• •

  August 2012: meeting of experts of the Mexican College of Rheumatology to define objectives, to evaluate the content of the recommendations and determine the update process through a universal and consensual approach to this objective.

• •

  September 1, 2012. Planning meeting where relevant issues were agreed upon and a directed selection of coordinators based on membership in the National System of Researchers with expertise in the subject, in the process of publication, with geographic, gender and potential conflict of interests balance was carried out. Each of them was asked to incorporate 3 rheumatologists to their teams, taking into account, among other criteria, residency training centers, the different health systems, private practice, academic profile and the different regions of the country.

• •

  September 8, 2012: It was decided to adopt and adapt the Canadian guidelinelines for treatment of RA, as a summary of the various published guidelinelines on the management of RA.6,7 This guidelineline was enriched by the addition of new structured clinical questions that the group of coordinators developed by consensus at that meeting.

The participants identified the issues to assess and the questions to respond based on the most common treatment problems facing health care professional, focused mainly on the pharmacological treatment of RA in adults.

The guideline is aimed at second and third level of care personnel with the objective of standardizing the actions concerning the pharmacological treatment of RA.

The application of these guidelinelines will improve the effectiveness, safety and quality of health care of this population. The different phases of dissemination and implementation of clinical recommendations should be properly planned and supervised by the respective regulations and regulatory bodies, as well as the respective government agencies.

This paper presents a series of recommendations based on the best scientific evidence available at the time of its development and is intended as a useful tool to expedite decision making for treatment, according to the best available scientific evidence available, always considering the needs and individual patient preferences, and the availability of local resource consumption of the clinic and/or institution. It is important to consider that new clinical research results provide current evidence, so in general, the performance of an update of the same is recommended every 2 years, especially now that the biotech biosimilar/biocomparable drugs are incorporated into our health system.

8 key elements that rule the management of patients with RA are considered:

• a)

  Early diagnosis.

• b)

  Timely treatment.

• c)

  Management by rheumatologist.

• d)

  Treat to target (remission or low activity level).

• e)

  Individualized.

• f)

  Regular follow up.

• g)

  Consider comorbidity.

• h)

  Adapted to the realities of clinical practice.

The main objective of treatment in patients with RA is remission or at least achieving a low level of clinical activity. The obligatory target in all patients is to control disease activity in order to improve symptoms, reduce joint damage, prevent functional limitations and improve the quality of life [LE: 1, DR: A].6,16

NSAIDs are useful for treating pain and inflammation. However, they do not alter the course of disease [LE: 1 + +, DR: A].17

They are used at the beginning of the disease and should be prescribed in combination with DMARDs [LE: 1, DR: A].1 They can also be used in case of a relapse and the continued uncontrolled symptoms despite a good objective response to DMARDs. Glucocorticoids especially should be used as “bridging” therapy in relation to the time needed to reach effective therapeutic DMARD levels or during relapse [LE 4, DR: D].6

Patients at risk of developing NSAID-associated gastric ulcers should receive gastroprotection based on a proton pump inhibitor [LE: 2, DR: A].17

All NSAIDs should be used at high doses for at least a week before considering a treatment failure. Once symptoms are controlled, NSAID should be used at the lowest effective dose and for the shortest time necessary, as adverse events are dependent on the dose and duration of treatment [LE: 1 + +, DR: A].17

In patients who continue to have activity in a few joints, despite a good therapeutic response to DMARD regimen, slow release glucocorticoid intraarticular infiltration with sterile technique at any time of the disease, after excluding septic arthritis and during up to 3-4 times a year may be carried out [LE: 1, DR: A].18

Due to its side effects, its use should be reduced to the lowest possible dose and be administered for the shortest period of time, according to the disease activity [LE: 4, DR: D].18

When there is severe pain, no analgesic response to previous treatments and no surgical options, opioid analgesics may be administered. There is limited evidence of the effectiveness of weak oral opioids to serve as effective analgesics in patients with RA, and, unfortunately, adverse events occur frequently. There is insufficient evidence for the use of weak opioids for periods of time over 6 weeks or the potential role of strong opioids.

If the pain is neuropathic, antidepressants (amitriptyline or duloxetine) and some neuromodulators (gabapentin, pregabalin or carbamazepine) can be used.

