Full Cases With Answers and Additional Resources

CASE 1: MS. SMITH

56-Year-Old Caucasian Woman With Seropositive RA and Breast CancerMs. Smith is a 56-year-old Caucasian patient with seropositive rheumatoid arthritis (RA) characterized by a peripheral arthritis affecting bilateral knees. She is on chronic infliximab 500 mg (6 mg/kg) IV every six weeks and methotrexate nine tablets (22.5 mg) orally weekly. She had no other medical problems. However, during follow-up in January 2014, an abnormal mass was found. Mammography and a biopsy revealed right breast ductal carcinoma, estrogen and progesterone receptors (ER/PR) positive. Her treatment plan by her oncologist was to proceed with a lumpectomy followed by radiation and hormonal therapy. At that visit, she had 15-20 minutes of morning stiffness and right knee moderate effusion and pain. Her left knee was fine, and her last infliximab was six weeks ago.

QUESTION 1 In January 2014, based on the existing 2012 American College of Rheumatology (ACR) guidelines for RA available at that time, what options were available for her RA treatment?

A. Continue methotrexate and infliximabB. Hold methotrexate and infliximabC. ContinuemethotrexateandholdinfliximabD. Continue infliximab and hold methotrexate

ExplanationBased upon the 2012 ACR guidelines for treatment of RA, in the setting of a solid organ malignancy, Ms. Smith needed to wait for 5 years before initiation or reinitiation of a biologic. The only biologic that was allowable prior to five years was rituximab and disease-modifying antirheumatic drugs (DMARDs) were allowable. Thus the best initial treatment decision after diagnosis of breast cancer was to continue the methotrexate and hold the infliximab.

ReferenceSingh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625-639.

QUESTION 2 Ms. Smith agreed with the treatment plan you discussed. At follow-up one month later in February 2014, she had removal of the mass with clear margins and sentinel lymph nodes were negative. She was about to initiate radiation therapy for six weeks. She was on methotrexate nine tablets orally weekly, folic acid, and tramadol. She complained of significant right knee swelling and an hour of morning stiffness, and her left knee had no issues. On exam, her vital signs were stable and her right knee had a large effusion with inability to fully extend the leg.

What options for augmentation of therapy are available for her? What would be your next therapeutic recommendation?

A. Hold methotrexateB. Continue methotrexate and resume infliximabC. Continue methotrexate and give a steroid injection in her right kneeD. Continue methotrexate and add prednisone 10 mg daily

ExplanationIn this case, she still had active disease, but predominantly in one location. She was still within the five-year period where biologics were not recommended, and she did not want to try rituximab. She had one swollen and one active joint. Intra-articular steroid injections can be given to help control disease.

ReferencesSingh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625-639.Singh JA, Saag KG, Bridges SL Jr, et al. 2015 update of the 2008 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68:1-25.

http://fantastykvoyage.blogspot.com/2010/03/double-up-in-pain-im-on-

my-knees.html

Photo is not the actual patient.

QUESTION 3 Ms. Smith was continued on methotrexate and received a right knee corticosteroid injection. She completed radiation; however, by April 2014, the swelling in her right knee worsened and her left knee began. She was switched to methotrexate injections. Despite this, she had ongoing significant disease at her follow-up visit in early May. She was ambulating with a cane, had several hours of morning stiffness, and had significant bilateral knee pain and swelling.

What would you do next?A. Continue methotrexate injections, add infliximab backB. Continue methotrexate injections, add hydroxychloroquineC. Continue methotrexate injections, add sulfasalazineD. Continue methotrexate injections, add prednisone

ExplanationHere, given the avoidance of biologic treatment for the first five years, with the exception of rituximab which she did not want, combination DMARD therapy is a palatable option to help achieve control. She had pretty active disease, and hydroxychloroquine efficacy is milder when compared to sulfasalazine, which is why the decision was made to add sulfasalazine to her methotrexate.

