1. Aetna considers adalimumab (Humira) medically necessary for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adults 18 years of age or older with moderate to severely active rheumatoid arthritis.  According to the Food and Drug Administration (FDA)-approved product labeling, adalimumab can be used alone or in combination with methotrexate or in combination with non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

2. Aetna considers adalimumab medically necessary for reducing signs and symptoms of active arthritis in adults with moderate to severely active psoriatic arthritis who have had an inadequate response to 2 or more non-biologic DMARDS.  According to the FDA-approved product labeling, adalimumab can be used alone or in combination with DMARDs.

3. Aetna considers adalimumab medically necessary for reducing signs and symptoms of members with active ankylosing spondylitis who have an inadequate response to 2 or more NSAIDs.

4. Aetna considers adalimumab medically necessary in adults with active Crohn's disease manifested by:

   1. Abdominal pain; or
   2. Arthritis; or
   3. Bleeding; or
   4. Diarheea; or
   5. Internal fistulae; or
   6. Intestinal obstruction; or
   7. Megacolon; or
   8. Perianal disease; or
   9. Spondylitis; or
   10. Weight loss.

   When Crohn's disease has remained active despite treatment with either 6-mercaptopurine, azathioprine, or corticosteroids.

5. Aetna considers adalimumab medically necessary for reducing signs and symptoms of moderate to severely active polyarticular juvenile idiopathic arthritis (juvenile rheumatoid arthritis) in persons 4 years of age and older.

6. Aetna considers adalimumab medically necessary for treatment of adults with moderate to severe chronic plaque psoriasis according to the criteria set forth in CPB 0658 - Psoriasis: Biological Therapies.

7. Aetna considers adalimumab necessary for the treatment of moderate-to-severe ulcerative colitis in adults who have not lost response to or are tolerant to tumor necrosis factor blockers.  (Note: Adalimumab should only continue to be used in individuals who have shown evidence of clinical remission by 8 weeks of therapy).

8. Aetna considers adalimumab experimental and investigational for all other indications, including any of the following conditions, because the safety and effectiveness of adalimumab for these conditions has not been established:

   • Active infections; or
   • Asthma; or
   • Cellulitis; or 
   • For use in combination with other tumor necrosis-factor blocking agents [(e.g., anakinra (Kineret), etanercept (Enbrel), or infliximab (Remicade)]; or
   • Guttate psoriasis; or
   • Lupus pernio; or
   • Osteoarthritis; or
   • Recurrent pregnancy loss; or 
   • Relapsing polychondritis; or
   • Sarcoidosis; or
   • Sciatica; or
   • Takayasu's arteritis, or
   • Uveitis (including uveitis-related macular edema).

See also CPB 0315 - Enbrel (Etanercept), CPB 0341 - Remicade (infliximab), and CPB 0595 - Kineret (Anakinra).

Adalimumab (Humira) (Abbott Laboratories, North Chicago, IL) is a recombinant human IgG1 monoclonal antibody that acts by inhibiting tumor necrosis factor alpha, an inflammatory protein that, when produced in excess, plays a key role in the inflammatory responses of some autoimmune diseases.  Adalimumab has been approved by the U.S. Food and Drug Administration (FDA) for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, plaque psoriasis, and juvenile idiopathic arthritis.

Adalimumab has been approved by the FDA for reducing signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis.  Adalimumab can be used alone or in combination with methotrexate or other non-biolgic disease modifying anti-rheumatic drugs (DMARDs).  The efficacy and safety of adalimumab were assessed in 5 randomized, double-blind studies in 2,869 subjects aged 18 years and older with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria.  All subjects had at least 6 tender and 9 swollen joints.  Humira was administered subcutaneously in combination with methotrexate or as monotherapy or with other DMARDs.  Two studies involved 815 patients who had failed to respond to DMARDS; 1 study involved 619 patients who had an inadequate response to methotrexate.  One study assessed 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy.  One study evaluated 799 patients with moderately to severely active rheumatoid arthritis of less than 3 years duration who were methotrexate naïve.  In all 5 studies, adalimumab showed significantly greater improvement than placebo in standardized indices of disability and health outcomes from baseline to the end of study.  One of the 5 studies also examined the effect adalimumab on inhibition of disease progression, as detected by X-ray results.  Subjects treated with adalimumab and methotrexate showed significantly less radiological progression of disease than subjects treated with methotrexate alone.  Subjects treated with adalimumab and methotrexate showed significantly less radiological progression of disease than subjects treated with methotrexate alone.

According to guidelines from the ACR (Saag et al, 2008), patients with early rheumatology with low or moderate disease activity (in study) were not considered candidates for biologic therapy.  The use of anti-tumor necrosis factor (TNF) agent in combination with methotrexate was recommended if high disease activity was present for less than 3 months with features of a poor prognosis.

Adverse events from adalimumab include upper respiratory infection, sinusitis, flu syndrome, nausea, and abdominal pain.  Cases of tuberculosis and invasive fungal infections have rarely been observed in patients receiving adalimumab.

The recommended dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.