Concomitant use of NSAIDs and MTX is safe with proper follow up; the objective of co-administration is to achieve the therapeutic goal in the shortest possible time, and identify cases resistant to initial therapy as soon as possible.19

In recent onset RA, the use of low-dose prednisone in combination with DMARDs was associated with higher rates of clinical remission [LE: 1, DR: A].20

Once the diagnosis of RA is established, DMARDs should be initiated. In Mexico the diagnosis is not usually made early [DR: A].21

There is evidence that the response and disease progression are superior when a DMARD is started within the first 3 months since disease onset compared to disease progression when treatment begins after 12 months. Therefore, treatment with DMARDs should be started as soon as possible [LE 2 b, DR: B].19

MTX should be used as the first-line synthetic DMARDs because it improves functional capacity and reduces radiographic progression with a good safety profile [LE: 1, DR: A].9

When there is a contraindication to MTX, LEF or SSZ should be used [LE: 1 a, DR: A].21

LEF, compared with placebo in studies has shown a capacity to reduce disease activity and slow radiographic progression. Its effectiveness was observed to be comparable to MTX in a meta-analysis [LE: 1 +, DR: A].22

CLQ, SSZ and HCQ are drugs that should be considered as first-line treatments in mild forms of the disease or recent-onset RA without unfavorable prognostic factors (rheumatoid factor [RF] or positive anti-CCP) [LE 1, DR: A].19

Before the start of MTX a CBC, LFT, RFT and chest X-ray should be performed, as well as screening tests for hepatitis B, C and HIV in high-risk patients [LE: 2, DR: B].9 Post-treatment monitoring should include CBC [LE: 2],9 LFT [LE: 1]9 and RFT [LE: 2].9 CBC and LFTs should be monitored every 4 weeks during the time of dose adjustment, then every 8-12 weeks. The MTX dose should be decreased if a transaminase elevation above 2-3 times its normal value is detected and suspended in case this measure does not achieve a reduction thereof. In rare cases, a liver biopsy should be considered if there is persistent elevation of aminotransferases above 2-3 times ULN which is not attributable to other causes, despite the suspension of MTX. It is important to rule out pregnancy before starting MTX. Patients of childbearing potential and sexually active should be informed of the potential risks during pregnancy [LE: 4, DR: D].19

Because of its increased bioavailability, the administration of intravenous MTX is more efficient than oral administration. We suggest considering the change to parenteral administration in cases of apparently inadequate response or gastrointestinal toxicity.19

The presence of chronic lung disease is a relative contraindication to treatment with MTX so, if identified, interstitial lung disease in patients with RA who are receiving MTX should be considered as a motive to switch to another DMARD such as LEF, CLQ, HCQ, SSZ or a biological agent, either singly or in combination, according to individual patient context.23

Combination therapy with DMARDs should be considered in the following situations: in patients with severe active early to moderate disease, subsequent persistence of symptoms at 3 months after starting DMARDs [LE: 1 + +, DR: A]21 and in the presence of several factors of poor prognosis.21

Combination therapy with DMARDs should include MTX as an axis. MTX combination therapy with LEF, CLQ or HCQ and/or SSZ has proven effective in reducing the signs and symptoms of active disease in cases of inadequate response to monotherapy.6

Combination therapy with LEF+MTX may be a therapeutic option for patients with persistent joint activity despite the use of MTX as monotherapy. There is evidence showing superior efficacy of LEF + MTX compared to MTX + placebo [LE: 1 + +, DR: A].24

The evidence in clinical practice for the permanence of the combination LEF+MTX has been compared with the use of LEF as monotherapy, and it has shown that about 65% of patients remain on the combination of LEF+MTX at 30 months, similar to LEF monotherapy, where 55% continued treatment at this time. In this same study, the adverse effects forced 15% of patients to abandon the treatment, which represents a significant, but not higher than what is seen with monotherapy, expected rate [LE: 2, DR: B].25

A meta-analysis demonstrated a higher rate of treatment discontinuation, including due to drug toxicity, in RA patients receiving combination therapy with synthetic DMARDs than those with DMARD monotherapy. The most commonly used combination therapy was MTX+SSZ/antimalarials.26

The general recommendation is to use the least possible number of DMARDs in order to obtain a significant improvement of the disease and, once obtained, to try spacing the dose of one of the DMARDs until its removal.