ReferencesSingh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625-639.Singh JA, Saag KG, Bridges SL Jr, et al. 2015 update of the 2008 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68:1-25.

QUESTION 4 Given her recent diagnosis of breast cancer, the decision was made to try triple combination DMARD therapy. Over the next few visits, sulfasalazine and eventually hydroxychloroquine were added, and she continued to receive intra-articular corticosteroid knee injections at quarterly intervals. Her pain and swelling in both knees continued despite all this, and prednisone 15 mg was added to her regimen. Finally, by October 2014, due to ongoing morning stiffness, pain and swelling in her knees, and inability to ambulate, and after discussion with her oncologist regarding her treated breast cancer, the decision was made to add back the infliximab.

Based on the 2015 ACR update on the management of RA, what are the treatment recommendations for patients with treated solid organ malignancies?

A. DMARDs are preferredB. Rituximab is preferred over anti-tumor necrosis factor agents (anti-TNFs)C. Abatacept is preferred D. Treatnodifferently

ExplanationAs long as the malignancy has been treated, there is no golden “five-year rule” that one needs to wait before initiation of biologics. (See table on next page for additional information.)

Reference Singh JA, Saag KG, Bridges SL Jr, et al. 2015 update of the 2008 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016;68:1-25.

2015 ACR Recommendations for Patients With RA andComorbidities(Adapted from Singh et al, 2016)

HIGH-RISK CONDITION RECOMMENDATIONLEVEL OF EVIDENCE

Congestive heart failure*

CHF Use combination DMARDs or non-TNF biologic or tofacitinib over TNFi (PICO C.1, C.2, and C.3; conditional recommendation)

Moderate to very low

CHF worsening on current TNFi therapy

Use combination DMARDs or non-TNF biologic or tofacitinib over TNFi (PICO C.4, C.5, and C.6; conditional recommendation) Very low†

Hepatitis B‡

Active hepatitis B infection and receiving/received effective antiviral treatment

Same recommendations as in patients without this condition (PICO D.1; strong recommendation) Very low

Hepatitis C‡

Hepatitis C infection and receiving/received effective antiviral treatment

Same recommendations as in patients without this condition (PICO E.1; conditional recommendation) Very low

Hepatitis C infection and not receiving or requiring effective antiviral treatment

Use DMARDs over TNFi (PICO E.2; conditional recommendation)§ Very low

Pasthistoryoftreatedoruntreatedmalignancy||

Previously treated or untreated skin cancer (nonmelanoma or melanoma)

Use DMARDs over biologics in melanoma (PICO F.1; conditional recommendation)

Use DMARDs over tofacitinib in melanoma (PICO F.2; conditional recommendation)

Use DMARDs over biologics in nonmelanoma (PICO F.3; conditional recommendation)

Use DMARDs over tofacitinib in nonmelanoma (PICO F.4; conditional recommendation)

Very low

Previously treated lymphoproliferative disorder

Use rituximab over TNFi (PICO G.1; strong recommendation)

Use combination DMARD or abatacept or tocilizumab over TNFi (PICO G.2, G.3, and G.4; conditional recommendation)

Very low

Previously treated solid organ malignancy

Same recommendations as in patients without this condition (PICO H.1; conditional recommendation) Very low

Previous serious infections¶

Previous serious infectionsUse combination DMARD over TNFi (PICO I.1)¶

Use abatacept over TNFi (PICO I.2; conditional recommendation)#Very low

TNFi=tumor necrosis factor inhibitor. DMARDs=disease-modifying antirheumatic drugs, including hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine. Non-TNF biologic=abatacept, rituximab, or tocilizumab (excludes anakinra). PICO=population, intervention, comparator, and outcomes.