The FDA has approved adalimumab for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis.  The FDA-approved product labeling for Humira states that adalimumab can be used alone or in combination with methotrexate or with DMARDs.  The FDA approval of Humira was based on 2 multi-center randomized controlled clinical studies evaluating the safety and efficacy of adalimumab compared with placebo in 413 patients with moderate to severely active psoriatic arthritis (greater than 3 swollen and greater than 3 tender joints) who have had an inadequate response to non-steroidal anti-inflammatory drugs (NSAIDS).  In 1 study (Mease et al, 2005), 313 patients with moderately to severely active psoriatic arthritis and a history of inadequate response to NSAIDS were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks.  Study participants had the following forms of psoriatic arthritis: (i) distal interphalangeal (DIP) involvement (n = 23); (ii) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis) (n = 210); (iii) arthritis mutilans (n = 1); (iv) asymmetric psoriatic arthritis (n = 77); or (v) ankylosing spondylitis-like (n = 2).  Patients on methotrexate therapy (158 of 313 patients) at enrollment (stable dose of less than or equal to 30 mg/week for greater than 1 month) could continue methotrexate at the same dose.  Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter.  The primary efficacy end points were the ACR 20 % improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 25.  Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3 % of body surface area.  At week 12, 58 % of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14 % of the placebo-treated patients (23 of 162) (p < 0.001).  At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (p < 0.001).  Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes.  Responses were similar in patients who were or were not receiving concomitant methotrexate therapy at baseline.  Patients with psoriatic involvement of at least 3 % body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses.  Among the 69 adalimumab-treated patients evaluated for PASI responses, 59 % achieved a 75 % PASI improvement response and 42 % achieved a 90 % PASI improvement response at 24 weeks, compared with 1 % of the 69 placebo-treated patients evaluated (p < 0.001).  The investigators reported that disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo.   

Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by greater than or equal to 3 tender joints and greater than or equal to 3 swollen joints at enrollment.

The manufacturer reported that the rates of adverse events and serious adverse events in clinical trials of adalimumab for psoriatic arthritis submitted for FDA approval were comparable with clinical trials of adalimumab in rheumatoid arthritis.  Among patients taking adalimumab, the most common adverse events (those affecting at least 5 % of patients) were upper respiratory infection, nasopharyngitis, injection site reaction, headache and hypertension.  The safety profile of adalimumab in these clinical trials was similar to that observed in the clinical trials of adalimumab for rheumatoid arthritis that were submitted for FDA approval.  The FDA-approved product labeling states that the safety and efficacy of adalimumab in pediatric patients has not been established.

The recommended dose of adalimumab for psoriatic arthritis is 40 mg every-other-week by subcutaneous injection, which is also the usual dose used for adalimumab in the treatment of moderate to severe rheumatoid arthritis.

Ankylosing spondylitis (AS) is a form of arthritis known as spondyloarthritis, which is a group of closely linked rheumatic diseases that can cause pain in the spine and joints as well as ligaments and tendons.  Ankylosing spondylitis is an autoimmune disorder in which TNF-alpha has been suggested to play a role in its pathogenesis.  A chronic disease, AS primarily affects the spine causing back stiffness and potential deformity over time.  Wendling and Toussirot (2004) noted that anti-TNF represents a major therapeutic advancement in the treatment of AS.  De Keyser and associates (2006) stated that AS is the prototype disease within the spondyloarthropathies, a group of diseases presenting mainly with spondylitis, pauci-articular peripheral arthritis and enthesiopathy. Non-steroidal anti-inflammatory drugs are the classical cornerstone of medical therapy in these patients; no real DMARD was available, until recently.  Tumor necrosis factor-alpha blocking agents (monoclonal antibodies or soluble receptors) are the first representative drugs, of which the indication has recently been expanded to encompass also patients with AS.  In a 52-week open-label study (n = 15, mean age of 40 years with a range of 19 to 55 years), Haibel and colleagues (2006) reported that adalimumab treatment of active AS resulted in a clear improvement in clinical (reduction of spinal symptom) as well as MRI outcome measurements, similar to that observed with other TNF-alpha blocking agents. 

On July 31, 2006, the FDA granted a supplemental indication for adalimumab -- for reducing signs and symptoms in patients with active AS.  This indication was approved by the European Commission in June 2006.  The recommended dosage of adalimumab for AS is 40 mg (subcutaneous injection) every other week.  The approval of adalimumab for the treatment of patients with active AS is based on data from the ATLAS (Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS) trial (n = 315), which was a randomized, placebo-controlled, double-blind, phase III study conducted in Europe and the United States of patients with AS who had failed to respond to NSAIDs or DMARDs.  Results at 12 weeks showed that 58 % of patients receiving adalimumab achieved and sustained a minimum 20 % reduction in pain and inflammation, as measured via the Assessment in AS (ASAS) International Working Group criteria for evaluating function, pain, patient global assessment, and inflammation.  At week 24, 42 % of adalimumab-treated patients versus 16 % of those receiving placebo achieved a reduction of 50 % or more in disease activity, as evaluated using a patient-assessed composite index for pain, stiffness, and fatigue (Bath AS Disease Activity Index [BASDAI]).  Moreover, approximately 1 of 5 patients achieved partial remission, defined as a value of less than 20 on a 0 to 100 scale in each of the 4 ASAS domains.