It is used in patients with severe extra-articular manifestations such as interstitial pneumonitis or rheumatoid vasculitis. It is not recommended to treat joint or synovitis activity due to its high toxicity profile [LE: 1, DR: A].27

They are indicated in patients who had failure or intolerance to DMARDs including a biologic [LE: 1, DR: A].6 Anti-TNF therapy should be continued only if there is response at 6 months [LE: 2, DR: B].18

The evidence for this recommendation is poor. Regarding the wash-out period, the clinician should individualize the decision in cases of lack of response of an anti-TNF, before starting another biologic with a different mechanism of action.

Anti-TNF therapy should be continued only if there is an adequate response at 6 months [LE: 2, DR: B].18 In patients who have failed an anti-TNF due to lack of efficacy or toxicity at 6 months, a switch to another anti-TNF can be made [LE: 1, II],6 a switch to another biologic with a different mechanism of action, such as RTX TCZ and abatacept [LE: 1],6 or MTX or another DMARD can be added in case the anti-TNF has been administered as initial monotherapy [LE: 1].6

The possibility of a good response to a second anti-TNF is better when the first anti-TNF was suspended due to side effects and inefficacy [LE: 2 +, DR: C].18

Increasing the dose of anti-TNF is not recommended [LE: 1, DR: A].18

Treatment with RTX is recommended as an option in cases of inadequate response, intolerance or failure to DMARDs, including at least one anti-TNF [LE: 2, DR: B].28 However, RTX may not be effective in all patients with RA. At least one trial suggests that patients who are seropositive for rheumatoid factor and anti-CCP antibodies are those which respond best, while seronegative do not respond so clearly. Seropositivity should be evaluated in patients in whom this change is being considered.

Adalimumab, etanercept, infliximab and abatacept, in combination with MTX, are recommended in cases of inadequate response, intolerance or failure to DMARDs, including at least one biological, and who cannot receive RTX or this must be removed due to adverse effects [LE: 2, DR: B].29

The anti-TNF drugs adalimumab, etanercept, infliximab, certolizumab pegol and golimumab in combination with MTX, are recommended as a therapeutic option in patients with severe activity, DAS28 greater than 5.1 and who have presented failure to conventional DMARDs, including MTX [LE: 2, DR: B].30

There is a 2-fold increase in the risk of developing infections with the use of anti-TNF. The most common sites of infection are the respiratory tract, bones and joints, urinary tract and skin [LE: 1, DR: A].31

Adverse events were more frequent in the treatment group receiving biological drugs, especially in reactivation of latent TB (OR: 4.68, CI 95%: 1.18–18.6) compared with the control group. Certolizumab has been associated with an increased risk of serious infections (OR: 2.04, 95% CI 1.43–2.91) compared with other anti-TNFs. Abatacept, adalimumab, etanercept and golimumab demonstrated fewer adverse events than infliximab [LE: 1 + +, DR: A].32

With regard to TB (considered as a positive PPD or tuberculin test with induration of 5mm or more), available data suggest a stronger risk of reactivation of TB with infliximab than with etanercept [LE: 3].7

The reactivation of herpes zoster virus is common in patients during treatment with anti-TNF. Few cases of varicella zoster have been documented [LE: 2, DR: B].7

In patients with hepatitis B virus infection, treatment with an anti-TNF should be considered in selected cases receiving antiviral treatment and always in consultation with the hepatologist. The treatment should be started 2 weeks before the biological drug and continued for 6–12 months 7.

TB prophylaxis should be initiated at least 3 weeks before the start of anti-TNF [LE: 2, DR: B].6 Treatment consists of rifampicin 10mg/kg/day plus isoniazid 3–5mg/kg/day for 3 months, once a day or, as an alternative scheme, isoniazid 3–5mg/kg/day for 9 months in patients with intolerance to rifampicin, hepatic cirrhosis or in elderly patients [LE: 1, DR: A].6

In patients with active TB the full treatment with rifampicin, isoniazid, ethambutol and pyrazinamide should be given from 6 to 18 months, and the anti-TNF not started until completion of this scheme [LE: 2, DR: B].6 In these patients, only if the benefit outweighs the risk can the anti-TNF be restarted after 2 months of presenting clinical, radiographic, and serologic evidence of disease resolution [LE: 2, DR: B].6