*Conditional recommendations supported by evidence level ranging from moderate level to no evidence, supported by clinical experience and the Food and Drug Administration safety warning with TNFis. †No studies were available, leading to very low-quality evidence, and the recommendation was based on clinical experience. ‡Strong recommendations for hepatitis B were largely based upon the recent American Association for the Study of Liver Diseases practice guidelines (85, 86) and clinical experience; conditional recommendations for hepatitis C were largely supported by very low-level evidence based upon case series and clinical experience. §Consider using DMARDs other than methotrexate or leflunomide, such as sulfasalazine or hydroxychloroquine. ||Conditional recommendations supported by level of evidence ranging from very low to no evidence are largely based upon expert opinion and clinical experience. ¶Conditional recommendation was supported by very low-level evidence. #There was no consensus for making recommendations regarding the use of rituximab over TNFi or the use of tocilizumab over TNFi in this setting due to indirect evidence (eg, no comparison to TNFi or including patients with tuberculosis) and differences of opinion. In one study, compared to patients who restarted their previous TNFi following hospitalized infections, patients who switched to abatacept exhibited lower risk of subsequent hospitalized infections among the therapies examined.

Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25.

CASE 2: MR. FERNÁNDEZ

57-Year-Old Hispanic Man With RA, Osteoarthritis, CarpalTunnelSyndrome,andHistoryofBladderCancerMr. Fernández has RA, osteoarthritis, carpal tunnel syndrome, and a remote history of bladder cancer. He has had RA, which is seronegative and erosive by magnetic resonance imaging (MRI), for seven years. At his follow-up visit, he is on methotrexate 8 tablets a week and sulfasalazine 1500 mg twice a day (BID) and is doing well without any active synovitis. His most recent lipid panel revealed a low-density lipoprotein (LDL) of 147, high-density lipoprotein (HDL) of 45, and total cholesterol of 205. He has a scheduled upcoming carpal tunnel repair and has a dobutamine stress test planned for next week.

QUESTION 1What would be your recommendation for his RA medications in anticipation of carpal tunnel surgery?

A. Hold methotrexate and sulfasalazine nowB. Hold methotrexate and sulfasalazine one week before and one week after surgeryC. Continue methotrexate and sulfasalazineD. Continue sulfasalazine and add prednisone 10 mg daily

ExplanationDMARDs do not need to be held for his surgical procedures.

References Goodman SM. Rheumatoid arthritis: Perioperative management of biologics and DMARDs. Semin Arthritis Rheum. 2015;44(6):627-632.Scherrer CB, Mannion AF, Kyburz D, Vogt M, Kramers-de Quervain IA. Infection risk after orthopedic surgery in patients with inflammatory rheumatic diseases treated with immunosuppressive drugs. Arthritis Care Res (Hoboken). 2013;65(12):2032-40. doi: 10.1002/acr.22077.

QUESTION 2How would you manage his lipid panel?

ExplanationThe point here is that there is no official ACR consensus on how to manage this as of yet. Some international societies provide specific recommendations for how to manage lipids in patients with RA.

References Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2016 Oct 3. pii: annrheumdis-2016-209775. doi: 10.1136/annrheumdis-2016-209775. [Epub ahead of print].Pereira IA, Mota LM, Cruz BA, et al. 2012 Brazilian Society of Rheumatology Consensus on the management of comorbidities in patients with rheumatoid arthritis. Rev Bras Reumatol. 2012;52(4):474-495.Roubille C, Richer V, Starnino T, et al. Evidence-based recommendations for the management of comorbidities in rheumatoid arthritis, psoriasis, and psoriatic arthritis: expert opinion of the Canadian Dermatology-Rheumatology Comorbidity Initiative. J Rheumatol. 2015;42(10):1767-80.

QUESTION 3After his visit with you, Mr. Fernández completed the dobutamine stress test and failed miserably. He was admitted to the hospital and had a cardiac catheterization, which revealed severe coronary artery disease (CAD), and subsequently had an urgent 4-vessel coronary artery bypass graft (CABG). You were consulted during his inpatient care to assist with medication management of his RA. The patient read on the Internet about infections with RA and is very concerned about contracting an infection.