ATLAS also explored the impact of adalimumab on enthesitis, a primary pathology in AS that is characterized by inflammation of the ligaments attachment to the bone.  At week 24, the mean change in the enthesitis symptom score as indexed by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in patients treated with adalimumab showed significant reduction.  MASES is an index that assesses enthesitis in certain locations, such as the rib cage, lower back, and Achilles tendons.

The British Society for Rheumatology (BSR, 2006) has stated that "there is evidence to support the use of adalimumab as a treatment for adult patients with active AS, who have had an inadequate response to non-steroidal anti-inflammatory drugs and conform to the current BSR guideline for the use of anti-TNF-? drugs in AS."  The BSR statement notes that "[w]hilst there have not been any direct comparisons between anti-TNF-α drugs in AS, adalimumab appears to be as effective as any other licensed agents."

Adalimumab has also been shown in clinical trials to be effective for moderate to severe Crohn's disease.  Colombel et al (2007) reported on the results of a controlled clinical trial, which demonstrated that adalimumab was effective in maintenance of response and remission in patients with moderate to severe Crohn's disease.  In this clinical study, patients received open-label induction therapy with adalimumab 80 mg at study initiation followed by 40 mg 2 weeks later.  Four weeks following study initiation, patients who responded to adalimumab were stratified by response (decrease in Crohn's Disease Activity Index greater than or equal to 70 points from baseline) and randomized to 3 treatment groups: (i) placebo, (ii) adalimumab 40 mg every other week, or (iii) adalimumab 40 mg weekly.  Patients were followed for 56 weeks.  Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score less than 150) at weeks 26 and 56.  The investigators reported that the percentage of randomized responders in remission was significantly greater in the groups receiving adalimumab weekly and every other week compared to the placebo group at week 26 (47 %, 40 %, and 17 %, respectively; p <  0.001) and at week 56 (41 %, 36 %, and 12 %, respectively; p <  0.001).  There were no significant differences in efficacy between adalimumab administered weekly and every other week.  The investigators noted that adalimumab was well-tolerated; more patients receiving placebo discontinued treatment because of an adverse event (13.4 %) than those receiving adalimumab (4.7 % and 6.9 % in the adalimumab weekly and every other week groups, respectively).  The investigators concluded that, among patients who responded to adalimumab, both weekly and every other week adalimumab was significantly more effective than placebo in maintaining remission in moderate to severe Crohn's disease through 56 weeks.

Hanauer et al (2006) reported that adalimumab was shown in a controlled clinical trial to be superior to placebo for induction of remission in patients with moderate to severe Crohn's disease.  A total of 299 patients with moderate to severe Crohn's disease naive to anti-TNF therapy were randomized to receive subcutaneous injections at study initiation and 2 weeks later with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo.  The primary endpoint was demonstration of a significant difference in the rates of remission (defined as a Crohn's Disease Activity Index score less than 150 points) at 4 weeks after study initiation among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups.  The investigators found that the rates of remission at the 4th week in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18 % (p = 0.36), 24 % (p = 0.06), and 36 % (p = 0.001), respectively, and 12 % in the placebo group.  The investigators reported that adalimumab was well-tolerated, noting that adverse events occurred at similar frequencies in all 4 treatment groups except injection site reactions, which were more common in adalimumab-treated patients.  The investigators concluded that adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn's disease naive to anti-TNF therapy.  The investigators stated that the optimal induction dosing regimen for adalimumab in this study was 160 mg at initiation of therapy followed by 80 mg 2 weeks later.

Colombel et al (2009) compared outcomes of induction dosing followed by continuous adalimumab treatment with those of induction dosing with re-initiation of adalimumab (in the event of clinical deterioration) for patients with moderate-to-severe Crohn's disease who participated in the Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM).  In the CHARM trial, all patients received open-label induction therapy with adalimumab 80 mg and 40 mg at weeks 0 and 2, respectively.  In total, 778 patients were randomized at week 4 to one of three groups: (i) placebo after initial induction doses (followed by re-initiation of adalimumab therapy); (ii) continuous maintenance treatment with adalimumab 40 mg every other week (e.o.w.); and (iii) continuous maintenance treatment with adalimumab 40 mg every week.  At/after week 12, patients receiving placebo with flare or non-response could re-initiate open-label adalimumab 40 mg e.o.w., and patients receiving continuous blinded adalimumab therapy could switch to open-label 40 mg e.o.w.  Patients in all groups could switch to weekly therapy with continued flare/non-response.  In the previously published primary analysis, results for only those patients who had responded at week 4 (decrease in Crohn's Disease Activity Index (CDAI) of greater than or equal to 70 points, referred to as "randomized responders") and remained on blinded therapy were analyzed.  In this analysis, data from all randomized patients were analyzed based on original randomized treatment using an intention-to-treat analysis, regardless of whether they subsequently switched to open-label therapy.  Disease activity, clinical remission, number of flares, Inflammatory Bowel Disease Questionnaire (IBDQ) score, number of Crohn's disease-related surgeries, and hospitalization incidence were compared between the continuous and induction only/reinitiation adalimumab groups.  Results for all outcome measures were superior for both continuous groups compared with the induction only/re-initiation group.  On the basis of median CDAI and IBDQ results, patients in both continuous treatment groups achieved statistically significantly greater improvements versus the induction only/re-initiation group (p < 0.05).  At week 56, a significantly greater percentage of patients who had received continuous adalimumab (51 % for e.o.w. and 49 % for weekly) were in clinical remission versus the induction only/re-initiation group (38 %, p < 0.05).  Continuous adalimumab therapy was also associated with fewer flares and fewer Crohn's disease-related surgeries (p < 0.05).  Patients in both continuous adalimumab groups had significantly lower risks of Crohn's disease-related and all-cause hospitalizations than did patients in the induction only/re-initiation group (p < 0.05).  The authors concluded that for patients with active Crohn's disease, continuous treatment with adalimumab was more effective than a strategy of induction dosing followed by re-initiation of adalimumab with clinical deterioration for maintenance of clinical remission, improved quality-of life outcomes, reduced flares, and a decrease in number of surgeries and risk of hospitalization.

