Curbside Consults - December 2015 Save

The following is a collection of cases presented to me by my colleagues in Canada during a day of workshop case discussions among clinical consultants. Each case is presented because of a challenging therapeutic issue. Answers are based on experience with references to the recent ACR 2015 RA treatment guideline where appropriate.

The commonly used term “Curbside Consults” was introduced by Dr. Bryan Mandell (from the Cleveland Clinic) and the ACR annual meeting planning committee almost 10 years ago and has become a favorite session at the ACR meeting. To see the ACR Curbside Consults along with other informative sessions (like The Year in Review, The Great Debate and Rheumatology Roundup), go to Session Select on the ACR website.

Case 1. HIV+ RA patient on MTX and NSAIDs but, still has active disease (CDAI=15). The patient's HIV is stable, undetectable viral loads, CD4 counts > 500. What biologic, if any, can be used?

Answer: There is little written about this, and what is can be considered anecdotal. HIV patients with RA or PsA have been safely treated with MTX, DMARDs, prednisone, NSAIDs and TNF inhibitors in the literature. Dr. John Reveille at the University of Houston has been working an HIV clinic for years and has shown consistent efficacy and safety using TNF inhibitors. To the best of my knowledge none of these HIV patients have progressed to full AIDs. Note that many of these patients are also receiving HRT. Lastly, the recent 2015 ACR guidelines disappointingly advocates that such patients should only receive DMARD therapy rather than TNF inhibitors (note that these are consensus recommendations from a group inexperienced in HIV with “low evidence” to support such guidance). 

Case 2. RA and Cancer. How would you treat a RA patient with: a) breast cancer diagnosed 3 years ago, failed all DMARDs; b) stable disease on a biologic and newly diagnosed with thyroid cancer; c) newly diagnosed basal cell skin cancer stable on a biologic; or d) a prior history of melanoma.

Answer: The best overall answer for these scenarios is – you treat the RA with the best available therapies and let the cancer be monitored and managed by the oncologist. The recent ACR RA treatment guideline states that RA patients with a previously treated solid organ cancer should be treated the same as you would treat an RA patient without a history of solid organ cancer. The evidence here is quite good that at least TNF inhibitors do not affect the risk for or outcome of cancers of the breast, colon, lung, prostate, etc. The same guideline states that melanoma and nonmelanoma skin cancers should receive DMARD therapy over biologics or tofacitinib. The cancer risks ascribed to TNFi and biologics is exactly the same as the cancer risk associated with RA alone and without biologics. Unfortunately, there is no data testing the efficacy and safety of DMARDs or rituximab in patients with skin cancer. Conversely, there is a plethora of reports and registry outcomes indicating that TNFi use does not worsen cancer outcomes including cancer deaths. The same cannot be said for other biologics (RTX, ABA, TCZ) or tofacitinib. So my specific answers for the above cases are: a) TNF inhibitor; b) continue the biologic that is working; c) continue the biologic that is working; and d) if the prior melanoma was a “melanoma in situ” then I would use any and all therapies including TNFi or biologics; but if this was an invasive melanoma – I would use the most effective non-TNFi regimen available (including DMARDs or non-TNFi biologics).

Case 3. RA patient treated with MTX and a biologic has been in remission for over 2 years (HAQ=0, CDAI=0). When would you consider stopping therapy? Which would you wean first or would you aim to stop both?