What is the top cause of mortality in patients with RA?A. InfectionB. Renal failure from amyloidosisC. Cardiovascular diseaseD. Malignancy

Photo is not the actual patient.

ExplanationCardiovascular disease remains the leading cause of mortality in RA. Rates of malignancy are increased relative to that of the general population, but overall are low. Amyloidosis is now a rare complication of RA given expanding biologic armamentarium.

Questions as one looks back: 57-year-old male with seronegative RA, osteoarthritis, history of bladder cancer. He has no hypertension, no diabetes, and is a nonsmoker. His risk factors for CAD are his age and RA. A calculated Framingham risk score which predicts a person’s chance of having a heart attack in the next 10 years, used for nondiabetics was calculated. It uses variables such as SBP, total cholesterol, HDL, smoking, age and gender. His score was 4%, which means 4/100 people with this level of risk will have a heart attack in the next 10 years.

Reference Minichiello E, Semerano L, Boissier MC. Time trends in the incidence, prevalence, and severity of rheumatoid arthritis: A systematic literature review. Joint Bone Spine. 2016 Sep 5. pii: S1297-319X(16)30129-4. doi: 10.1016/j.jbspin.2016.07.007. [Epub ahead of print]

Photo is not the actual patient.

CASE 3: MS. SHANE

33-Year-Old African-American Woman With Seropositive RA andHistoryofJuvenileIdiopathicArthritis

Ms. Shane is a 33-year-old African-American woman with a long-standing history of juvenile idiopathic arthritis (JIA) since age 12 and adult seropositive (rheumatoid factor [RF], cyclic citrullinated peptide [CCP]) RA. She saw a rheumatologist off and on when she was a teenager, but as an adult has not seen a rheumatologist since age 22. As a teenager, she was off and on methotrexate and hydroxychloroquine but not consistently. She now has multiple joint deformities due to untreated JIA/RA. She developed a cough and fever with extreme fatigue, which progressed to rigors that prompted her to go to the emergency room. She was found to have pneumonia with empyema and loculated parapneumonic effusion that required surgical decortication. You see her 4 weeks after hospitalization, and she is now off all antibiotics. On physical exam, she has multiple swollen and tender joints with a Clinical Disease Activity Index (CDAI) of 40. She reports morning stiffness for up to four hours, and she says she has felt this way for at least two years. Her medical history is otherwise benign.

QUESTION 1 You are going to start treatment today in the setting of recent severe infection.

She had transaminitis due to multiple antibiotics. How would you treat her disease?

A. Treat, with combination low dose prednisone + methotrexateB. Treat with prednisone onlyC. Treatwithcombinationlowdoseprednisone+TNFiD. Treat with combination high dose prednisone + methotrexateE. No, wait on all treatment, not safe to start treatment

ExplanationC. Prednisone is a potent anti-inflammatory, and is an important adjunctive therapy for RA, but should never

suffice as monotherapy for any prolonged period of time due to its adverse event profile. In general, prednisone (glucocorticoids) can be prescribed at low dose and for as short a time as possible. They can be used in a “bridging strategy”—used and tapered once the DMARD or biologic is fully therapeutic. TNFi (eg, etanercept) would be the next appropriate agent. According to the SABER data collected from 1998-2007, infliximab showed more serious infections when compared to etanercept and abatacept (Grijalva et al, 2011). Also, risk of serious infection is associated with increase dose prednisone: less risk 0-5 mg, more 5-10 mg, and highest >10 mg/day (adjusted hazard ratio 95% Cl 2.95).

A. Methotrexate might not be appropriate if her liver enzymes are still elevated. Also, the patient has high disease activity, associated with increased mortality, and “patients treated with TNF alpha inhibitors (or rituximab) had a significantly reduced premature mortality compared to those treated with methotrexate alone or in combination with other synthetic DMARDs” (Listing et al, 2015).

B. Prednisone alone is not appropriate as described above.

© 2016 American College of Rheumatology. Used with permission.