HIV infection is a relative contraindication for the use of all biological products. However, given the new antiretroviral therapies, they should be considered for use in patients with disabling disease and without the possibility of receiving other treatments.33

The information regarding the risk of cancer in patients with RA treated with TNF inhibitors is highly variable and is biased by factors that include the underlying disease itself, which increases the risk of some forms of cancer (mainly lymphomas, more associated with serious disease and high inflammatory activity), the high degree of disease activity, to the dose of treatment used, to the other treatments used to control the disease (which may also increase the risk of cancer) and factors related to each individual (genetic predisposition). In the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases (BIOBADASER) there was no association found between the use of anti-TNF and the occurrence of lymphoma.

In a series of 26 cases (18 with etanercept, 8 with infliximab) there was a higher prevalence of non-Hodgkin lymphomas observed. The interval between start of treatment and diagnosis of lymphoma was very short (average of 8 weeks) and 2 patients (one with each drug) had lymphoma regression after discontinuation. Two patients previously treated for lymphoma and who were in remission at the start of anti-TNF therapy, quickly developed a recurrence.34

The association between anti-TNF and solid tumors is lower, although there seems to be an increased risk in relation to basal cell skin tumors (but not melanoma).35 Recently six cases of hepatosplenic lymphoma with a very aggressive course have been reported in young patients with Crohn's disease treated with infliximab as well as with ASA or 6-mercaptopurine (Centocor communication).

Follow up data are required in the longer term, as well as a greater number of patients to clarify the existence of an association of TNF inhibitors in the development of tumors. Meanwhile, caution should be taken to indicate the use of these drugs when there is a history of previous tumors.

Certolizumab reduces the symptoms of the disease, slows radiographic progression, improves quality of life and functional capacity in patients with moderate to severe RA, and can be used alone or in combination with MTX in patients without prior treatment with DMARDs, and those refractory to MTX and anti-TNF [LE: 2 +, DR: D].36

Golimumab reduces the symptoms of the disease, slows radiographic progression in RA patients with moderate to severe disease, and can be used as monotherapy or in combination with MTX in patients without prior treatment with DMARDs and refractory to MTX and anti-TNF [LE: 2 +, DR: A].37

Implementation barriers. The anti-TNF etanercept, infliximab, adalimumab and certolizumab are very expensive drugs and which are not available in all health institutions; only the Mexican Social Security Institute (IMSS), the Institute of Social Security and Services for the Government Workers (ISSSTE) and Petroleos Mexicanos (PEMEX) hospitals have them. To the date of the preparation of this document golimumab is not available in Mexico.

They are recommended for patients who had an inadequate response to treatment with DMARDs or anti-TNF [LE: 1, DR: A].6 They are also recommended in patients who have not responded to treatment with 2 anti-TNF agents [LE: 2, DR: C].

In the case of rituximab, clinical response is better in patients with positive rheumatoid factor (RF) and/or anti-CCP [LE: 1, DR: A] antibodies.6

Generally, their use is not recommended as first-line treatment. However, abatacept itself could be used as a first-line in combination with MTX, according to the results of the AGREE study38 and the post hoc analysis of data from that study.39 However, our group does not recommend the use of these three drugs as first-line without having tried MTX first.

With regard to their use as a first biologic agent, it has already been mentioned that the 3 agents are recommended in patients who had an inadequate response to DMARD therapy.6 Rituximab may be used before an anti-TNF agent, especially in patients who have a relative or absolute contraindication for this type of drug, according to the guidelinelines of the British Society of Rheumatology,40 or in some special situations such as a history of B cell lymphoma, or the presence of latent TB, multiple sclerosis, vasculitis or concomitant overlap syndromes, as recommended by the guidelinelines of the Canadian Rheumatology Association [LE: 1, DR: A].6

Implementation barriers. Rituximab, tocilizumab and abatacept are very expensive drugs and not available in all health institutions. In some cases special administrative procedures are required to obtain them.