Adalimumab has been approved by the FDA for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients 4 years of age and older.  In the United States, JIA is commonly referred to as juvenile rheumatoid arthritis (JRA).  JIA is the most common chronic rheumatic disease in children with onset before age 16.  Typical symptoms include stiffness when awakening, limping, and joint swelling.  Any joint can be affected and inflammation may limit the mobility of the affected joints.  Polyarticular JIA is a form of arthritis affecting 5 or more joints, usually in a symmetrical fashion.  While it was once believed that most children eventually outgrow JIA, it is now known that between 25 and 70 % of children with JIA will still have active disease into adulthood.

The approval of adalimumab for JIA was based on the results of a 48-week study and a subsequent open-label extension evaluating the efficacy and safety of adalimumab in children with JIA.  The 48-week phase III study included 171 children (4 to 17 years of age) with polyarticular JIA.  In the first part of this study, 2 groups of children -- those taking methotrexate (MTX) and those not taking MTX -- received open-label adalimumab (up to a maximum of 40 mg) every other week for 16 weeks.  Patient responses were measured using the American College of Rheumatology Pediatric (ACR Pedi) 30 score, which represents a 30 % or greater improvement in JIA signs and symptoms.  Children who showed a positive clinical response (n = 133) entered the second part of the study and were randomized to receive adalimumab or placebo for an additional 32 weeks or until disease flare.  A flare was defined as a worsening of 30 % or more in at least 3 of the 6 ACR Pedi response variables, a minimum of 2 active joints, and no more than 1 indicator improving by 30 % . In the second part of this study, significantly fewer children receiving adalimumab demonstrated disease flare compared to children on placebo, both without MTX (43 % versus 71 %) and with MTX (37 % versus 65 %).  Additionally, more children treated with adalimumab continued to show ACR Pedi 30/50/70 responses at week 48 compared to placebo.  At the conclusion of the 48-week study or at the time of disease flare during the double-blind phase, children could enter the open-label extension period.  Efficacy and safety were assessed at routine intervals throughout the study.  ACR Pedi responses were maintained for up to 2 years in children who received adalimumab throughout the study.  Upon initiation of treatment with adalimumab, the most common adverse reactions that occurred were injection site pain and injection site reaction (19 % and 16 %, respectively).  In general, adverse reactions in children were similar in frequency and type to those seen in adult patients.  Severe adverse reactions reported in the clinical trial in JIA included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia and appendicitis.  Serious infections were observed in 4 % of children within approximately 2 years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.  Recommended dosing in JIA is based upon weight.  For children 15 kg (33 lbs) to less than 30 kg (66 lbs), recommended dose is 20 mg by injection every other week.  For children 30 kg (66 lbs) and greater, recommended dose is 40 mg by injection every other week.

Adalimumab has been approved by the FDA for the treatment for adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.  According to the FDA-approved labeling, adalimumab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.  Chronic plaque psoriasis is an autoimmune disease characterized by inflammed, scaly skin lesions known as plaques, which may crack and bleed.  While psoriasis can occur in people of all ages, it typically appears in patients between the ages of 15 and 35 years.  Approximately 25 % of persons with chronic plaque psoriasis exhibit moderate to severe disease.  Up to 30 % of psoriasis patients develop psoriatic arthritis.  Treatment may include topical agents, phototherapy or oral or injectable medications.