D. High-dose prednisone as mentioned above is associated with serious infections, as well as other complications such as avascular necrosis, etc.

E. She needs treatment now; she already has deformities and advanced seropositive RA from years of not getting treatment. High disease activity is associated with high mortality: infections, lymphoma, CAD, osteoporosis, amyloidosis, etc.

References Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011;306: 2331-2339.Listing J, Kekow J, Manger B, et al. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNF alpha inhibitors and rituximab. Ann Rheum Dis. 2015;74:415-421.Listing J, Gerhold K, Zink A. The risk of infections associated with arthritis, with its comorbidity and treatment. Rheumatology. 2012:10.1093.RABBIT - Rheumatoide Arthritis: Beobachtung der Biologika-Therapie. Rheumatoid Arthritis. Last accessed October 19, 2016.

QUESTION 2 During her workup for empyema, she had a chest computed tomography (CT), and with the decortication, she had a lung biopsy. Her chest CT revealed interstitial lung fibrosis (ILF), and the biopsy confirmed nonspecific interstitial pneumonia (NSIP).

How would this change your management of the treatment of her seropositive RA In view of her ILF/NSIP?

A. No change, continue low dose prednisone and TNFiB. Stop TNFi, continue low dose prednisone, add abataceptC. Stop TNFi, continue low dose prednisone, add rituximabD. StopTNFi,continuelowdoseprednisone,addmycophenolateE. Stop TNFi, stop prednisone, start rituximab

ExplanationA. TNFis may have a negative effect on RA-associated interstitial pneumonitis in some cases, as TNF alpha

antagonists are profibrotic. Since she has NSIP; the most severe case of interstitial lung disease (ILD), would be better to stop TNFi, and use a different agent that treats both severe RA and ILD. Therefore continuing on a TNFi might not be appropriate in this patient.

B. A literature search found one case report in rheumatology using abatacept for RA arthritis with ILD (Hayes & Östör, 2014), but it has not been used extensively.

C. There is some controversy around rituximab and ILD; some studies report improvement and other studies report development of ILD, therefore at this time it is best to hold off starting rituximab.

D. Mycophenolate showed—in a review of patients, of which 18 in 125 had rheumatoid-related ILD—improvement in pulmonary function testing (PFT) in patients with non-usual interstitial pneumonia patterns of ILD, and led to stabilization among those with usual interstitial pneumonia. Since mycophenolate might not control her arthritis.

E. Low dose prednisone is part of the treatment for ILD. Rituximab is controversial as discussed above.

References Chatterjee S. Severe interstitial pneumonitis associated with infliximab therapy. Scand J Rheumatol. 2004;33:276-277.Hayes F, Östör A. Refractory rheumatoid arthritis with interstitial lung disease: could abatacept be the answer? Rheumatology. 2014;53(suppl 1): i65.Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Euro Resp Rev. 2015;24:1-16.

QUESTION 3 At her three-month follow-up, liver enzymes are within normal but on the upper limit. She is currently on prednisone 5 mg daily and mycophenolate mofetil 1000 mg BID. On exam, she has four swollen and four tender joints and weighs 50 kg.

What is the best next drug to add in her step-up therapy plan?A. Hydroxycholoraquine 300 mg po QDB. Increase her prednisone to 10 mg QDC. Methotrexate 15 mg SQ weekly + folic acid dailyD. Addabatacept125mgSQwklyE. Make no changes at this time

Image courtesy of Dr. Rebecca Muntean.

ExplanationAccording to systematic review of literature and expert opinion, a treat-to-target approach was recommended for RA and with that in mind, this patient needs to have step up therapy since she is not at goal with four swollen and tender joints on exam.

Methotrexate compared to hydroxychoraquine has better data in achieving remission even as monotherapy, but with her history of elevated liver enzymes and currently on full dose mycophenolate mofetil, it might be wise to avoid methotrexate, more so since abatacept might work according to the case report for both for ILD and her arthritis.

