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 moderately 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 nonbiologic 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 non-steroidal anti-inflammatory drugs (NSAIDS).  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 NSAIDs and to any one of the DMARDs (sulfasalazine, methotrexate, corticosteroids, azathioprine, cyclosporine, cyclophosphamide).

4. Aetna considers adalimumab medically necessary for members with active Crohn's disease, as manifested by any of the following signs/symptoms:

   1. Diarrhea;
   2. Abdominal pain;
   3. Bleeding;
   4. Weight loss;
   5. Perianal disease;
   6. Internal fistulae;
   7. Intestinal obstruction;
   8. Megacolon; 

   9. Extra-intestinal manifestations: arthritis or spondylitis; and

      Crohn's disease has remained active despite treatment with either of the following:

      1. Corticosteroids; or

      2. 6-mercaptopurine/azathioprine.

5. Aetna considers adalimumab medically necessary for reducing signs and symptoms of moderately 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 (i.e., patients with greatet than or equal to 10% body surface area (BSA) involvement, Psoriasis Area and Severity Index (PASI) greatet than or equal to 12 within 3 treatment periods, and Physician’s Global Assessment (PGA) of at least moderate disease severity (see appendix))  who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.  

7. 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., etanercept (Enbrel) or infliximab (Remicade) or with anakinra (Kineret)]; or
   • Guttate psoriasis; or
   • Osteoarthritis; or
   • Relapsing polychondritis; or
   • Ulcerative colitis; or
   • Uveitis.

See also CPB 315 - Enbrel (Etanercept), CPB 341 - Remicade (infliximab), and CPB 595 - 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 who have had an inadequate response to one or more DMARDs. Adalimumab can be used alone or in combination with methotrexate or other nonbiolgic DMARDs. The efficacy and safety of adalimumab were assessed in five randomized, double blind studies in 2869 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 disease modifying anti-rheumatic drugs. Two studies involved 815 patients who had failed to respond to DMARDS; one 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 five 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 five 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 American College of Rheumatology (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-TNF agent in combination with methotrexate was recommended if high disease activity was present for less than three 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 two multicenter 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 one 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: 1) distal interphalangeal (DIP) involvement (n = 23); 2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis) (n = 210); 3) arthritis mutilans (n = 1); 4) asymmetric psoriatic arthritis (n = 77); or 5) 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 American College of Rheumatology 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 three percent 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 percent 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 tumor necrosis factor (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 two 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 three treatment groups: placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly. Patients were followed for 56 weeks. Coprimary 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-tumor necrosis factor (TNF) therapy were randomized to receive subcutaneous injections at study initiation and two 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 <150 points) at four 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 fourth 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 four 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 two 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 four 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 percent 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 (four to 17 years of age) with polyarticular JIA. In the first part of this study, two 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 three of the six ACR Pedi response variables, a minimum of two active joints, and no more than one 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 two 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 two 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 percent 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 two 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 1212 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 (two 40 mg injections) followed by one adalimumab injection (40 mg) one 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. In an open-label study, Peyrin-Biroulet et al (2007) assessed the effectiveness of adalimumab induction therapy in patients with ulcerative colitis who previously responded to infliximab and then lost response or became intolerant. A total of 10 patients with ulcerative colitis 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 two 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 ulcerative colitis 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 ulcerative colitis, Lawson et al (2006) did not mention the use of adalimumab.

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 non-steroidal anti-inflammatory drug 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.

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 tuberculosis including reactivation of latent tuberculosis has been reported in patients taking Humira. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Anti-TB treatment of patients with latent TB infection reduces the risk of reactivation 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.

Appendix

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