The FDA approval of adalimumab for chronic plaque psoriasis was based on 2 pivotal trials, REVEAL and CHAMPION, showing that approximately 3 out of 4 patients achieved 75 % clearance or better at week 16 of treatment versus placebo.  Both studies evaluated the efficacy and safety of HUMIRA in clearing skin in moderate to severe adult plaque psoriasis patients versus placebo.  In addition, CHAMPION compared a biologic medication to methotrexate, a standard systemic treatment for psoriasis.  In each trial, reduction in disease activity was determined by the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA).  In REVEAL, a 52-week trial, the short-term and sustained clinical efficacy and safety of adalimumab were evaluated in 1,212 patients with moderate to severe chronic plaque psoriasis.  Patients experienced a significant reduction in the signs and symptoms of their disease at 16 weeks when treated with adalimumab.  Specifically, 71 % of patients receiving adalimumab achieved PASI 75 compared to 7 % of patients receiving placebo at week 16.  At week 16, 62 % of adalimumab-treated patients achieved a PGA score of clear or minimal compared to 4 % of placebo-treated patients.  In CHAMPION, a 16-week study evaluating 271 psoriasis patients, adalimumab-treated patients experienced a significant reduction in the signs and symptoms of their disease compared with methotrexate or placebo-treated patients.  Seventy-eight percent of patients treated with adalimumab (n = 99) achieved a PASI 75 response, compared to 19 % of patients treated with placebo (n = 48).  Seventy-one percent of patients treated with adalimumab achieved a PGA score of clear or minimal at 16 weeks of treatment, compared with 10 % of placebo-treated patients.  The safety profile of adalimumab in the plaque psoriasis clinical trials was reported to be similar to that seen in adalimumab clinical trials for rheumatoid arthritis.  The most commonly reported adverse events in adalimumab psoriasis trials were upper respiratory tract infection, nasopharyngitis (inflammation of the nose and pharynx), headache, sinusitis and arthralgia.  In clinical studies of plaque psoriasis, patients are treated with an initial 80-mg dose of adalimumab (2 40-mg injections) followed by 1 adalimumab injection (40 mg) 1 week later.  After that, a maintenance dose of 40 mg  was administered every other week.

Adalimumab has not been proven to be effective for ulcerative colitis (UC).  In an open-label study, Peyrin-Biroulet et al (2007) assessed the effectiveness of adalimumab induction therapy in patients with UC who previously responded to infliximab and then lost response or became intolerant.  A total of 10 patients with UC were enrolled in a 4-week trial.  Patients received a loading dose of 160 mg adalimumab at week 0 followed by 80 mg at week 2.  The primary outcome measure was clinical improvement at week 4, as defined by a decrease in clinical activity index (CAI) of more than 4.  Four of 10 patients (40 %) benefited from subsequent adalimumab therapy; 1 patient achieved remission (CAI less than 4) and 3 had clinical improvement at week 4; 6 patients had no response (60 %); 2 of 6 (33.3 %) subsequently underwent colectomy.  This was accompanied by a decrease in median CRP concentration from 16.8 mg/ml at baseline to 3.85 mg/ml at week 4, excluding 2 patients who underwent colectomy after 2 infusions of adalimumab.  Among the 6 patients with severe colitis (CAI greater than 12) at baseline, none achieved remission and only 1 patient had clinical improvement at week 4.  The authors concluded that the small advantage of adalimumab in patients with mild to moderate UC and lost response or intolerance to infliximab needs to be confirmed in randomized, double-blind, placebo-controlled trials.  Furthermore, in a Cochrane review on TNF-alpha blocking agents for induction of remission in UC, Lawson et al (2006) did not mention the use of adalimumab.

Fiorino et al (2011) summarized available data on the safety and effectiveness profile of adalimumab in patients with UC.  The authors concluded that adalimumab may be effective and well-tolerated in UC.  Moreover, they stated that its effectiveness in maintaining clinical remission needs to be confirmed in a randomized controlled trial.

In a pilot study (n = 12), Magnano et al (2007) examined if adalimumab can safely improve symptoms of erosive/inflammatory osteoarthritis (EOA).  Patients greater than 45 years of age with EOA of the hands defined by greater than or equal to 2 tender and greater than or equal to 2 swollen joints (distal inter-phalangeal, proximal inter-phalangeal, first carpo-metacarpal) despite NSAID therapy were eligible.  Patients were excluded for autoimmune arthritis, recent disease modifying anti-rheumatic drug use, prior use of anti-TNF therapy, infection, malignancy, or poorly controlled medical conditions.  All patients received adalimumab 40 mg every other week for 12 weeks.  Safety was assessed 4 weeks after the final dose.  Primary endpoints included safety and ACR response.  Patients were predominantly female with a mean age of 60 years and 12 years of arthritis.  All subjects completed the study and safety follow-up.  Adverse events were mild without necessitating discontinuation of study drug.  After 12 weeks, there was a statistically significant improvement in the number of swollen joints compared to baseline (p < 0.01).  One patient achieved an ACR20 response and 42 % achieved an OMERACT-OARSI response.  Although these investigators detected no statistically significant improvement in the number of tender joints, grip strength, disability, pain, or global disease assessments, trends suggested modest improvement in all efficacy measures.  The authors concluded that the findings of this small open-label study of patients with EOA demonstrated that adalimumab was well-tolerated.  Treatment with adalimumab for 3 months did not significantly improve the signs and symptoms of EOA and most patients did not achieve an ACR20.  Trends suggested improvement and individual patients had some benefit.  Factors limiting interpretation of this study include the lack of a control group, outcomes chosen, number of patients treated, and the duration of treatment.