A. Hydroxycholoraquine is a mild DMARD and will not probably be enough for her long term.B. Increasing prednisone might help, but it is not appropriate long term.C. Methotrexate, might worsen her liver enzymes.D. Abatacept will treat her arthritis and her ILD per recent literature.E. She needs treatment, she is not at goal.

References Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomized controlled trial. Lancet. 2004;364:263-269.Hayes F, Östör A. Refractory rheumatoid arthritis with interstitial lung disease: could abatacept be the answer? Rheumatology. 2014;53(suppl 1): i65.Smolen JS, Han C, van der Heidje DM, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis. 2009;68:823-827.Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75:3-15.Verstappen SMM, Jacobs JWG, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66:1443-1449.

CASE 4: MS. PORTA

48-Year-OldWomanWithSeropositiveRAWhoRecentlyMoved From Ecuador Ms. Porta is a 48-year-old woman who recently moved from Ecuador with a 25-year history of seropositive RA treated with prednisone for more than 20 years. She started on methotrexate about three years ago. At the initial consultation 8 months ago, her Clinical Disease Activity Index (CDAI) was 32, and she was seen regularly to get her to goal. She is on methotrexate 25 mg subcutaneous weekly, etanercept 50 mg subcutaneous weekly for six months, and hydroxychloroquine 300 mg daily and has been off prednisone for four months. As of her last visit six weeks ago, she was at goal with low disease activity but continues to complain of worsening left hip pain.

QUESTION 1What is the most likely cause of Ms. Porta’s worsening left hip pain?

A. Active RAB. OsteoarthritisC. Septic jointD. Hip fractureE. Avascular necrosis of the hip

ExplanationA. She is on combination DMARDs, and her overall disease everywhere else is in remission, thus she is less likely

to have active disease in the hip. B. Osteoarthritis, is part of the process, but the underlying disease is avascular necrosis.C. She is on multiple DMARDs and TNFi, her risk of infection is higher, but she is off prednisone, and her disease is

well controlled, less likely to have a septic joint, and she does not have any systemic symptoms.

Photo is not the actual patient.

D. With her history of long-term active RA and long-term prednisone use, she has a high risk of osteoporosis and hip fracture. But progressive hip pain is not a typical symptom of fracture, which is typically accompanied by acute pain.

E. Avascular necrosis/osteonecrosis is seen in patients that have been on steroids. Accumulated data from numerous clinical reports and risk factor studies provide strong evidence for a causal relationship between corticosteroid exposure and development of osteonecrosis. Although there is a general trend in the more systematic analyses toward increased risk of osteonecrosis with greater dose and longer duration of use of corticosteroids, the identification of individuals at particular risk is difficult.

References Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 2002;32:94-124.Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford). 2000; 39:1383-1389.

QUESTION 2Ms. Porta comes in two weeks later with mid-back pain. You suspect she has a thoracic compression fracture and order a thoracic spine X-ray that confirms the diagnosis. Her dual-energy X-ray absorptiometry (DEXA) eight months ago showed femoral neck T-score of -2.6 and lumbar spine -2.2. She is already on alendronate weekly for eight months, calcium, and vitamin D.

What would you recommend for osteoporosis treatment in this patient?

A. There is no other treatment for her osteoporosis besides alendronate-like medicationsB. Cannot changed to denosumab while patient on a biologic like abataceptC. Teriparatideisbeabettermedicationforher osteoporosis at this timeD. Can add denosumab to alendronateE. Can add teriparatide to alendronate

ExplanationTeriparatide is a recombinant human parathyroid hormone, stimulates osteoblast function, increases calcium absorption, and increases renal tubular reabsorption of calcium; these effects lead to increase bone mineral density, bone mass, and strength. One of the recommendations for the use of this drug is for the patients that sustain a fracture while on antiresorptive therapy, like our patient.