There are no reports of an increased risk of TB in patients treated with rituximab for lymphoma. The risk regarding the use of tocilizumab and abatacept is unknown [LE: 4, DR: B].7

Tofacitinib has demonstrated clinical and radiographic benefit in patients with active RA who have failed at least one DMARD [LE: 2 +, DR: C].41

Studies show higher ACR 20, 50, 70 responses, increased frequency of DAS28 remission and better functionality in patients receiving tofacitinib than in those receiving placebo [LE: 2 +, DR: C].42

A close eye should be kept on the decrease in neutrophil and in lymphocyte counts, hemoglobin levels, and increases in blood lipid. Recently, long term studies following tofacitinib-treated patients have warned of the presence of serious and difficult to manage complications (opportunistic infections) as well as certain tumors, hepatotoxicity, gastrointestinal perforation and infection. Therefore, the European Drug Regulatory Agency (EMA) has denied approval for to facitinib marketing in Europe and the Food and Drug Administration (FDA) has issued an international alert, recommending that patients currently involved in long term studies continue to receive the medicine.43,44

Implementation barriers. It should be noted that data from long-term monitoring are limited, it is expected to have a high cost (similar to anti-TNF), and as with other DMARDs, an increased risk of serious infections, including TB, fungal infections and infections generated by opportunistic pathogens, so patients receiving this drug must be closely monitored.43

Methotrexate. During pregnancy the use of MTX is formally contraindicated. It should be discontinued preferably 4 months before pregnancy, and in case of lack of planning, it should be discontinued immediately [LE: 4, DR: D].45

Leflunomide. Women treated with LEF must wait 2 years after suspending it to schedule a pregnancy. In pregnant women who wish to get pregnant before 2 years, we recommend a wash out with cholestyramine 8 every/8h, or activated charcoal 50g every 6h for 11 days (in both cases), thus achieving elimination of the drug in 3 months. After washing, it is desirable to quantify plasma levels of the active metabolite, which must be less than 0.02mg/l. This level will be verified 14 days after the first determination [LE: 1, DR: A].45

A case series (n=45) showed 2 products of pregnancy with congenital malformations when exposure occurred in the first trimester (n=16) and no malformation in patients who discontinued treatment before conception (n=29).[LE: 4, DR: D].46

Anti-TNF. Therapy with anti-TNF is contraindicated in pregnancy. The interval the patient should be free of anti-TNF to conceive, with infliximab is 6 months, with adalimumab, 5 months and with etanercept without recommendation [LE: 3, DR: C].10 In the event of a pregnancy in women with RA under biological treatment, this treatment should be discontinued immediately [LE: 4, DR: C].45

Some published recommendations suggest that the safety interval between the last dose of anti-TNF and conception is 5 half-lives of the drug.

Not all patients with RA improve during pregnancy. Both HCQ and CLQ 47, azathioprine45 and SSZ47 are safe pharmacological interventions in patients with RA disease activity during pregnancy.

Azathioprine is recommended with caution if necessary during pregnancy, to suppress the activity of RA [LE: 4, DR: D].45

CLQ and HCQ are safe pharmacological treatments during lactation in patients with RA [LE: 4, DR: D].45 SSZ can be used with caution while breastfeeding. Its use is not recommended if the infants renal function is affected [LE: 4, DR: D].48

The British guidelines mention discontinuing infliximab 6 months before initiating breastfeeding, with the same indication for adalimumab and etanercept [LE: 2, DR: B].10

In women there are no reports. However, in men, SSZ generates reversible oligospermia.

Evaluation of the vaccination status of the patient is recommended during the initial evaluation of patients with inflammatory rheumatic diseases. Ideally, vaccination should be administered during the stable phase of the disease [LE: 4, DR: D].49 Vaccination recommendations should be reviewed by age group and gender.

Barriers to implementation: none.

Immunization with live attenuated microorganisms should be avoided whenever possible in immunosuppressed patients with autoimmune inflammatory rheumatic diseases [LE: 4, DR: D].49

Barriers to implementation: none.

When it is necessary to administer an immunization with live attenuated microorganisms (measles, mumps, rubella, typhoid, polio [oral]), it is suggested it be given 2 weeks before and ideally four weeks before the onset of treatment with DMARDs or biological drugs [LE 4, DR: D].7

Barriers to implementation: none.

Vaccination against influenza and pneumococcal disease in RA patients before or during treatment with DMARDs or biological drugs is recommended. Pneumococcal vaccine should be reapplied every 5 years [LE: 2, DR: B].7,45,49

Barriers to implementation: none.