Cutaneous sarcoidosis may be a chronic disease with important morbidity requiring aggressive therapy.  The effectiveness of different anti-TNF-alpha treatments in refractory cutaneous and systemic sarcoidosis has been reported previously.  Thielen et al (2009) reported the first patient with chronic cutaneous sarcoidosis who responded to dose escalation of anti-TNF-alpha agents that have been ineffective at the standard dosage, illustrating that the optimal dosing regimen has still to be defined for this indication before considering difficult-to-treat patients as non-responders.  This case report also illustrated that the fusion protein etanercept, even used at a high dosage, may be less effective for the treatment of cutaneous sarcoidosis than the monoclonal antibodies infliximab and adalimumab.

Patel (2009) stated that sarcoidosis is an inflammatory disorder characterized by the presence of non-caseating granulomas in affected organs.  The presence of CD4-positive T lymphocytes and macrophages in affected organs suggests an ongoing immune response.  Systemic corticosteroids remain the mainstay of treatment, but therapy is often limited by adverse effects.  This is the first report of the use of adalimumab in a patient with systemic sarcoidosis with bone marrow involvement.  The patient was a 42-year old African-American man with a medical history significant for hypertension and diabetes mellitus presented with anemia and thrombocytopenia of 2-month duration.  He underwent physical examination, bone marrow aspiration and biopsy, chest X-ray, acid-fast bacilli stain, computed tomography with contrast, and additional laboratory tests; and was diagnosed with systemic sarcoidosis with splenomegaly and bone marrow involvement.  Drug therapy included prednisone, which had to be discontinued owing to adverse effects, and adalimumab.  The author concluded that this is the first report describing the use of adalimumab in a patient with systemic sarcoidosis with bone marrow involvement.  Tumor necrosis factor antagonism with adalimumab was effective and well-tolerated in this patient and may be considered as a treatment option for similar cases.

Antoniu (2010) noted that sarcoidosis is a granulomatous disease with various organ manifestations in which TNF-alpha has been demonstrated to play a major pathogenic role.  Conventional therapies are not always able to minimize TNF-alpha-driven inflammation and other approaches should be used.  The author reviewed TNF-alpha roles in sarcoid inflammation and granuloma formation based on the literature published in the last 20 years and the therapies able to target it specifically or non-specifically in sarcoidosis were discussed.  In some subsets of sarcoidosis with more rapid progession and/or therapeutic refractoriness TNF-alpha plays a more prominent role in disease pathogenesis, and its blockade might represent an appropriate therapeutic approach.

In a multi-center, double-blind, randomized, controlled trial, Genevay and colleagues (2010) evaluated the effectiveness of adalimumab in patients with radicular pain due to lumbar disc herniation.  Patients with acute (less than 12 weeks) and severe (Oswestry Disability index greater than 50) radicular leg pain and imaging-confirmed lumbar disc herniation were randomized to receive as adjuvant therapy either 2 subcutaneous injections of adalimumab (40 mg) at 7-day interval or matching placebo.  The primary outcome was leg pain, which was recorded every day for 10 days and at 6 weeks and 6 months based on a visual analog scale (0 to 100).  Of the 265 patients screened, 61 were enrolled (adalimumab = 31) and 4 were lost to follow-up.  Over time, the evolution of leg pain was more favorable in the adalimumab group than in the placebo group (p < 0.001).  However, the effect size was relatively small and at last follow-up the difference was 13.8 (95 % confidence interval: -11.5 to 39.0).  In the adalimumab group, twice as many patients fulfilled the criteria for "responders" and for "low residual disease impact" (p < 0.05) and fewer surgical discectomies were performed (6 versus 13, p = 0.04).  The authors concluded that the addition of a short course of adalimumab to the treatment regimen of patients suffering from acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.  Limitations of this study include small sample sizes, inability to determine the sufficient dose and best route of administration for TNF-alpha inhibitors in radiculopathy because of disk herniation, or to identify subgroups of patients most likely to respond to this treatment. More studies are needed to ascertain the adequate dose and the best route of administration of TNF-alpha inhibitors, elucidating the effective therapeutic role of TNF-alpha inhibitors in this disease and determining the dosage, times and route of administration, as well as evaluating the possible occurrence of harmful events, as serious infections or adverse cardiovascular events, as seen in patients with rheumatoid arthritis treated with biological drugs.

The FDA-approved product labeling for Humira includes a black box warning about the risk of serious infections with adalimumab.  The labeling states that patients treated with Humira are at increased risk of developing serious infections that may lead to hospitalizations or death.  Most patients who developed these infections were taking concomitant immunosuppresents such as methotrexate or corticosteroids.  The labeling states that Humira should be discontinued if a patient develops a serious infection or sepsis.

The labeling states that tuberculosis (TB), invasive fungal infections, and other opportunistic infections, have been observed in patients receiving adallimumab.  The labeling notes that some of these infections have been fatal.

Active TB including reactivation of latent TB has been reported in patients taking Humira.  Patients with TB have frequently presented with disseminated or extra-pulmonary disease.  Anti-TB treatment of patients with latent TB infection reduces the risk of re-activation in patients receiving adalimumab.  However, active TB has developed in patients receiving adalimumab whose screening for latent TB infection was negative.  The labeling recommends that patients should be evaluated for TB risk factors and be tested for latent TB prior to initiationg adalimumab and during therapy.  According to the product labeling, when TB skin testing is performed, an induration size of 5 mm or greater should be considered positive, even if the patient was previously vaccinated with Bacille Calmette-Guerin (BCG).  Treatment of latent TB should be initiated prior to therapy with adalimumab.  The labeling recommends that physicians should monitor patients receiving adalimumab for signs and symptoms of active TB, including patients who tested negative for latent TB.