Denosumab is a fully human monoclonal IgG2 antibody that binds to Receptor activator of nuclear factor kappa-B ligand (RANKL) and mimics the effect of osteoprotegerin on RANKL. Though RANKL is a member of the TNF- family, and important mediator of bone remodeling, combing this medication with another biologic has not been shown to increase serious infection event.

As of now, we do not have enough data on combination therapy for denosumab + alendronate, or teriparatide + alendronate, to support combination therapy and therefore they should not be used together in a patient.

References Black DM, Greenspan SL, Ensrud KE, et al; PaTH Study Investigators. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207-1215.Gallagher JC, Genant HK, Crans GG, Vargas SJ, Krege JH. Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. J Clin Endocrinol Metab. 2005;90:1583-1587.Maricic M. Update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 2011;37:415-431.McClung MR, San Martin J, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165:1762-1768.

Image courtesy of Dr. Rebecca Muntean.

QUESTION 3Ms. Porta would like to travel around the world now that she feels better, she has had her left hip replaced, and her RA is under control—in remission for one year. She is on methotrexate, hydroxychloroquine, etanercept, and teriparatide. She brings you the list of vaccines, and among them you see that she needs the yellow fever vaccine.

What would you recommend for her immunization at this time?A. She can have the yellow fever vaccine anytimeB. Hold etanercept for two to four weeks, have the vaccine, then restart the etanercept two weeks laterC. She should stop all her medications for two to four weeks, have the vaccine, then restart them two weeks laterD. She cannot ever have the yellow fever vaccineE. She should stop etanercept and methotrexate only for 2-4 weeks, have the vaccine, then restart both of them two weeks later.

ExplanationYellow fever vaccine is a live vaccine and should not be give while on a biologic (eg, TNFi); but, she can have it since her disease has been in remission for a year, by holding her etanercept at least two weeks, then restarting it two weeks after the vaccine. No need to stop methotrexate or hydroxychloroquine for live vaccines per ACR guidelines 2015.

References Bruyand M, Receveur MC, Pistone T, Verdière CH, Thiebaut R, Malvy D. Yellow fever vaccination in non-immunocompetent patients. Med Mal Infect. 2008;38:524-532. [Article in French]Davies K, Woo P. Immunization in rheumatic diseases of childhood: an audit of the clinical practice of British Pediatric Rheumatology Group members and a review of the evidence. Rheumatology (Oxford). 2002;41:937-941.Mota LM, Oliveira AC, Lima RA, Santos-Neto LL, Tauil PL. Vaccination against yellow fever among patients on immunosuppressors with diagnoses of rheumatic diseases. Rev Soc Bras Med Trop. 2009;42:23-27. [Article in Portuguese]Scheinberg M, Guedes-Barbosa LS, Mangueira C, et al. Yellow fever revaccination during infliximab therapy. Arthritis Care Res (Hoboken). 2010;62:896-898.Van Assen S, Agmon-Levin N, Elkayam O, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2011;70:414-422.

REFERENCES Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2016 Oct 3. pii: annrheumdis-2016-209775. doi: 10.1136/annrheumdis-2016-209775. [Epub ahead of print].

Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 2002;32:94-124.

Black DM, Greenspan SL, Ensrud KE, et al; PaTH Study Investigators. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207-1215.

Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population based study. Arthritis Rheum. 2010;62:1583-1591.

Bruyand M, Receveur MC, Pistone T, Verdière CH, Thiebaut R, Malvy D. Yellow fever vaccination in non-immunocompetent patients. Med Mal Infect. 2008;38:524-532. [Article in French]

Chatterjee S. Severe interstitial pneumonitis associated with infliximab therapy. Scand J Rheumatol. 2004;33:276-277.

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Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73:62-68.

