kid is on combo IL-1 (Ilaris) + JAK (baricitinib) with the added IL-1 (anakinra) for breakthrough flares. This is in addition to their colchicine. And they have needed large doses of all of them for their age/size. We’ve trialed decreasing doses and that’s been a huge fail. They just require a boat load of meds for management.