Invasive fungal infections, including histoplasmosis, coccidiodomyocosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis, have been reported in patients taking Humira.  Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease.  Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection.  The labeling states that empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

Bacterial, viral and other infections due to opportunistic infections have been reported.  The labeling recommends that the risks and benefits of treatment with Humira should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.  Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Humira, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

The labeling states that cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers.  Humira has not been formally studied in patients with CHF; however, in clinical studies in CHF of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed.  The labeling recommends to exercise caution when using Humira in patients who have heart failure, and to monitor patients with heart failure carefully.

Tato and colleagues (2005) noted that treatment of patients with Takayasu's arteritis remains a demanding challenge to clinicians.  In many patients, the course of the disease is characterized by frequent relapses and disease progression under conventional treatment with glucocorticoids and cytotoxic drugs.  These researchers presented the case of a young woman with severe cerebrovascular and aortic involvement, who experienced disease progression in spite of more than 2 years of treatment with high doses of prednisone, methotrexate and cyclophosphamide.  In this patient, treatment with adalimumab achieved clinical remission and allowed tapering of prednisone within a few months.  The present case, as well as previous reports on the use of infliximab in giant cell and Takayasu's arteries, suggested that TNFalpha-blockade may be a new, promising treatment for glucocorticoid-refractory large-vessel vasculitis.

Ramos-Casals et al (2008) stated that in 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project, a multi-center study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases (SAD).  The information source is a periodic surveillance of reported cases by a MEDLINE search (last update before this writing: December 31, 2007).  The analysis included a total of 19 SAD and 6 biological agents.  By December 31, 2007, the Registry included 1,370 patients with SAD who had been treated with biological agents (562 received infliximab, 463 rituximab, 285 etanercept, 42 anakinra, and 18 adalimumab).  Systemic autoimmune diseases included Sjogren syndrome (SS; 215 cases), Wegener granulomatosis (261 cases), sarcoidosis (219 cases), systemic lupus erythematosus (SLE; 172 cases), Behçet disease (173 cases), adult-onset Still disease (118 cases), cryoglobulinemia (88 cases), and other diseases (80 cases).  The higher rate of therapeutic response was found for the use of rituximab in patients with SLE (90 %), SS (91 %), anti-phospholipid syndrome (92 %), and cryoglobulinemia (87 %); infliximab in sarcoidosis (99 %), adult-onset Still disease (90 %), and polychondritis (86 %); and etanercept in Behçet disease (96 %).  Results from controlled trials showed lack of efficacy for the use of infliximab in SS and etanercept in SS, Wegener granulomatosis, and sarcoidosis.  In addition, an excess of side effects (greater than 50 % of reported cases) was observed for the use of infliximab in inflammatory myopathies and sarcoidosis, and for the use of etanercept in polymyositis.  Sufficient data are not yet available to evaluate fully the safety and effectiveness of adalimumab and anakinra in patients with SAD.  The authors concluded that current scientific evidence on the use of biological therapies in patients with SAD is mainly based on uncontrolled, observational data.  The best results have been observed in the use of rituximab for SS, SLE, and cryoglobulinemia; infliximab for sarcoidosis and adult-onset Still disease; and etanercept for Behçet disease.  Lack of efficacy was demonstrated for infliximab and etanercept in SS, for etanercept in Wegener granulomatosis and sarcoidosis, and for TNF in SS.  They stated that future controlled trials are needed to confirm the potential use of biological therapies in patients with SAD.

Androudi et al (2010) evaluated the safety and effectiveness of intra-vitreal adalimumab injections on refractory cystoid macular edema (CME) secondary to non-infectious uveitis.  A total of 8 consecutive patients with controlled uveitis and chronic, refractory CME who had failed steroid treatment were included in this study.  Intra-vitreal adalimumab injections were given monthly for 3 months.  Main outcome measure was mean change in central retinal thickness (CRT) on optical coherence tomography (OCT); secondary objective was the mean change in best-corrected visual acuity (BCVA).  Five of the 8 patients completed the 6-month follow-up.  For all 5 patients, the changes in BCVA from baseline to 3 months were not statistically significant (p = 0.070).  Similarly, the change in BCVA from baseline to 6 months was not statistically significant (p = 1.0).  The mean CRT at baseline was 692 microm.  The changes from baseline to 3 months were not statistically significant (p = 0.466); the changes from baseline to 6 months were also not statistically significant (p = 0.808).  These researchers did not observe any ocular or systemic adverse effects.  The authors concluded that intra-vitreal adalimumab showed no efficacy in improving BCVA or reducing CRT in patients with chronic uveitic macular edema.  Furthermore, Neri et al (2011) stated that adalimumab is a promising drug for the treatment of uveitis, although further studies are needed on its application in uveitis.