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ABBREVIATION LIST

Abbreviation ExpandedTerm

ACR .........................................................................American College of Rheumatology

AVN .........................................................................avascular necrosis

anti-TNFs ...............................................................anti-tumor necrosis factor agents

BID .........................................................................twice a day

CABG ......................................................................coronary artery bypass graft

CAD ........................................................................coronary artery disease

CCP..........................................................................cyclic citrullinated peptide

CDAI ........................................................................clinical disease activity index

CHF .........................................................................congestive heart failure

CI .............................................................................confidence interval

COMORA ................................................................comorbidities in rheumatoid arthritis

COPD ......................................................................chronic obstructive pulmonary disease

CT ............................................................................computed tomography

DEXA ......................................................................dual-energy X-ray absorptiometry

DMARDs .................................................................disease-modifying antirheumatic drugs

ER/PR .....................................................................estrogen and progesterone receptors

GI .............................................................................gastrointestinal

HDL ........................................................................high-density lipoprotein

ILD ...........................................................................interstitial lung disease

ILF ............................................................................interstitial lung fibrosis

JIA ...........................................................................juvenile idiopathic arthritis

LDL .........................................................................low-density lipoprotein

MI ............................................................................myocardial infarction

MRI ..........................................................................magnetic resonance imaging

NSIP ........................................................................non-specific interstitial pneumonia

OPG .........................................................................osteoprotegerin

PFT ..........................................................................pulmonary function testing

PICO ........................................................................population, intervention, comparator, and outcomes

RA ............................................................................rheumatoid arthritis

RANKL .....................................................................Receptor activator of nuclear factor kappa-B ligand

RF ............................................................................rheumatoid factor

SIE ...........................................................................serious infection event

SQ ............................................................................subcutaneous

TNFi .........................................................................tumor necrosis factor inhibitor

UIP ..........................................................................usual interstitial pneumonia

COMORAStudy:PrevalenceofComorbiditiesin Patients With RA (N=3920)

% o

f Pat

ient

s (M

ean

95%

CI)

CI=confidence interval. MI=myocardial infarction. COPD=chronic obstructive pulmonary disease. GI=gastrointestinal.

Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62-68.

MI

Stro

keAny

Prosta

te

Breast

Uteru

sColon

Melanoma

Basoce

llular

Anyskin Lung

Lymphoma

Anysolid

Anysolidexcludingbasocellular

Hepatitis

B

Hepatitis

C

Diverticu

litis

Gastroduodenal u

lcer

COPD

Asthm

a

Depress

ion

Ischemic Cardiovascular

Diseases

Cancers

Infections

GI Diseases

Pulmonary Diseases

PsychiatricDiseases

The ACR 2012 Recommendations for Use of Biologics inPatientsWithRAandComorbidConditions

Comorbidity/ClinicalCircumstance RecommendedNot

Recommended Level of

Evidence

Hepatitis

Hepatitis C Etanercept C

Untreated chronic hepatitis B or treated chronic hepatitis B with Child-Pugh class B and higher*

Any biologic agent C

Malignancy

Treated solid malignancy >5 years ago or treated nonmelanoma skin cancer >5 years ago

Any biologic agent C

Treated solid malignancy within the last 5 years or treated nonmelanoma skin cancer within the last 5 years† Rituximab C

Treated skin melanoma† Rituximab C

Treated lymphoproliferative malignancy Rituximab C

Congestive heart failure NYHA class III/IV and with an ejection fraction of <50%‡ Anti-TNF biologic C

NYHA=New York Heart Association. anti-TNF=anti–tumor necrosis factor.

*Therapy defined as an antiviral regimen deemed appropriate by an expert in liver diseases. The Child-Pugh classification liver disease scoring system is based on the presence of albumin, ascites, total bilirubin, prothrombin time, and encephalopathy. Patients with a score of 10 or more (in the class C category) have a prognosis with 1-year survival being about 50%. Patients in class A or B have a better prognosis of 5 years, with a survival rate of 70-80%. †Little is known about the effects of biologic therapy on solid cancers treated within the past 5 years, due to exclusion of these patients from most randomized controlled trials. ‡NYHA class III=patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. NYHA class IV=patients with cardiac disease resulting in inability to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency or of anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625-639. 64: 625-639.