Answer: There have been many DMARD and biologic withdrawal studies in the last few years and most of these have been consistent in their takeaway messages. First, the ability to withdraw all therapy and achieve drug-free remission is probably no more than 10%. Moreover, this number may be 15-20% when considering patients with early RA of less than 1 year’s disease duration. Hence, I tell my patients when starting DMARD or biologic therapy that this is likely to be lifelong therapy and that roughly 10% of patients will be able to fully stop therapy in the future. Second, the 2015 ACR RA treatment guideline says weaning therapy is reasonable and prudent for established RA in remission, but discontinuation of DMARD or biologic therapy is not advisable. Patients who are in doing well in low disease activity (DAS28 3.2) should NOT try to wean therapy unless they have achieved remission. For those in remission, weaning therapy is reasonable and prudent for one but not both drugs; thus discontinuation of DMARD and biologic therapy is not advisable. The clinical trials that have addressed drug weaning have shown that weaning and stopping MTX is preferable to TNFi weaning. Patients on MTX+TNFi can maintain remission or LDA when they continue on TNFi monotherapy. Attempts to stop the TNFi are far less successful. Protocols that decreased the dose or frequency of the TNFi (+ maintaining MTX) have shown near comparable clinical outcomes but worsening of X-ray outcomes. Hence the cost and convenience savings may have ongoing structural consequences. In addition, I’m not aware that any of these “half dose” TNFi regimens have shown a clear safety advantage.

Case 4. 58 yr. old woman has 5 yrs. of refractory CCP+, RF+, active RA. She has failed all available DMARDs (MTX, HCQ, SSZ, LEF) and biologics (ETN, ADA, INFLX, ABA, TCZ, RTX). She is currently on maximum doses of MTX, tofacitinib, risedronate, and NSAIDs with swollen joints and a CRP 17.7 mg/L. What are her treatment options?

Answer: This is the prototypic “difficult RA” scenario, for which I have several approaches to gain control of refractory unrelenting synovitis. First, has MTX been optimized? Ensure optimal absorption with either parenteral (25 mg sc/wk) or split oral (4 tabs bid q Friday) dosing. Rarely would I advocate for polyglutamate testing to optimize MTX dosing. Second, use prednisone at 2.5-7.5 mg daily as part of a combination regimen, striving for the lowest effective dose. Third, aggressive RA merits more than aggressive therapy. Thus what combination of DMARDs or DMARD plus biologic is worth considering? For this case above I would strongly advocate for anakinra 100 mg daily with low dose prednisone and a DMARD (either cyclosporine, tacrolimus, azathioprine, mycophenolate) and give this 4-6 weeks to determine success or not. If this were successful, then other IL-1 inhibitors may be substituted in the future. But if there is no response (>50% reduction in TJC/SJC), it’s time to keep changing as there are many options still, including triple DMARD therapy (MTX, SSZ, HCQ), combination MTX+CyA, combination gold+MTX, and consideration of high dose azathioprine, penicillamine, oral cyclophosphamide. Unapproved therapies also worth considering may include apremilast (probably in combination), minocycline, and chlorambucil. Lastly, a major lifestyle intervention may also be necessary. Stop smoking, better gingival and dental care, weight loss, low salt diet, an anti-inflammatory (gluten free, low/no carbohydrate) diet, and rest. Rest may require total bed rest or cessation of work until major improvement is achieved.

Case 5. A 28 yr. old woman with RA took hydroxychloroquine and sulfasalazine throughout her recent pregnancy. She recently gave birth to a healthy baby and has been breast feeding for 5 months (she wants to breast feed for 12 mos.). Despite HCQ and SSZ she has active RA, trouble caring for the baby, swollen joints, ESR 40 and CRP 2.0 mg/dl. What therapies can be safely added? Can you use MTX or a TNF inhibitor here?

Answer: The choice of HCQ and SSZ during and after pregnancy is reasonable and safe. MTX is contraindicated during pregnancy and is relatively contraindicated while breast feeding. Other than MTX, leflunomide and cytotoxics, all DMARDs and biologics can safely be used during breast feeding. The TNF inhibitors are best studied here. A fraction of TNFi is secreted in breast milk and none of this appears to be absorbed into the infants’ circulation. Hence, the options for this patient would be take a TNF inhibitor, abatacept or tocilizumab. I would prefer the TNF inhibitor.

If you have a challenging or interesting clinical case that you would like an expert opinion on please email the case vignette (diagnosis, duration, therapies, important findings) and clinical or therapeutic question to info@rheumnow.com.