Hyams et al (2012) evaluated the safety and effectiveness of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate-to-severe Crohn's disease (CD).  These investigators studied 192 patients with Pediatric Crohn's Disease Activity Index (PCDAI) scores greater than 30 for whom conventional treatment was unsuccessful.  Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight [BW] greater than or equal to 40 kg or less than 40kg).  At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as PCDAI decrease less than or equal to 15 points from baseline, 155/188 [82.4 %]) and prior exposure to infliximab (82/188, 43.6 %).  Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for BW greater than or equal to 40 kg or less than 40 kg; n = 93) or low doses (20 mg or 10 mg for BW greater than or equal to 40 kg or less than 40 kg; n = 95), every other week for 48 weeks.  Clinical remission (PCDAI less than or equal to 10) at week 26 (the primary endpoint) was compared between groups using the Cochran-Mantel-Haenszel test, adjusting for strata, with non-responder imputation.  Adverse events were monitored to evaluate safety; 152/188 patients (80.9 %) completed all 26 weeks of the study.  At week 26, 63 patients (33.5 %) were in clinical remission, with no significant difference between high- and low-dose groups (36/93, 38.7 % versus 27/95, 28.4 %; p = 0.075).  No new safety signals were detected.  The authors concluded that adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to of adult patients with CD.  More children that received high than low dose were in remission at week 26, but the difference between dose groups was not statistically significant.

In a prospective case series, Díaz-Llopis et al (2012) evaluated adalimumab therapy in refractory uveitis.  A total of 131 patients with refractory uveitis and intolerance or failure to respond to prednisone and at least 1 other systemic immunosuppressive drug participated inthis study.  Patients received a 40-mg adalimumab subcutaneous injection every other week for 6 months.  The associated immunosuppressants were tapered after administering 3 adalimumab injections (week 6).  Main outcome measure were degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), immunosuppression load (as defined by Nussenblatt et al), VA (logarithm of the minimal angle of resolution [logMAR]), and macular thickness (OCT).  There were 61 men and 70 women (mean age of 27.3 years).  The most common causes were juvenile idiopathic arthritis in 39 patients, pars planitis in 16 patients, and Behçet's disease in 13 patients.  Twenty-seven patients had uveitis of idiopathic origin.  Inflammation in the anterior chamber was present in 82 % of patients and in the vitreous cavity in 59 % of patients.  Anterior chamber inflammation and vitreous inflammation decreased significantly (p < 0.001) from a mean of 1.51 and 1.03 at baseline to 0.25 and 0.14, respectively, at 6 months.  Macular thickness was 296 (102) μ at baseline versus 240 (36) μ at the 6-month visit (p < 0.001).  Visual acuity improved by -0.3 logMAR in 32 of 150 eyes (21.3 %) and worsened by +0.3 logMAR (-15 letters) in 5 eyes (3.3 %).  The dose of corticosteroids also decreased from 0.74 (3.50) to 0.20 (0.57) mg/kg/day (p < 0.001).  Cystoid macular edema, which was present in 40 eyes at baseline, showed complete resolution in 28 eyes at 6 months.  The mean suppression load decreased significantly (8.81 [5.05] versus 5.40 [4.43]; p < 0.001).  Six months after the initiation of the study, 111 patients (85 %) were able to reduce at least 50 % of their baseline immunosuppression load.  Only 9 patients (6.9 %) had severe relapses during the 6 months of follow-up.  The authors concluded that adalimumab seems to be well-tolerated and helpful in decreasing inflammatory activity in refractory uveitis and may reduce steroid requirement.  Moreover, they stated that further controlled studies of adalimumab for uveitis are needed.

On September 28, 2012, the FDA approved adalimumab for the treatment of moderate-to-severe ulcerative colitis in adults.  The approval was based on findings of 2 clinical studies showing the safety and effectiveness of adalimumab for ulcerative colitis.  A total of 908 patients who had never been treated with a TNF-blocker, or who lost response to or were intolerant to TNF-blockers participated in the studies.  All patients enrolled in the studies had a Mayo score of 6 to 12 and an endoscopy subscore of 2 to 3.  Patients were randomly assigned to take adalimumab or a placebo.  The studies were designed to measure the percentage of patients whose Mayo score decreased to 2 or less with no individual subscore of more than 1 after 8 weeks of treatment.  Patients who obtained such reductions in the Mayo score were determined to have achieved clinical remission.  Results from both studies showed 16.5 % to 18.5 % of patients treated with adalimumab achieved clinical remission compared with 9.2 % to 9.3 % of patients receiving placebo.  Additionally, in the 2nd study, 8.5 % of patients treated with adalimumab sustained clinical remission compared with 4.1 % of patients treated with placebo.  The effectiveness of adalimumab has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers.

The FDA-approved dosing regimen for adalimumab for ulcerative colitis begins with an initial dose of 160 milligrams, a 2nd dose 2 weeks later of 80 mg, and a maintenance dose of 40 mg every other week, thereafter.  The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy.

Appendix

Information about the Psoriasis Area and Severity Index (PASI) and the Physicians' Global Assessment (PGA) is available from the following reference (Feldman and Kruger, 2005): http://ard.bmj.com/cgi/content/full/64/suppl_2/ii65.