In patients who have not been immunized against pneumococcus and prior to the start of RTX, the administration of pneumococcal polysaccharide 23-valent vaccine, with 4-6 of anticipation is recommended [LE: 2, DR: B].40

Barriers to implementation: none.

It is recommended that the influenza vaccine be administered before the start of RTX and annually, preferably before retreatment [LE: 2, DR: B].40

Barriers to implementation: none.

Patients with autoimmune inflammatory rheumatic diseases should be vaccinated with tetanus toxoid, in accordance with established recommendations for the general population [LE: 4, DR: D].4,40

Barriers to implementation: none.

The administration of the vaccine against herpes zoster is recommended in patients receiving MTX at doses ≤25mg/week and/or glucocorticoids at doses <20mg/day [LE: 4, DR: D].7

Barriers to implementation: vaccine not available in Mexico.

The ideal time for its application would be between 2 and 4 weeks before the onset of biological treatment.

The vaccine against herpes zoster should be considered in patients with RA over 60 years of age [LE: 4, DR: D].7

Barriers to implementation: depends on the availability of the vaccine in Mexico.

Vaccination against hepatitis B should also be carried out.

Prior to initiation of treatment with biological agents, it is recommended to investigate the possibility of infection with HIV and hepatitis viruses in patients with risk factors [LE: 4, DR: D].40,50,51

In patients infected with hepatitis C (active or inactive), anti-TNFs appear to be safe. However, it should be used with caution if any evidence of viral replication is present.

The use of biopharmaceuticals in patients with viral infections should be avoided. In patients under treatment, the development of viral infections should be carefully monitored. If present, suspension of the biological should be carried out and the patient should receive specific treatment according to the type and site of infection [LE: 1, DR: A].51

When suspecting varicella infection in patients receiving biological agents, treatment should be discontinued and specific antiviral treatment indicated immediately [LE: 2, DR: B].45

The safety profile of the TNF inhibitors is similar. The Biobadamex 1.0 Mexican Registry identified an increased risk for infections (RR 2.05, 95% CI: 1.5–2.7, P<.001) in subjects under biological therapy vs those receiving traditional DMARDs. In patients with infections, the use of agents anti-TNF drugs should be avoided [LE: 2, DR: C].7,31,52,53

Yes it is recommended, since treatment with traditional and biologic DMARDs is immunosuppressive, there is an increased risk of infectious complications surrounding a surgical procedure. The revised guidelinelines summarize the evidence on the safety of treatment with MTX in elective surgeries, as well as the suspension a week before surgery.

As to the suspension of biological therapy, this will depend on the individual circumstances of each patient and the nature of the surgery and the half-life of drugs. The evidence underpinning the Canadian guidelinelines mentions that 1-2 months before surgery anti-TNF should be discontinued. As for RTX, time is defined more by the amount of B cells and in situations where the disease is well controlled.

The restoration of a biologic drug depends on the clinical setting (RA activity and postoperative course free of infection) [LE: 4, DR: B].45,51

For all patients undergoing biological treatment a complete history, Combe, intradermal testing and chest X-ray should be performed. Another test used for latent TB, called IGRA (INF γ release assays), evaluates the in vitro production of IFN in the presence of Mycobacterium tuberculosis-specific antigens by enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunosorbent Spot assay (ELISPOT), demonstrating a greater sensitivity and specificity than tuberculin, especially in patients who have received the Bacillus Calmette-Guérin (BCG) vaccine.54

Barriers to implementation: none for traditional screening, but IGRA is not readily available in Mexico.

All patients presenting a PPD equal or greater than 5mm, whether or not they have been vaccinated with BCG or have a positive Combe with a chest X-ray suggestive of TB.

This is not clearly defined. It is recommended that one to two months pass before starting biological agents or, starting at the same time, if the case merits it [LE: 4, DR: D].50

Management Algorithm

The authors state that no experiments were performed on persons or animals for this study.

The authors state that they have followed their workplace protocols regarding the publication of patient data and all patients included in the study have received enough information and have given their written informed consent to participate in the study.

The authors state that they have obtained informed consent from patients and/or subjects referred to in this article. This document is in the possession of the corresponding author.